melphalan and Leukemia--Myeloid--Acute

The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed to other cytotoxic drugs besides HDM. The latency interval from therapy to t-MN was 4.9 years (range, 0.6-21.9 years). Patients who received HDM-ASCT in addition to other cytotoxic therapies had a longer latency period to t-MN compared with patients who only received HDM-ASCT (6.1 vs 4.7 years, P = .009). Notably, 11 patients developed t-MN within 2 years. Therapy-related myelodysplastic syndrome was the most common type of neoplasm (n = 60), followed by therapy-related acute myeloid leukemia (n = 4) and myelodysplastic syndrome/myeloproliferative neoplasm (n = 2). The most common cytogenetic aberrations included complex karyotypes (48.5%), del7q/-7 (43.9%), and/or del5q/-5 (40.9%). The most frequent molecular alteration was TP53 mutation, in 43 (67.2%) patients and the sole mutation in 20 patients. Other mutations included DNMT3A, 26.6%; TET2, 14.1%; RUNX1, 10.9%; ASXL1, 7.8%; and U2AF1, 7.8%. Other mutations in less than 5% of cases included SRSF2, EZH2, STAG2, NRAS, SETBP, SF3B1, SF3A1, and ASXL2. After a median follow-up of 15.3 months, 18 patients were alive and 48 died. The median overall survival after the diagnosis of t-MN in the study group was 18.4 months. Although the overall features are comparable to the control group, the short interval to t-MN (<2 years) underscores the unique vulnerable status of myeloma patients.

Topics: Aged; Aged, 80 and over; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Pregnancy; Transplantation, Autologous

Therapy-related myeloid neoplasms (t-MN), including therapy-related acute myeloid leukaemia and myelodysplastic syndrome, are second primary malignancies (SPM) that are of growing importance as patients with plasma cell disorders (PCD) such as multiple myeloma (MM) are living longer with more effective therapies. Both patient-specific and treatment-specific factors likely impact the risk of t-MN development after diagnosis and treatment of PCD. Alkylating chemotherapy, especially melphalan, has been strongly tied to the risk of t-MN. More recently, there has been a shift away from long-term alkylating therapies to immunomodulatory agents and high-dose therapy with autologous stem cell transplant (HD-ASCT). This shift has led to improved survival and long-term outcomes for most MM patients. However, the risks of t-MN remain despite the improved efficacy of these treatments, and patients who develop t-MN have a poor prognosis. Understanding the risk factors predisposing MM patients to t-MN can thus help to tailor individualized therapy to maximize anti-myeloma efficacy and minimize the risks of t-MN.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Prognosis; Risk Factors; Transplantation, Autologous

This is a review regarding the current therapeutic strategies in the management of multiple myeloma. Due to the introduction of several new effective therapeutic agents, multiple myeloma is one of the most active and changing fields in clinical oncology. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chain). High-dose chemotherapy supported with autologous peripheral blood stem cells is an effective treatment for the disease. However, multiple myelomas are still difficult to cure and require long-term disease control. In recent years, the introduction of novel drugs (bortezomib, lenalidomide and thalidomide) has improved treatment.

Topics: Age Factors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Bone Density Conservation Agents; Boronic Acids; Bortezomib; Clinical Trials as Topic; Creatinine; Cyclophosphamide; Denosumab; Dexamethasone; Diphosphonates; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Imidazoles; Immunoglobulins; Kidney; Lenalidomide; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Melphalan; Molecular Targeted Therapy; Multiple Myeloma; Neoplasms, Second Primary; Precision Medicine; Prednisolone; Pyrazines; Quality of Life; Recurrence; Remission Induction; Survival Rate; Thalidomide; Zoledronic Acid

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Evaluation; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Lomustine; Melphalan; Mitoxantrone

Topics: Antineoplastic Agents; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Etoposide; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Melphalan; Recurrence

Topics: Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Graft vs Host Disease; Granulocytes; Hematopoietic Stem Cells; Histocompatibility Antigens Class II; HLA-DR Antigens; Humans; Leukemia, Myeloid, Acute; Melphalan; Time Factors; Transplantation Immunology; Transplantation, Autologous; Whole-Body Irradiation

The results of a follow-up study of 112 patients with multiple myeloma are presented. Three of these patients developed acute leukaemia during the respective period of clinical observation (maximum: 11 years)--one case of acute myeloblastic leukaemia, myelomonocytic leukaemia and erythroleukaemia, respectively. For estimating the incidence of acute leukaemia in the presence of multiple myeloma an extended life table method was applied. On the basis of our data this method gave a probability of 5.9% for a patient to develop acute leukaemia at any time after the diagnosis of multiple myeloma. In a statistical discussion this result is considered to confirm the assumption of a highly increased AL-risk in patients with multiple myeloma. In a survey of the literature some important data of 100 cases with the association acute leukaemia--multiple myeloma are reported.

Topics: Acute Disease; Aged; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Probability; Time Factors

Although cytotoxic immunosuppressive agents play an unquestionably useful role in treating many neoplastic and non-neoplastic disorders, there is accumulating evidence that the toxicity associated with their use is considerable. The therapeutic successes obtained with antitumor agents have led to increases in the life span of cancer patients, but have also provided the opportunity for this toxicity to become manifest. A search of the available literature was carried out, with emphasis on cases in which a malignancy developed in patients following chemotherapy for either neoplastic or non-neoplastic (e.g., renal transplantation, psoriasis) conditions; particular focus was given to the incidence of acute myelogenous leukemia in various groups of Hodgkin's disease and multiple myeloma patients. That patients with nonmalignant conditions treated with cytotoxic immunosuppressive agents are also at increased risk of developing a malignancy raises the possibility that these agents may have oncogenic potential. Therefore, one may be faced with the paradox that the patients benefiting most from chemotherapy may be at highest risk of suffering its consequences.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azathioprine; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myeloid, Acute; Lymphoma; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Prednisone; Pregnancy; Procarbazine; Time Factors; Vincristine

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Drug Therapy, Combination; Female; Hematocrit; Hemoglobins; Humans; Immunoglobulins; Leukemia; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission, Spontaneous; Syndrome

Considering the unsatisfactory results of salvage therapies for patients with relapsed/refractory acute myeloid leukaemia (R/R-AML), their value before allogeneic haematopoietic stem cell transplantation (HSCT) remains questionable. However, direct allogeneic HSCT following established conditioning regimens applied in patients with R/R-AML during active disease has been equally disappointing. In this retrospective observational study, high-dose melphalan, as part of a sequential preparative regimen, followed by a total body irradiation (4 × 2 Gy)-based or a treosulfan-based dose-adapted conditioning therapy for allogeneic HSCT was administered to 292 adult patients (median age 56 years, range 17-74) with primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). Overall survival rates at 3 years were 34%, 29% and 41%, respectively. Risk factors associated with an inferior survival were higher age, transplantation from a human leucocyte antigen-mismatched donor and high disease burden. Patients transplanted with blast infiltration <20% showed a notable survival rate of 51% at 3 years. In particular, patients with primary refractory AML showed a more favourable outcome when transplanted early during their disease course. Thus, high-dose melphalan-based sequential conditioning chemotherapy followed by an allogeneic HSCT is feasible and enables long-term remission to be achieved in a substantial proportion of patients with active R/R-AML.

Topics: Adolescent; Adult; Age Factors; Aged; Allografts; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Recurrence; Risk Factors; Survival Rate; Transplantation Conditioning; Whole-Body Irradiation

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cause of Death; Cyclosporine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Recurrence; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation; Young Adult

Post-transplantation cyclophosphamide (PTCY) therapy has made haploidentical transplantation a global reality in adults, but the literature is largely silent on the feasibility of this approach in children. We conducted a prospective study of 20 patients (median age, 12 years; range, 2-20 years) with advanced acute leukemia to evaluate the feasibility of PTCY-based haploidentical peripheral blood stem cell (PBSC) transplantation in children. The conditioning regimen comprised fludarabine, i.v. busulfan, and melphalan (Flu-Bu-Mel). PTCY on days +3 and +4 was followed by mycophenolate mofetil for 14-21 days and cyclosporine for 60 days. Thirteen patients (65%) had refractory or relapsed myelogenous leukemia, and the remainder had high-risk lymphoblastic leukemia. Prompt engraftment was noted at a median of 14 days, with full donor chimerism by day +28. The cumulative incidence of acute and chronic graft-versus-host disease was 35% and 5%, respectively. Nonrelapse mortality at 1 year was 20%. The incidence of disease progression was 25.7%. The actuarial overall survival at 2 years was 64.3% (95% confidence interval, 53.4%-75.2%). Our data suggest that Flu-Bu-Mel-based conditioning followed by PTCY-based haploidentical PBSC transplantation with reduced duration of immunosuppression is feasible in pediatric patients with advanced leukemia.

Topics: Acute Disease; Adolescent; Adult; Allografts; Busulfan; Child; Child, Preschool; Chronic Disease; Cyclophosphamide; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Vidarabine

Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality.

Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Female; Graft vs Host Disease; HLA Antigens; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Melphalan; Myeloablative Agonists; Myelodysplastic Syndromes; Peripheral Blood Stem Cell Transplantation; Severity of Illness Index; Siblings; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous

Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution.. Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy.. A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years.. EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Blast Crisis; Bone Marrow; Busulfan; Child; Cyclophosphamide; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lymphatic Irradiation; Melphalan; Middle Aged; Myelodysplastic Syndromes; Organ Sparing Treatments; Organs at Risk; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Radiotherapy Dosage; Recurrence; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation; Young Adult

Clofarabine is a novel purine nucleoside analog with immunosuppressive and antileukemia activity. We performed a phase I study of the combination of clofarabine plus melphalan as a reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with acute myelogenous leukemia. Patients over age 18 in complete remission or with active disease (up to 50% marrow blasts) who had a matched related or unrelated donor were eligible. The conditioning regimen consisted of escalating doses of clofarabine plus melphalan, followed by allogeneic stem cell transplantation. Sixteen patients (median age, 63 years) were treated at 3 dose levels; 4 of these patients had primary induction failure, and 3 were in first relapse. One patient at dose level 2 and 1 patient at dose level 3 died of multiorgan toxicity; no other dose-limiting toxicities were seen. All other patients at both doses of clofarabine studied demonstrated complete engraftment by day 30, with a median time to absolute neutrophil count recovery of 14 days, and 16 days for platelet recovery. With a median follow-up of 17 months, only 2 patients relapsed, and 4 patients died. Clofarabine plus melphalan at dose level 2 is a well-tolerated conditioning regimen with activity in patients with advanced acute myelogenous leukemia.

Topics: Adenine Nucleotides; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Clofarabine; Combined Modality Therapy; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous

Patients suffering from high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) secondary to MDS (sAML) are characterized by poor response to conventional cytotoxic chemotherapy. The purpose of our prospective single-center study was to examine the safety and efficacy of an allogeneic hematopoietic stem cell transplantation (HSCT) following a sequential conditioning regimen as first-line therapy for previously untreated patients with high-risk MDS or sAML. Between November 2003 and June 2010, 30 patients (20 high-risk MDS, 10 sAML) received fludarabine (4 × 30 mg/m(2)), amsacrine (4 × 100 mg/m(2)), and Ara-C (4 × 2 g/m(2), FLAMSA). After 2 to 3 days of rest, patients received high-dose melphalan alone (200 mg/m(2) for patients with an age <50 years, 150 mg/m(2) for patients with an age between 50 and 60 years, and 100 mg/m(2) for patients with an age >60 years; n = 24) or melphalan and thiotepa (10 mg/kg, Mel/Thio, n = 6). Following these high-dose conditioning regimens, a median number of 7.7 × 10(6) CD34(+) cells/kg body weight (range: 2.9 × 10(6)-17.2 × 10(6)) were transplanted from 13 related or 17 unrelated donors. Antithymocyte globulin (Fresenius 30-60 mg/kg) as well as tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. All patients except 1 with primary graft failure achieved complete remission after HSCT. After a median follow-up time of 28 months (range: 7-81), 21 patients (70%) were alive and free of disease. Overall, 4 patients relapsed. At 2 years, overall survival, event-free survival, and treatment-related mortality were 70%, 63%, and 30%, respectively. Because of undue toxicity, thiotepa is no longer part of the conditioning regimen. Our results add to the body of evidence that a FLAMSA-based sequential conditioning therapy is effective for previously untreated patients with high-risk MDS or sAML.

Topics: Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Transplantation Conditioning; Transplantation, Homologous; Unrelated Donors; Vidarabine

We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m(2) × 5, melphalan 140 mg/m(2) × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.

Topics: Acute Kidney Injury; Adenine Nucleotides; Adult; Age Factors; Aged; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arabinonucleosides; Clofarabine; Female; Glomerular Filtration Rate; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Recurrence; Risk; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous

Using population-based data from Sweden, we identified all multiple myeloma (MM) patients (n = 8740) and 5652 monoclonal gammopathy of undetermined significance (MGUS) patients diagnosed between 1986 and 2005. We calculated standardized incidence rates (SIRs) for all subsequent hematologic and nonhematologic malignancies for MM patients diagnosed before/after 1995 (introduction of high-dose melphalan/autologous stem cell transplantation [HDM-ASCT]) and 2000 (introduction of immunomodulatory drugs [IMiDs]), respectively. MM patients had an 11.51-fold (95% confidence interval: 8.19-15.74) increased risk of acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS); risk was very similar before/after 1995 and 2000, respectively. MGUS patients had an 8.01-fold (5.40-11.43) increased risk of AML/MDS. Risk was confined to IgG/IgA, while no IgM MGUS patients developed AML/MDS; patients with monoclonal-protein (M-protein) concentrations > 1.5 g/dL (SIR = 11.12; 3.61-25.96) had higher risk than those < 1.5 g/dL (SIR = 4.67; 1.71-10.16). An excess risk of nonmelanoma skin cancer was observed subsequent to both MM (SIR = 2.22; 1.74-2.80) and MGUS (SIR = 3.30; 2.76-3.90). Our novel observations of an excess risk for AML/MDS following IgG/IgA (but not IgM) MGUS, and the highest risk associated with M-protein concentrations > 1.5 g/dL, support a role for nontreatment-related factors in plasma cell dyscrasias. AML/MDS risk following MM was the same before/after the introduction of HDM-ASCT. Longer follow-up is needed to characterize second tumor risks in the IMiD era.

Topics: Aged; Antineoplastic Agents, Alkylating; Female; Humans; Immunologic Factors; Incidence; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Sweden; Transplantation, Autologous

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies.

Topics: Adolescent; Adult; Antilymphocyte Serum; Child; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Myelodysplastic Syndromes; Survival Rate; T-Lymphocytes; Thiotepa; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Young Adult

Lymphocyte and platelet recovery may influence outcomes of allo-SCT for treatment of AML. It is not clear, however, if this impact is independent of patient and transplant characteristics. To investigate this question, we evaluated the influence of pre- or post transplant factors on day +30 absolute lymphocyte count (ALC) and the speed of platelet engraftment. We studied 106 AML patients treated with fludarabine and melphalan reduced-intensity conditioning and allo-SCT. Twenty nine percent of patients were in CR at the initiation of the conditioning, 39% had active disease with circulating blasts and 32% had active disease without circulating blasts. The graft source was peripheral blood from a matched sibling donor in 55% and BM from a matched unrelated donor in 45%. Our data showed that the presence of circulating blasts before transplantation is significantly correlated with low post-SCT day +30 ALC and slow platelet engraftment. This finding suggests that the impact of early ALC and platelet recovery on transplant outcome may not be independent of disease status at transplantation.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Female; Graft Survival; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Kinetics; Leukemia, Myeloid, Acute; Lymphocytes; Male; Melphalan; Middle Aged; Neoplastic Cells, Circulating; Transplantation Conditioning; Transplantation, Homologous; Tumor Burden; Vidarabine

The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected.

Topics: Adolescent; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Child; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Transplantation Conditioning; Treatment Outcome; Vidarabine Phosphate; Young Adult

Inhibiting mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) blasts and leukemic stem cells may enhance their sensitivity to cytotoxic agents. We sought to determine the safety and describe the toxicity of this approach by adding the mTOR inhibitor, sirolimus (rapamycin), to intensive AML induction chemotherapy.. We performed a phase I dose escalation study of sirolimus with the chemotherapy regimen MEC (mitoxantrone, etoposide, and cytarabine) in patients with relapsed, refractory, or untreated secondary AML.. Twenty-nine subjects received sirolimus and MEC across five dose levels. Dose-limiting toxicities were irreversible marrow aplasia and multiorgan failure. The maximum tolerated dose (MTD) of sirolimus was determined to be a 12 mg loading dose on day 1 followed by 4 mg/d on days 2 to 7, concurrent with MEC chemotherapy. Complete or partial remissions occurred in 6 (22%) of the 27 subjects who completed chemotherapy, including 3 (25%) of the 12 subjects treated at the MTD. At the MTD, measured rapamycin trough levels were within the therapeutic range for solid organ transplantation. However, direct measurement of the mTOR target p70 S6 kinase phosphorylation in marrow blasts from these subjects only showed definite target inhibition in one of five evaluable samples.. Sirolimus and MEC is an active and feasible regimen. However, as administered in this study, the synergy between MEC and sirolimus was not confirmed. Future studies are planned with different schedules to clarify the clinical and biochemical effects of sirolimus in AML and to determine whether target inhibition predicts chemotherapy response.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Drug Administration Schedule; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Protein Kinases; Recurrence; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with i.v. busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. Sixty-seven patients received BuCy2, and subsequently, 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these nonrandomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 versus 39 years, P < .01), more often had unrelated donors (47.3% versus 20.9%, P < .0003), and had shorter median follow-up (39.7 versus 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome ("period" effects), 78 acute myelogenous leukemia (AML) patients receiving Melphalan-Flu (MF), treated in parallel during this time (1997-2004) were used to estimate the period effect. The MF patients' outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in the first complete remission (CR1) had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, whereas CR1 patients younger than age 41 had a 3-year EFS of 83%. These results support replacing BuCy +/- ATG with Bu-Flu +/- rabbit-antithymocyte globulin (ATG), and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1.

Topics: Adolescent; Adult; Antilymphocyte Serum; Antineoplastic Agents; Bayes Theorem; Busulfan; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Myelodysplastic Syndromes; Peripheral Blood Stem Cell Transplantation; Survival Analysis; T-Lymphocytes; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Results of allogeneic hematopoietic stem cell transplantation (HCT) to treat advanced leukemia or myelodysplastic syndrome (MDS) remain poor due to excessive relapse and transplant-related mortality. To improve transplant outcome in this patient population, 43 patients (median age, 46.1 years) with high-risk or advanced lymphoid (n = 5) or myeloid malignancy (n = 38) were prospectively enrolled on a pilot trial of cytoreduction with intravenous busulfan and melphalan followed by an unmodified HLA-A, -B, and -DRbeta1-matched related (n = 18) or unrelated (n = 25) HCT. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-four patients had > or = 5% blasts at the time of HCT; 12 of these had > 20% blasts. Seventeen patients had unfavorable cytogenetics, 8 patients underwent transplantation for secondary MDS or acute myelogenous leukemia, and 4 patients had relapsed after a previous allogeneic transplantation. Although mucositis was the most significant regimen-related toxicity, requiring the addition of folinic acid rescue and failure to receive all 4 doses of methotrexate in 23 patients, the nonrelapse mortality at 30 and 100 days was low at 0% and 16%, respectively. The cumulative incidence of grade II-IV acute GVHD was 24%, and that of extensive chronic GVHD was 7%. With a minimum follow-up of 18 months, the estimated 3-year overall survival is 37% and the estimated disease-free survival (DFS) is 33%. For 18 patients with MDS (< or = RAEB-2) or high-risk myeloproliferative disorder, the estimated 3 year DFS is 61%. These data demonstrate the curative potential of this regimen in patients with high-risk myeloid malignancies.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Survival Analysis; Tacrolimus; Transplantation Conditioning

Reduced-intensity conditioning has extended the use of allogeneic hematopoietic stem cell transplantation (HSCT) to patients otherwise not eligible for this treatment due to older age or frailty. One hundred twelve acute myelogenous leukemia/myelodysplastic syndromes patients received fludarabine and melphalan (FM) conditioning with allogeneic HSCT. Most patients (73%) were not in remission. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Median age was 55 years (range, 22-74). Donors were related (53%) and unrelated (47%). Median follow-up of surviving patients (n = 43) was 29.4 months (range, 13.1-87.7). The complete remission (CR) rate was 82%. Estimates of 2-year survival were 66%, 40%, and 23% for patients in CR, with active disease without and with circulating blasts at HSCT, respectively. In multivariate analysis, survival was negatively influenced by active disease at HSCT and development of grade II-IV acute GVHD. Presence of circulating blasts at HSCT negatively influenced freedom from disease progression. Incidence of nonrelapse mortality (NRM) was significantly higher for patients with active disease, but was not influenced by patient age. Patients in CR had a day-100 and 2-year NRM of 0% and 20%, respectively. Use of unrelated donors increased the risk of NRM only among patients with active disease. FM and HSCT elicited long-term disease control in a significant fraction of this high-risk cohort.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Risk Factors; Survivors; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

We describe treatment, outcomes and prognostic factors for patients who relapse following transplantation with a reduced intensity conditioning regimen. Seventy consecutive patients with high-risk myeloid malignancies underwent transplant and 25 (36%) relapsed, a median of 120 days later. The median percentage of bone marrow blasts at relapse was 24, the median donor chimerism was 73% and new karyotypic abnormalities occurred in 8 out of 20 (40%) evaluable patients. Twenty-one patients (84%) received aggressive treatment for relapse, including chemotherapy (60%), second hematopoietic cell transplantation (HCT; 52%) and/or donor lymphocyte infusion (DLI; 12%). Thirteen achieved a complete response (CR) and four remain in CR. Median overall survival (OS) after relapse was 6 months (95% confidence interval=2.7-9.9 months), and actuarial 1 year OS was 24%. Most deaths were due to disease progression (17/20, 85%). We did not observe an advantage for cellular therapy (DLI or second transplant) compared to chemotherapy. Salvage therapy for relapse after reduced intensity HCT is feasible, associated with low treatment-related mortality, and may result in prolonged survival in select patients. Studies exploring the optimal treatment for relapse following reduced intensity HCT are warranted.

Topics: Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Prognosis; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Treatment Outcome; Vidarabine

In a pilot study high-dose melphalan (HD-Mel, 200 mg/m2) and autologous stem cell transplantation (ASCT) were administered to 14 patients (median age 52, range 29-60 years) with acute myeloid leukaemia (AML) in first relapse after a previous ASCT in first complete remission (n=11) or chemotherapy (n=3). A first cohort of five patients received HD-Mel as salvage therapy after a previous cycle of mitoxantrone, topotecan and cytarabine (MTC) had failed in four out of five patients, while a second cohort of nine patients received HD-Mel in untreated relapse. Thirteen (93%) of 14 patients achieved a second complete remission (CR2), including all four patients who had been refractory to MTC. No treatment-related mortality was observed after HD-Mel. Thirteen (93%) patients were able to proceed to a dose-reduced allogeneic stem cell transplantation (allo-SCT) from human-leucocyte-antigens-compatible unrelated (n=12) or sibling donors (n=1) in CR2 (n=11) or poor recovery/relapse (n=2) after a median of 2 (1.7-4.5) months following HD-Mel. Three MTC-refractory patients, but none of the upfront HD-Mel patients, died due to an allograft-related non-relapse cause. Nine patients are alive in CR2 after a median of 6 (2-49) months after HD-Mel and a median of 4 (0.6-47) months after a sequential allo-SCT. Although median follow-up is still short, the proportion of patients achieving a CR2, as well as of those proceeding to a subsequent reduced-intensity-conditioning-allo-SCT, is superior to those previously reported. Our results highly encourage to further investigate HD-Mel and ASCT as a promising salvage regimen for relapsed AML patients for whom autologous peripheral blood stem cells are available.

Topics: Adult; Antineoplastic Agents, Alkylating; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Recurrence; Salvage Therapy; Stem Cell Transplantation; Transplantation, Autologous

This retrospective study from the Italian Association of Pediatric Hematology Oncology-Bone Marrow Transplant Group (AIEOP-TMO) reports the results of consolidation with high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1). From October 1994 to July 1999, 20 patients (median age 9.9 years, range 0.11-16.2) were treated in six centers. Eighteen had de novo AML and two had secondary AML. According to BFM criteria, 10 were classified as standard- and 10 as high-risk patients, respectively. The median time from diagnosis to CR1 and from diagnosis to Auto-HSCT were 1.1 months (range 0.8-1.6) and 4.3 months (range 3.1-6.2), respectively. Purging with either mafosfamide (three) or in vivo interleukin-2 (four) was performed in seven of 20 patients. Melphalan was administered at a dosage of 150-220 mg/m(2) (median 180). Median total number of nucleated cells infused was 2.5 x 10(8)/kg (range 1.1-8.9). The myeloablative regimen was well tolerated with no toxic death, veno-occlusive disease or life-threatening complications. All patients had hematopoietic recovery in a median time of 27 days for neutrophils and 44 days for platelets. Eight of 20 patients relapsed after a median time of 7.2 months from transplant (range 5.7-15.9). Six of them died (five of progression of disease and one of sepsis) while the remaining two patients are alive in CR2. The 3-year cumulative probability of survival and event-free-survival (EFS) is 62% and 56%, respectively. This study showed that in pediatric patients with AML consolidation of CR1 with high-dose melphalan allows survival and EFS to be obtained comparable to other auto-HSCT or chemotherapy published series with a potential sparing effect both on duration of treatment (with respect to chemotherapy) and on long-term side-effects (with respect to auto-HSCT with TBI or busulfan containing regimens).

Topics: Adolescent; Antineoplastic Agents, Alkylating; Bone Marrow Purging; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Interleukin-2; Italy; Leukemia, Myeloid, Acute; Male; Melphalan; Patient Selection; Retrospective Studies; Survival Rate; Transplantation, Autologous

Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66-206). The melphalan dose was 90 mg/m2 intravenously on days -4 and -3 with PBSC infusion on day 0. GVHD prophylaxis consisted of cyclosporine and methylprednisolone. The median time to an absolute neutrophil count >0.5 x 10(9)/l and to a platelet count >20 x 10(9)/l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II-III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56-614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6-614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for short-term disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence.

Topics: Acute Disease; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Child; Chronic Disease; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation Chimera

Of 41 pediatric patients currently alive after total body irradiation (TBI) and bone marrow transplantation (BMT), 30 (allogeneic 20, autologous 10) participated in the study. Pre-transplant therapy included high-dose cyclophosphamide (CY) and TBI (n = 12), high-dose CY alone (n = 4), high-dose Ara C and TBI (n = 5), cisplatinum, high-dose melphalan, VP-16 and TBI (n = 9). Acute cardiotoxicity was suggested by a > 15% decrease in the QRS voltage sum of the limb leads in all patients. Late cardiotoxicity was evaluated 0.5-10 years (median 5 years) post-transplant by ECG, chest radiograph, radionuclide cineangiography (RNCA) and echocardiography (ECHO). Six patients had a persistent decrease in the QRS amplitudes. They were all asymptomatic but had abnormal systolic function at the time of the study. BMT patients differed from their controls in the mean values of both the systolic and diastolic indices of myocardial function shown by RNCA and ECHO. Treatment was associated with decreased myocardial contractility. Isovolumic relaxation time and deceleration time were longer in BMT patients than in controls. Myocardial damage seemed to be worst after CY while high-dose Ara C was tolerated best. We conclude that both acute and late cardiotoxicity may occur after BMT, calling for long-term cardiac follow-up.

Topics: Adolescent; Adult; Blood Pressure; Bone Marrow Transplantation; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Echocardiography; Female; Heart; Humans; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radionuclide Angiography; Time Factors; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

In a randomised multicentre trial a combination of methylprednisolone, vincristine, lomustine, cyclophosphamide and melphalan (MOCCA) was compared with the same regimen omitting methylprednisolone after the first course (COLA) in previously untreated patients with multiple myeloma. The MOCCA arm showed a response rate of 72% among 79 patients and the COLA arm a response rate of 60% among 59 patients. This difference was not statistically significant. The median survival time was 56 months in the MOCCA arm and 61 months in the COLA arm. There was a slight increase of early deaths (within the first 6 months) in the MOCCA arm as compared with the COLA arm. We conclude that, in multidrug therapies, the continuation of corticosteroid at conventional dosage beyond the first course does not improve response rate or survival time in multiple myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia, Myeloid, Acute; Lomustine; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Survival Rate; Vincristine

From October 1983 until December 1988, 50 patients with asymptomatic multiple myeloma stage I were included in a prospective randomized multi-centre study comparing melphalan-prednisone (MP) therapy started at the time of diagnosis with deferred therapy where MP was started at the time of disease progression. Twenty-five patients were randomized to each group. The median time from diagnosis to start of therapy in the group with deferred therapy was 12 months. The reasons for starting therapy were increasing M-protein in 8 cases, symptomatic bone disease in 9 and anaemia in 5. In 2 cases, disease progression was complicated by vertebral fractures necessitating radiotherapy. Two patients in the group in which MP was started at the time of diagnosis developed acute leukaemia. No differences in response rate, response duration or survival were observed between the treatment groups. We conclude that in asymptomatic myeloma deferral of chemotherapy is feasible in well-informed and well-controlled patients but conveys no advantage in survival. In clinical practice the benefits of treatment deferral are to some extent outweighed by disease progression before start of treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Whole-Body Irradiation

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Cyclophosphamide; Cyclosporine; Follow-Up Studies; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Melphalan; Methotrexate; Transplantation, Autologous; Transplantation, Homologous

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study.

Topics: Actuarial Analysis; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Transplantation, Autologous

Between June 1981 and April 1986 63 patients with acute myeloid leukaemia (AML) in first remission and HLA-identical sibling donors were entered into a prospective study comparing cyclophosphamide (CY) + total body irradiation (TBI) with melphalan + TBI as conditioning therapy prior to transplantation. Thirty-six patients received CY/TBI and 27 received melphalan/TBI. The actuarial probability of remaining in remission for patients receiving melphalan/TBI was 94% compared with 66% following CY/TBI (p greater than 0.01). By including a comparable group of 41 patients with AML in first remission, conditioned with CY/TBI prior to the onset of the study, the greater anti-leukaemic effect of melphalan/TBI compared to CY/TBI was unchanged and statistically the chance of this being wrong is 1 in 10 (p less than 0.1). The overall survival in remission of both arms of the study was the same with 15/27 patients (55%) surviving in remission following melphalan/TBI compared with 19/36 patients (53%) following CY/TBI. The benefit obtained in reduced relapse was offset by the combined nephrotoxic effect of melphalan and cyclosporin which was not identified until the programme had been underway for a period of time. This shows that misinterpretation of 'no survival advantage' for the new treatment may occur due to unforeseen and preventable toxicities.

Topics: Actuarial Analysis; Adolescent; Adult; Blood Cell Count; Bone Marrow; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Kidney; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Preoperative Care; Remission Induction; Sibling Relations; Transplantation, Homologous; Whole-Body Irradiation

Twelve of 648 patients in the Medical Research Council's first two trials in myelomatosis have developed myelodysplasia or acute leukaemia. This corresponds to a 5-year actuarial prevalence of 3% and an 8-year prevalence of 10%. Patients were randomised to treatment with either melphalan or cyclophosphamide and the relative capabilities of these two drugs to cause these conditions were examined as a function of duration of treatment. A significant relationship with length of melphalan treatment was found but no relationship was observed for cyclophosphamide treatment. The amount of melphalan treatment given in various intervals before diagnosis of myelodysplasia or leukaemia was studied and it was found that the amount of treatment in the most recent 3-year period was the most important determinant of risk (P = 0.0001). It is estimated that the risk of haemopoietic neoplasia after 10 years of follow-up is about 3% for each year of melphalan treatment and that much of this risk will occur within three years of the last treatment.

Topics: Aged; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Models, Biological; Multiple Myeloma; Myelodysplastic Syndromes; Random Allocation; Risk; Time Factors

We evaluated the occurrence of acute nonlymphocytic leukemia (ANL) among 1399 women with ovarian cancer who were treated in five randomized clinical trials. Of the 1399 women, 998 had been treated with alkylating agents, and among these, 12 cases of ANL were observed; the expected number was 0.11. Ten patients with ANL had received melphalan, and two chlorambucil. ANL was not observed in 401 women who had been treated with surgery or radiation or both, without alkylating agents. The excess risk of ANL that was associated with alkylating-agent therapy was 5.8 cases per 1000 women per year, and the cumulative seven-year risk of ANL among patients who were treated with chemotherapy alone was indistinguishable from that observed in patients receiving both radiation and chemotherapy. A positive correlation between initial drug dose and the risk of ANL was suggested. These data underscore the need to assess other cytotoxic agents and regimens of drug administration to identify those that do not have harmful late effects.

Topics: Acute Disease; Adult; Aged; Alkylating Agents; Animals; Chlorambucil; Clinical Trials as Topic; Female; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Ovarian Neoplasms; Random Allocation; Risk

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies.. We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor therapies.. With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II-IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025).. Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.

Topics: Adolescent; Busulfan; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Myelodysplastic Syndromes; Retrospective Studies; Siblings; Transplantation Conditioning; Young Adult

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers.

Topics: Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Neoplasms, Second Primary; Transplantation, Autologous

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for selected patients with acute myeloid leukemia. Yet, the influence of total body irradiation (TBI)-based conditioning as compared to non-TBI-based conditioning on long-term mortality is unclear. We retrospectively evaluated outcomes after TBI-based (n = 91) and non-TBI-based conditioning (melphalan-based, n = 248) for 1st allo-HSCT patients transplanted at the University Hospital Regensburg between 1999 and 2020. TBI was performed with an average dose rate of 4 cGy/min. Median follow-up was 8.3 years (interquartile range, 4.8-12.9 years). Cumulative incidence rates of 5-year non-relapse mortality (NRM) were 17% (95% confidence interval, CI, 10-25) and 33% (95% CI, 27-40) after TBI- and non-TBI-based conditioning (P < 0.001). Five-year cumulative incidences of relapse (CIR) were 42% (95% CI, 32-52) and 29% (95% CI, 23-35) after TBI- and non-TBI-based conditioning (P = 0.030). The 5-year OS was 54% (95% CI, 43-64) and 55% (95% CI, 48-62) after TBI- and non-TBI-based conditioning. Both groups had similar 100-day acute graft-versus-host disease (aGVHD, 43% vs. 40%) and 5-year chronic GVHD (34% vs. 36%). The multivariable regression models found no associations of TBI with the outcomes NRM, CIR, PFS, OS, aGVHD, and cGVHD. TBI was no risk factor for NRM, even including mortality caused by secondary malignancies. NRM was influenced by patient age, advanced disease status, and the use of female donors for male recipients. TBI- and non-TBI-based conditioning appear to be equally effective and tolerable for AML patients eligible for 1st allo-HSCT.

Topics: Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Recurrence; Retrospective Studies; Transplantation Conditioning; Whole-Body Irradiation

We retrospectively compared the impact of the conditioning regimen in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received high-dose myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) from 2010 to 2021 with either high-dose cytarabine, etoposide and busulfan (BEA), busulfan with cyclophosphamide (BUCY) or busulfan and high-dose melphalan (BUMEL) registered in the EBMT database. Overall 1560 patients underwent ASCT, of which 156, 1143 and 261 received BEA, BUCY and BUMEL, respectively. Compared to BUCY and BUMEL, BEA patients were younger (p < 0.001) and less frequently had NPM1 mutations (p = 0.03). Transplant outcomes at 5 years with BEA, BUCY and BUMEL were: cumulative incidence of relapse 41.8%, 46.6% and 51.6%; non-relapse mortality (NRM) 1.5%, 5.2% and 7.3%; probability of leukemia-free survival (LFS) 56.7%, 48.2% and 41.1%; and overall survival (OS) 71.3%, 62.3% and 56%, respectively. In multivariable analysis the BEA regimen showed significant improvement in OS compared to BUCY (hazard ratio [HR] 0.65; 95% CI, 0.42-0.83; p = 0.048) and BUMEL (HR 0.59; 95% CI, 0.37-0.94; p = 0.029). In conclusion, high-dose myeloablative combination chemotherapy with BEA offered improved outcomes compared to classical BUCY or BUMEL in patients with AML in CR1 undergoing ASCT.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cyclophosphamide; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Topics: Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma

Multiple myeloma (MM) is the second most common hematologic malignancy diagnosed in the United States. With a growing arsenal of novel therapies, patients are living longer and hence are at increased risk of secondary cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While MDS-associated cytogenetic abnormalities have been described in patients with a diagnosis of for decades, clonal hematopoiesis (CH) has been described only recently. CH has been shown to correlate with inferior survival in MM due to increased risk of disease progression in patients who are treated with high-dose melphalan without lenalidomide maintenance. When involving specific high-risk genes, multiple genes, or when present at high variant allelic frequencies, CH could also potentially elevate the risk of secondary MDS and/or AML, cardiovascular events, and venous thromboembolic events. Despite growing knowledge about CH in patients with MM, many questions remain unanswered. Further studies are needed to better understand the prognostic and therapeutic significance of CH in MM and its precursor conditions, as well as the effect of specific treatments on long-term outcome.

Topics: Clonal Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary

Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curative option for relapsed/refractory acute myeloid leukemia and other high-risk myeloid malignancies. To improve alloHCT results in this setting, sequential regimens were designed as a strategy to lower tumor burden and quickly induce the graft-versus-leukemia effect. We analyzed long-term outcomes of a sequential regimen based on IDA-FLAG and high-dose melphalan, as set forth by the CETLAM cooperative group. This protocol yielded a high complete response rate (89%) and a lower cumulative relapse incidence (30% at five years) compared to other regimens. Five-year non-relapse mortality, however, reached 45%, with grade 3-4 acute graft-versus-host disease being the most frequent adverse event (a 100-day incidence of 29%). Altogether, 5-year overall survival was 25% in this group of patients with otherwise dismal prognosis. Long-term survivors enjoyed a good quality of life after a median follow-up of 68 months.

Topics: Disease-Free Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Myeloproliferative Disorders; Quality of Life; Recurrence; Retrospective Studies; Transplantation Conditioning

We report a case of donor-derived diffuse large B-cell lymphoma (DLBCL), which developed 5 years after stem cell transplantation from a human leukocyte antigen (HLA)-haploidentical donor for acute myeloid leukemia (AML). A 51-year-old male was diagnosed with AML with variant KMT2A translocation involving t(6;11)(q13;q23). After 12 cycles of azacitidine treatment, fluorescence in situ hybridization (FISH) for KMT2A split signal indicated that 94% of his bone marrow (BM) cells were positive. He underwent peripheral blood stem cell transplantation (PBSCT) from his HLA-haploidentical son. The preconditioning regimen consisted of fludarabine, busulfan, melphalan, and antithymocyte globulin (ATG). The graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short-term methotrexate. On day 28, KMT2A FISH analysis indicated that he had achieved a complete response (CR). He continued to receive tacrolimus for the limited type of cutaneous chronic GVHD. Five years after the transplantation, positron emission tomography/computed tomography (PET/CT) showed an abdominal tumor. The tumor was diagnosed as DLBCL without Epstein-Barr virus. BM aspiration revealed the infiltration of lymphoma cells with t(8;14)(q24;q32). Chimerism analysis showed that both the peripheral blood (PB) and abdominal lymphoma cells were of donor origin. After 4 cycles of salvage chemotherapy, PET/CT showed that a CR had been achieved. He underwent a second PBSCT from an HLA-identical unrelated donor. The preconditioning regimen and GVHD prophylaxis were the same as those for the first PBSCT without ATG. The patient's PB revealed complete second donor-type chimerism, and the patient has maintained a CR since the second transplantation.

Topics: Antilymphocyte Serum; Azacitidine; Busulfan; Epstein-Barr Virus Infections; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; HLA Antigens; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Positron Emission Tomography Computed Tomography; Tacrolimus; Transplantation Conditioning

Hyperproliferative crises with hyperleukocytosis occur frequently in the disease course of refractory or relapsed acute myeloid leukemia (AML). Palliative cytoreduction aims to control blast count in order to avoid life-threatening complications and preserve quality of life in patients unfit for intensive treatment. In our center, low-dose intravenous melphalan is sometimes used with this intent.. We performed a retrospective analysis of patients with AML who were treated with low-dose intravenous melphalan (15-30 mg/m. Thirty patients with AML who received low-dose melphalan (15-25 mg/m. Intravenous low-dose melphalan is effective, quick and safe as palliative cytoreductive therapy in patients with hyperproliferative AML. It can be considered in palliative care of patients refractory to prior treatment with preserving acceptable quality of life. Our small retrospective cohort is the first to report the use of low-dose intravenous melphalan as palliative cytoreductive treatment in this population.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytoreduction Surgical Procedures; Humans; Leukemia, Myeloid, Acute; Melphalan; Palliative Care; Quality of Life; Retrospective Studies

Outcomes of patients with Shwachman-Diamond syndrome (SDS) who developed myeloid malignancies are poor because of refractory disease and high hematopoietic stem cell transplantation-related mortality. We herein report a case of a 7-year-old girl with SDS who developed acute myeloid leukemia with monosomy 7. She was successfully treated with chemotherapy followed by unrelated cord blood transplantation with reduced-intensity conditioning consisting of fludarabine, melphalan, and high-dose cytarabine without significant toxicity. Reduced-intensity conditioning presented in this report might be a preferable option for SDS patients with acute myeloid leukemia, although further evaluation in a larger number of similar cases is necessary.

Topics: Antineoplastic Agents, Alkylating; Child; Cytarabine; Female; Fetal Blood; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Melphalan; Myeloablative Agonists; Shwachman-Diamond Syndrome; Transplantation Conditioning; Vidarabine

The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM).. We identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26 627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis.. The cumulative melphalan exposure was significantly higher (OR = 2.8, 95% CI 1.7-5.2; P < .001) among cases (median 988 mg; IQR 644-1640) compared with controls (median 578 mg; IQR 360-967). Median time to AML/MDS development was 3.8 years (IQR 2.8-5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy.. In this nationwide population-based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long-term risks.

Topics: Antineoplastic Agents, Alkylating; Disease Susceptibility; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Public Health Surveillance; Risk Assessment; Risk Factors; Sweden

Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non-CR AML undergoing allo-HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo-HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266-0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia-free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c-indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi-drug conditioning regimens in patients undergoing CBT.

Topics: Adult; Age Factors; Bone Marrow Transplantation; Busulfan; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Karnofsky Performance Status; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Nomograms; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Topics: Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Recurrence; Retrospective Studies; Transplantation Conditioning; Vidarabine

Given the poor prognosis of relapsed/refractory myeloid malignancies, the concept of sequential conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven to be an effective approach. We sought to evaluate a sequential scheme combining fludarabine, amsacrine, and cytarabine (FLAMSA) for cytoreduction, followed by reduced-intensity conditioning with busulfan and melphalan (FLAMSA-BuMel), which was designed to be suitable for both HLA-matched and haploidentical HSCT. This single-center retrospective study included 36 adult patients with high-risk myeloid malignancies who underwent allo-HSCT from HLA-matched (n = 19) or haploidentical (n = 17) donors. Along with the standard prophylaxis for graft-versus-host disease (GVHD), patients with a haploidentical donor received post-transplantation high-dose cyclophosphamide. A post-transplantation consolidation treatment with low-dose 5-azacytidine and prophylactic donor lymphocyte infusions was provided whenever possible. Thirty patients (83%) achieved complete remission on day +30. With a median follow-up of 30.0 months, the 2-year overall survival was 89% in the HLA-matched group versus 34% in the haploidentical group (P = .0018). The 2-year disease-free survival in these 2 groups was 68% and 34%, respectively (P = .013). At 2 years, the probability of relapse was 32% and 20%, respectively, and nonrelapse mortality was 0% and 58%, respectively (P = .0003). The leading cause of death was relapse in the HLA-matched group (3 of 19) and hemorrhagic events (5 of 17) in the haploidentical group, favored by significantly delayed platelet reconstitution and a severe GVHD context. These data confirm the feasibility of FLAMSA-BuMel as a sequential conditioning in allo-HSCT for high-risk myeloid malignancies. The use of bone marrow as the preferred graft source might reduce the incidence of acute GVHD and nonrelapse mortality in the haploidentical transplantation setting.

Topics: Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Neoplasm Recurrence, Local; Retrospective Studies

The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen.

Topics: Age Factors; Aged; Antineoplastic Agents; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6-8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P < 0.001 and HR 0.41, P = 0.030, respectively). After stratification according to conditioning and GVHD prophylaxis into four groups (TBI-MMF [n = 17], TBI-MTX [n = 16], alkylator-MMF [n = 6], alkylator-MTX [n = 5]), TBI-MMF was associated with improved overall survival (OS) and LFS (P = 0.001 and P < 0.001, respectively). Patient and disease characteristics did not differ between the groups. The associations of TBI-based conditioning and MMF with prolonged LFS were observed across the CMML (n = 29), secondary AML (n = 15), and UD allograft (n = 34) subgroups. In summary, our study suggests that allografting based on intermediate-dose TBI conditioning and MMF-containing GVHD prophylaxis is associated with increased disease control in CMML. Larger (registry-based) studies are warranted to confirm our findings.

Topics: Adult; Aged; Antilymphocyte Serum; Busulfan; Calcineurin Inhibitors; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Male; Melphalan; Methotrexate; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Neoplasms, Second Primary; Proportional Hazards Models; Retrospective Studies; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

The optimal conditioning regimen for alloHCT in children with myeloid malignancies remains undefined.. We performed a retrospective review of children undergoing alloHCT for AML and MDS over a 10-year period (2008-2018) at our institution, comparing the outcomes of recipients of either a myeloablative busulfan- or reduced toxicity mel/thio-based conditioning regimen.. A total of 49 patients underwent alloHCT for AML/MDS (mel/thio, N = 21; busulfan, N = 28). Mel/thio recipients were selected due to pretransplant comorbidities. Recipients of mel/thio were more likely to have t-AML, and less likely to have MRD <0.1% at the time of alloHCT (57.1% vs 82.1%). Graft failure was more common in busulfan recipients; engraftment kinetics were similar between groups. Sinusoidal obstructive syndrome was diagnosed in 21% of busulfan and no mel/thio recipients (P = .03). One patient in each group died from TRM. Relapse incidence was comparable (mel/thio-29% vs busulfan-32%); however, relapse occurred significantly later in recipients of mel/thio conditioning (median d + 396 vs d + 137; P = .01). As a result, there was a trend toward improved OS at 1 and 3 years in mel/thio recipients (95% vs 74%, P = .06; and 75% vs 50%, P = .11; respectively).. In our single institution, when compared to myeloablative busulfan-based conditioning, use of a mel/thio-based reduced toxicity regimen resulted in comparable outcomes, despite higher risk patient and disease characteristics. Mel/thio recipients had both more comorbidities and higher risk disease profile, which did not translate into higher rates of either TRM or relapse.

Topics: Adolescent; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Myeloablative Agonists; Myelodysplastic Syndromes; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous

Reduced-intensity conditioning (RIC) has been facilitating allogeneic hematopoietic cell transplantation (allo-HCT) for patients originally considered ineligible for HCT with myeloablative conditioning. Fludarabine (Flu) with reduced doses of busulfan (Bu) (Flu + Bu) and Flu with reduced doses of melphalan (Mel) (Flu + Mel) are widely used RIC regimens for acute myeloid leukemia (AML). A nationwide retrospective study comparing clinical outcomes of adult patients with AML receiving first allo-HCT after RIC between 2001 and 2010 was performed. Cumulative incidences of relapse were not significantly different among the Flu + ivBu-based (FBiv), Flu + poBu-based (FBpo), and Flu + Mel-based (FM) groups (p = 0.29). Non-relapse mortality (NRM) was significantly lower in patients receiving FBiv compared with FBpo (p = 0.003) and FM (p < 0.001). On multivariate analysis, there was no significant difference in overall survival, but FM was associated with a significantly lower risk of relapse (hazard ratio (HR) = 0.65, 95% confidence interval (CI): 0.50-0.85, p = 0.002), higher NRM (HR = 1.60, 95% CI: 1.10-2.33, p = 0.013) and better leukemia-free survival (HR = 0.77, 95% CI: 0.63-0.95, p = 0.015) compared with FBiv. These results suggest that Flu + Mel has a more intense disease control potential and Flu + ivBu is less toxic than the other. Both RIC regimens provide similar survival outcomes and are effective and useful regimens for patients with AML who received allo-HCT.

Topics: Adult; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Retrospective Studies; Transplantation Conditioning; Vidarabine

Topics: Busulfan; Humans; Leukemia, Myeloid, Acute; Melphalan; Transplantation Conditioning; Vidarabine

Primary refractory acute myeloid leukemia (AML) is associated with dismal prognosis. No standard treatment options are available, and it remains an unmet clinical need. Here, we report a case of a tandem allogeneic hematopoietic stem cell transplantation (allo-HSCT) performed in a patient who did not achieve remission after 2 courses of induction chemotherapy.. The treatment was approved by the Bioethical Commission of the Medical University of Warsaw and was performed in accordance with the Declaration of Helsinki. The patient gave informed consent.. A 41-year-old woman was diagnosed with AML, high cytogenetic risk, with concomitant skin and central nervous system involvement, bone marrow necrosis, and hemophagocytic lymphohistiocytosis. She received "3+7" induction and HAM (cytarabine, mitoxantrone) reinduction, after which she did not achieve remission and hematopoietic recovery. Tandem allo-HSCT was performed from the same HLA-identical brother---the first after reduced intensity conditioning (cladribine, cytarabine, mitoxantrone, melphalan) and the second after myeloablative conditioning (BuCy--busulphan, cyclophosphamide). The patient obtained complete remission after the first allo-HSCT and remains disease-free after the second for 5 years CONCLUSION: Tandem allo-HSCT may be a treatment option for primary refractory AML.

Topics: Adult; Busulfan; Cladribine; Cyclophosphamide; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Melphalan; Mitoxantrone; Salvage Therapy; Transplantation Conditioning

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Topics: Adult; Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Transplantation Conditioning

Topics: Adult; Aged; Alemtuzumab; Busulfan; Female; Humans; Leukemia, Myeloid, Acute; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Unrelated Donors; Young Adult

Relapsed or refractory (R/R) disease remains challenging in acute myeloid leukemia (AML), especially in elderly patients not considered eligible for intensive treatment options. We retrospectively evaluated the safety and efficacy of low-dose melphalan (LD-Mel) in a multicenter analysis in patients over 65 years with R/R AML, who previously had received ≥1 non-curative treatment line. The study included 31 patients (median age 77 years) with 1-4 previous treatment lines. Three patients (9.7%) achieved a complete remission. Two patients (6.5%) achieved a partial remission, nine patients (29.0%) had disease stabilization with reduction of peripheral or bone marrow blast burden, resulting in an overall response rate of 16.1% and 45.2% achieved clinical benefit. Responders showed a significantly longer median overall survival than non-responders (16.3 vs. 2.3 months, p < 0.001). Multivariate analysis identified complex karyotype as the only risk factor associated with inferior survival (p < 0.001), whereas prior treatment with hypomethylating agents (HMAs) in 25 of 31 patients was associated with superior OS, regardless of prior response to HMAs (p = 0.03). LD-Mel was well tolerated, with mild myelosuppressive side effects. Conclusively, LD-Mel is an effective treatment option in elderly patients with R/R AML, particularly after HMA therapy and in the absence of a complex karyotype.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Melphalan; Proportional Hazards Models; Recurrence; Retreatment; Treatment Failure; Treatment Outcome

There have been conflicting results regarding the impact of minimal/measurable disease at transplant on acute myeloid leukemia (AML) outcomes after haploidentical transplantation (haplo-SCT). We assessed the impact of pre-transplant disease status on post-transplant outcomes of 143 patients treated with haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy). With a median follow-up of 29 months, the two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 (95% CI: 2.05-6.1; P < .001) and 2.3 (95% CI: 1.3-3.9; P = .002), respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41) (HR 1.85, 95%CI: 0.9-4.0; P = .1). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes. Our findings suggest that haplo-SCT with FM conditioning regimen and PTCy-based GVHD prophylaxis has a protective effect, and may potentially abrogate the inferior outcomes of MRD positivity for patients with AML. Patients with positive MRD may benefit from proceeding urgently to a haplo-SCT, as this does not appear to negatively impact transplant outcomes.

Topics: Adult; Aged; Bone Marrow; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Neoplasm, Residual; Progression-Free Survival; Proportional Hazards Models; Remission Induction; Retrospective Studies; Transplantation Conditioning; Transplantation, Haploidentical; Treatment Outcome; Vidarabine; Young Adult

Indications for hematopoietic stem cell transplantation (HSCT) have decreased with the improvement in chemotherapy for pediatric acute myeloid leukemia (AML) in the last decade. We conducted reevaluation of autologous HSCT (AHSCT) to compare myeloablative conditioning (MAC) regimens for pediatric AML without the need for consideration of toxicities caused by allogeneic immune reactions.. This retrospective study analyzed the clinical outcomes of 220 children with AML who underwent consecutive AHSCT between 1989 and 2002 in Japan by the national prospective registry. The transplantation outcomes of various conditioning regimens were compared.. The median follow-up period of the survivors was 160 months. The clinical outcomes of busulfan + cyclophosphamide ± etoposide or busulfan + melphalan regimens were significantly superior compared with other busulfan-based and total body irradiation-based regimens (leukemia-free survival [LFS]: 68% vs 42% and 55%, P = 0.001; overall survival [OS]: 74% vs 49% and 61%, P < 0.001). Multivariate analysis showed that busulfan + cyclophosphamide ± etoposide and busulfan + melphalan regimens were independent favorable factors for LFS (hazard ratio: 0.46; P < 0.001) and OS (hazard ratio: 0.40; P < 0.001) compared with the other busulfan-based regimen, and both age 2 years or older and advanced stage at AHSCT were independent poor predictors for LFS and OS, simultaneously.. Busulfan + cyclophosphamide ± etoposide and busulfan + melphalan regimens exhibited superior antileukemic effects compared with other BU-based myeloablative regimens.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Cyclophosphamide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Japan; Leukemia, Myeloid, Acute; Male; Melphalan; Prognosis; Prospective Studies; Remission Induction; Retrospective Studies; Survival Rate; Transplantation Conditioning; Transplantation, Autologous

Women are at high risk of hypergonadotropic hypogonadism after hematopoietic cell transplantation (HCT). Hypogonadism is universal after irradiation or busulfan. We hypothesized that reduced intensity conditioning (RIC) might protect ovarian function after HCT. We retrospectively reviewed data from patients with acute leukemia treated according to the Japan Association of Childhood Leukemia Study and nationwide multicenter study protocol. We selected 11 female patients with acute leukemia who received first HCT with RIC, had survived for three or more years after HCT, and were aged ≥ 12 years at the last follow-up visit. Median age at diagnosis, HCT, and last visit were 8, 10, and 17 years. Six patients received HLA-matched bone marrow (BM), two HLA-mismatched BM, and three cord blood. Melphalan was used as conditioning regimen in all patients. At the last visit, six of seven post-pubertal patients at transplantation recovered menstruation, and four of four patients who underwent transplantation at the pre-pubertal began menstruation. Height z scores showed no significant reduction between pre-transplant and post-transplant. No patients received growth hormone treatment. Only one recipient displayed subclinical hypothyroidism. Melphalan-based RIC may be an encouraging option for patients with acute leukemia to avoid ovarian and endocrine dysfunction after HCT.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Fertility Preservation; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid, Acute; Melphalan; Menstruation; Ovary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning

Fludarabine and melphalan (Flu/Mel) has emerged as a more tolerable chemotherapy-based conditioning regimen compared with busulfan and cyclophosphamide (Bu/Cy) for allogeneic stem cell transplant (allo-hematopoietic stem cell transplantation (HSCT)) patients with acute myelogenous leukemia (AML). We conducted a retrospective review of a single-institution database including patients with AML who received allo-HSCT following conditioning with Mel/Flu or Bu/Cy-based regimens. We performed descriptive statistical analysis to examine patient demographics and clinical outcomes. We identified 156 patients meeting criteria between 2005 and 2014. Overall, patients conditioned with Bu/Cy were significantly younger, but more likely to be treated in an earlier era than those receiving Flu/Mel. Regimen choice was not associated with relapse rates (RR), relapse-free survival (RFS), or overall survival (OS) on both univariate and multivariable analyses. Bu/Cy was associated with increased non-relapse mortality (NRM) on multivariable analysis. These findings demonstrate that Flu/Mel provides non-inferior disease control and could be an appropriate regimen for selected patients.

Topics: Adult; Age Factors; Busulfan; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Patient Selection; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Comorbidity; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Neoplasm Staging; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia-free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Remission Induction; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

Allogeneic stem cell transplantation (Allo-HSCT) is sine qua non to cure high-risk acute myeloid leukaemia (AML). In spite the advent of highly active antiretroviral treatment, HIV-infected patients display a remarkable risk for haematological neoplasms such as non-Hodgkin lymphomas, Hodgkin lymphoma and acute leukaemia. Several case series have confirmed the efficacy of the autologous stem cell transplantation for the treatment of non-Hodgkin lymphomas in the HIV setting. Nonetheless, there is a paucity of data for the role of the Allo-HSCT in HIV-infected individuals with haematological malignancies. Herein, we presented the successful long-term outcome of a HIV-infected patient who received reduced intensity conditioned, matched unrelated donor transplant with alemtuzumab as graft-versus-host disease prophylaxis for therapy-related acute myeloid leukaemia. We propose that Allo-HSCT in HIV patients is safe and that alemtuzumab-based conditioning could further work to eradicate HIV in those whose donor is not CCR5 homozygous.

Topics: Adult; Alemtuzumab; Antineoplastic Combined Chemotherapy Protocols; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Transplantation Conditioning; Vidarabine

Topics: Adolescent; Adult; Aged; Animals; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid, Acute; Lymphocyte Depletion; Melphalan; Middle Aged; Myelodysplastic Syndromes; Rabbits; Risk Assessment; Survival Analysis; Transplantation, Homologous; Treatment Outcome; Vidarabine; Young Adult

The optimal conditioning regimen for elderly patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed 1607 patients aged 50 years or older with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2007 and 2014. We compared the clinical outcomes among FB2 (busulfan at 6.4 mg/kg iv, n = 463), FB4 (busulfan at 12.8 mg/kg iv, n = 721), and FM140 (melphalan at 140 mg/m

Topics: Aged; Aged, 80 and over; Busulfan; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation.. From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%.. Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03).. In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients > 2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P < .01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P = .04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P < .01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P = .79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Cyclophosphamide; Europe; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Recurrence; Registries; Remission Induction; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34+ progenitor cells and a more differentiated CD34+ derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.

Topics: Animals; Antigens, CD34; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Synergism; Female; HL-60 Cells; Humans; Inhibitory Concentration 50; Leukemia, Myeloid, Acute; Male; Melphalan; Mice, SCID; Middle Aged; Neoplastic Stem Cells; Phenylalanine; Time Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

High-dose melphalan (HDM) is an integral component of conditioning regimens for autologous and allogeneic hematopoietic stem cell transplantation for patients with malignant and non-malignant diseases. The gonadotoxic effects of HDM are often obscured by previous or concurrent administration of alkylating agents. From April 1996 to January 2006 our acute myeloid leukemia treatment regimen included induction and consolidation therapy with cytosine arabinoside, anthracyclines and etoposide, followed by HDM and autologous stem cell infusion. We explored gonadal function in surviving female patients so treated, who represent a unique group of patients exposed to HDM as a single gonadotoxic agent.. The fertility assessment included a questionnaire, blood tests for luteinizing hormone, follicle stimulating hormone and anti mullerian hormone (AMH), and a gynecological ultrasound exam for antral follicular count (AFC).. Eight female survivors participated. Although fertility assessment showed considerable damage to ovarian reserve in all participants, four of the eight female survivors conceived and bore children without medical intervention.. In this cohort, HDM treatment reduced fertility potential but did not preclude fecundity. Early referral to a fertility clinic and long term follow-up including serial measurements of AMH levels and AFC for female patients receiving HDM are recommended.

Topics: Adolescent; Adult; Anthracyclines; Consolidation Chemotherapy; Cytarabine; Etoposide; Female; Fertility; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Myeloablative Agonists; Survivors; Transplantation Conditioning; Young Adult

Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively (P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively (P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did not alter relapse risk or NRM. Patients with Karnofsky performance status ≥ 90 who received FM had a 2-year OS rate of 74.8% versus 48.3% for FB (P = .03). FB use remained prognostic for relapse in multivariable analysis (hazard ratio, 2.75; 95% confidence interval, 1.28 to 5.89; P = .0097). In summary, in spite of AUC-directed dosing, FB compared with FM was associated with a significantly higher CIR.

Topics: Adolescent; Adult; Aged; Area Under Curve; Busulfan; Female; Humans; Karnofsky Performance Status; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Myelodysplastic Syndromes; Recurrence; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Vidarabine; Young Adult

Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are 2 widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT).. The current survey compared transplantation outcomes for a cohort of 394 acute myeloid leukemia (AML) patients given bone marrow or peripheral blood stem cells from human leukocyte antigen-identical siblings after FB (n = 218) or FM (n = 176). Patients given manipulated grafts and those given T-cell-depleting agents (anti-thymocyte globulins or alemtuzumab) were not included.. At the time of transplantation, 266 patients (68%) were experiencing their first complete remission (CR), 69 (18%) were experiencing a later CR, and 59 (15%) had advanced disease. The incidences of acute and chronic graft-versus-host disease were similar in the 2 groups of patients. The 2-year relapse incidence (RI), nonrelapse mortality (NRM) rate, leukemia-free survival (LFS) rate, and overall survival (OS) rate were 31% ± 3%, 18% ± 3%, 51% ± 4%, and 54% ± 4%, respectively, for FB patients and 20% ± 3% (P = .007), 20% ± 3% (P = .4), 60% ± 4% (P = .08), and 62% ± 4% (P = .2), respectively, for FM patients. Among FB patients given intravenous busulfan (n = 81), the 2-year RI, NRM, LFS, and OS rates were 26% ± 5% (P = .43 vs FM patients), 25% ± 6% (P = .18), 49% ± 7% (P = .07), and 54% ± 7% (P = .13), respectively. In multivariate analyses, FM was associated with a lower RI (hazard ratio [HR], 0.5; P = .01) and a trend toward higher NRM (HR, 1.6; P = .1) with similar LFS (HR, 0.8; P = .2) and OS (HR, 0.9; P = .6).. These results suggest that although FM provides better AML control than FB as an RIC regimen for allo-SCT, the 2 regimens provide similar survival. Multicenter randomized studies are needed to confirm these findings.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Combined Modality Therapy; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Remission Induction; Retrospective Studies; Survival Rate; Transplantation Conditioning; Vidarabine; Young Adult

The relative efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) after reduced toxicity conditioning (RTC) compared with standard myeloablative conditioning (MAC) in pediatric patients with acute myeloid leukemia (AML) has not been studied extensively. To address whether RTC is a feasible approach for pediatric patients with AML in remission, we performed a retrospective investigation of the outcomes of the first transplant in patients who had received an allo-HCT after RTC or standard MAC, using nationwide registration data collected between 2000 and 2011 in Japan.. We compared a fludarabine (Flu) and melphalan (Mel)-based regimen (RTC; n = 34) with total body irradiation (TBI) and/or busulfan (Bu)-based conditioning (MAC; n = 102) in demographic- and disease-criteria-matched childhood and adolescent patients with AML in first or second complete remission (CR1/CR2).. The incidence of engraftment, early complications, grade II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were similar in each conditioning group. The risk of relapse (25% vs. 26%) and non-relapse mortality (13% vs. 11%) after 3 years did not differ between these groups, and univariate and multivariate analyses demonstrated that the 3-year overall survival (OS) rates after Flu/Mel-RTC and MAC were comparable (mean, 72% [range, 51-85%] and 68% [range, 58-77%], respectively).. The results suggest that the Flu/Mel-RTC regimen is a clinically acceptable conditioning strategy for childhood and adolescent patients with AML in remission. Although this retrospective, registry-based analysis has several limitations, RTC deserves to be further investigated in prospective trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Japan; Leukemia, Myeloid, Acute; Male; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Remission Induction; Retrospective Studies; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Topics: Aged; Combined Modality Therapy; Drug Administration Schedule; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Survival Analysis; Transplantation Conditioning; Treatment Outcome; Vidarabine; Whole-Body Irradiation

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Australia; Bone Marrow Transplantation; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multivariate Analysis; Myeloablative Agonists; New Zealand; Recurrence; Remission Induction; Retrospective Studies; Risk Factors; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult

The conventional conditioning regimen for patients with leukemia prior to allogeneic stem cell transplantation is myeloablation to eradicate residual leukemic cells and host immunocompetent cells. This helps prevent leukemic relapse as well as rejection after transplantation. A myeloablative conditioning regimen with busulfan (BU) or total body irradiation (TBI) is effective for eradication of leukemic cells but is also associated with significant toxicities in the acute or late phase in pediatric patients. In an effort to minimize these adverse effects, we conducted bone marrow transplantation (BMT) from unrelated volunteer donors using a conditioning regimen without BU or TBI.. Ten patients with acute leukemia in first or second remission were given a "non-BU, non-TBI conditioning regimen," which consisted of fludarabine (FLU), cytarabine (CA), and melphalan (L-PAM) after FLAG combined with L-PAM.. Engraftment was obtained in all patients, and two patients died of relapse. Eight of 10 patients have been disease-free for a median of 126 months (116-142) after transplantation. The overall survival, event-free survival, relapse rate, and treatment-related mortality were 80.0%, 80.0%, 20.0% and 0.0%, respectively. In female patients, spontaneous menstruation with normal luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) levels was observed in all four patients at post-pubertal age.. This conditioning regimen of FLAG combined with L-PAM (which did not contain BU and TBI) was associated with good outcomes and minimal late adverse effects in children with acute leukemia who have undergone allogeneic BMT from unrelated volunteer donors.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Female; Follow-Up Studies; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Melphalan; Neoplasm Recurrence, Local; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (P<0.001). In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (P<0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of <6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR=1.1), whereas there was a suggestion for higher relapse risk in patients given 6 mg/kg ATG (HR=1.4, P=0.08). In summary, these data suggest that a certain amount of in vivo T-cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC.

Topics: Adult; Aged; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Disease-Free Survival; Europe; Female; Graft vs Host Disease; HLA Antigens; Humans; Incidence; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Recurrence; Remission Induction; Retrospective Studies; Siblings; Stem Cells; T-Lymphocytes; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Young Adult

Topics: Abnormal Karyotype; Aged; Antineoplastic Agents, Alkylating; Bone Marrow; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma

The use of new agents (NAs) such as bortezomib, thalidomide, and lenalidomide has extended the survival of patients with multiple myeloma (MM). However, whether long-term treatment using NAs may increase the risk of second primary malignancies is a concern. Three hundred and thirty-three patients with MM were treated at our hospital from 1998 to 2013. Additional chromosomal abnormalities (CAs), associated with secondary myelodysplastic syndrome/acute myeloid leukemia, were observed in 13 of 152 users of NAs, but in 38 of 181 non-users of NAs. The cumulative CA incidence was higher in non-users of NAs. The CAs frequently observed were 13q-, 20q-, +8 in users of NAs, while -5/5q- and -7/7q- were detected in non-users of NAs. The total dose and treatment period of NAs did not differ between CAs-positive and -negative patients. However, a higher dose of melphalan was observed to have been used in patients who had CAs. Longer follow-up periods are necessary for an accurate risk assessment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Boronic Acids; Bortezomib; Chromosome Aberrations; Female; Humans; Immunosuppressive Agents; Lenalidomide; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Pyrazines; Retrospective Studies; Thalidomide; Time Factors

This study was conducted to retrospectively compare the clinical outcomes after transplantation of T cell-depleted (TCD) and unmodified allografts in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients received TCD grafts at Memorial Sloan-Kettering Cancer Center (MSKCC, N = 115) between 2001 and 2010 using the following preparative regimens: hyperfractionated total body irradiation (HFTBI)+thiotepa+fludarabine; HFTBI+thiotepa+cyclophosphamide; or i.v. busulfan+melphalan+fludarabine. TCD was performed by 1 of 2 immunomagnetic CD34(+) cell selection methods for peripheral blood grafts or by soybean lectin agglutination followed by sheep red blood cell-rosette depletion for bone marrow grafts. No additional graft-versus-host disease (GVHD) prophylaxis was administered. Patients received unmodified grafts at M.D. Anderson Cancer Center (MDACC, N = 181) after conditioning with busulfan+fludarabine and GVHD prophylaxis with tacrolimus+mini-methotrexate. Patients with unrelated or human leukocyte antigen-mismatched donors received anti-thymocyte globulin (ATG) at both centers, with some recipients of matched related donor TCD transplants also receiving ATG, depending upon the preparative regimen. TCD graft recipients were more likely to be older, receive a mismatched transplant, and have peripheral blood used as the graft source. The incidences rates of grades 2 to 4 acute GVHD and chronic GVHD were significantly lower in the TCD graft group (5% versus 18%, and 13% versus 53%). Three-year relapse-free and overall survival rates were 58% and 57%, respectively, in recipients of TCD grafts, and 60% and 66% in recipients of unmodified grafts (P = not significant). Survival and relapse-free survival are similar after TCD and conventional transplants from related/unrelated donors in patients with AML in CR1, but TCD significantly reduces GVHD.

Topics: Adult; Aged; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Recurrence; Remission Induction; Retrospective Studies; Survival Analysis; T-Lymphocytes; Thiotepa; Transplantation, Homologous; Treatment Outcome; Vidarabine

Topics: Adolescent; Anthracyclines; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Child; Cyclophosphamide; Genetic Predisposition to Disease; Humans; Leukemia, Myeloid, Acute; Melphalan; Neoplasms, Second Primary; SEER Program; United States; Young Adult

Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals. Sixty out of 109 children (55%) received BuCyMel. Median age at HSCT was 12.2 years (range 3.0; 18.3). GVHD prophylaxis mostly consisted of CsA and short term MTX with or without antithymocyte globulin. Matched-sibling donors were used for 6/60 analyzed recipients, the remainder either received grafts from matched unrelated (30/60) or mismatched donors. OS after 5 years was 62% (s.e. 6%), relapse incidence 35% (18/60 children) and treatment-related mortality accounted for 12% (7/60) of fatal events. In conclusion, even taking into account possible selection bias in this retrospective analysis, HSCT in CR2 using BuCyMel resulted in a respectable OS. Based on this data the prospective, controlled and centrally monitored AML SCT-BFM 2007 trial has started to recruit patients in January 2010 aiming to generate valid outcome data for further strategy decisions.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Randomized Controlled Trials as Topic; Retrospective Studies; Transplantation Conditioning

To assess therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) risk in patients treated for Hodgkin lymphoma (HL) on successive generations of Stanford clinical trials.. Patients with HL treated at Stanford with at least 5 years of follow-up after completing therapy were identified from our database. Records were reviewed for outcome and development of t-AML/MDS.. Seven hundred fifty-four patients treated from 1974 to 2003 were identified. Therapy varied across studies. Radiotherapy evolved from extended fields (S and C studies) to involved fields (G studies). Primary chemotherapy was mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or procarbazine, mechlorethamine, and vinblastine (PAVe) in S studies; MOPP, PAVe, vinblastine, bleomycin, and methotrexate (VBM), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in C studies; and VbM (reduced dose of bleomycin compared with VBM) or mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) in G studies. Cumulative exposure to alkylating agent (AA) was notably lower in the G studies compared with the S and C studies, with a 75% to 83% lower dose of nitrogen mustard in addition to omission of procarbazine and melphalan. Twenty-four (3.2%) of 754 patients developed t-AML/MDS, 15 after primary chemotherapy and nine after salvage chemotherapy for relapsed HL. The incidence of t-AML/MDS was significantly lower in the G studies (0.3%) compared with the S (5.7%) or C (5.2%) studies (P < .001). Additionally, in the G studies, no t-AML/MDS was noted after primary therapy, and the only patient who developed t-AML/MDS did so after second-line therapy.. Our data demonstrate the relationship between the cumulative AA dose and t-AML/MDS. Limiting the dose of AA and decreased need for secondary treatments have significantly reduced the incidence of t-AML/MDS, which was extremely rare in the G studies (Stanford V era).

Topics: Academic Medical Centers; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; California; Chemotherapy, Adjuvant; Clinical Trials as Topic; Dacarbazine; Databases, Factual; Doxorubicin; Drug Administration Schedule; Female; Hodgkin Disease; Humans; Incidence; Leukemia, Myeloid, Acute; Male; Mechlorethamine; Melphalan; Methotrexate; Myelodysplastic Syndromes; Neoplasm Staging; Neoplasms, Second Primary; Prednisone; Procarbazine; Radiotherapy Dosage; Radiotherapy, Adjuvant; Retrospective Studies; Risk; Vinblastine; Vincristine

A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores ≥3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34-103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Young Adult

A variety of reduced-intensity conditionings have been used in the reported studies of allogeneic hematopoietic stem cell transplantation (HSCT) for elderly patients with myeloid hematological malignancies. This study retrospectively analyzed the outcome of allogeneic HSCT for 10 patients aged 50 years or older with myeloid hematological malignancies after conditioning with fludarabine (125 mg/m(2)), melphalan (140 mg/m(2)) and total body irradiation (TBI; 8 Gy). Median age of the patients was 56.5 years, and diagnoses included acute myelogenous leukemia, advance myelodysplastic syndrome, and secondary myelofibrosis. Sources of stem cells were bone marrow from sibling (n=4) or unrelated donor (n=6). Both overall and disease-free survival rates were 40.0% (95% CI: 10.6~69.4%). Causes of death were relapse (n=2), fungal infection (n=2), and secondary malignancies (n=2). Because of a high incidence of transplant-related mortality, further refinement of this conditioning is required.

Topics: Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

We describe 41 cases of myeloid neoplasms (MNs) secondary to plasma cell myeloma (PCM). The types of MN included myelodysplastic syndrome (MDS) in 34 (82.9%), acute myeloid leukemia (AML) in 4 (9.8%), and myeloproliferative neoplasm (MPN) or MDS/MPN in 3 (7.3%) cases. The latency from treatment to diagnosis of MN ranged from 9 to 384 months, with a median of 60 months. Of 37 cases with cytogenetic studies, complex abnormalities were detected in 22 (59.5%), -5(q)/-7(q) in 4 (10.8%), other abnormalities in 8 (21.6%), and normal karyotype in 3 (8.1%) cases. Complex abnormalities and -5(q)/-7(q) correlated directly with multiple chemotherapeutic regimens, particularly with combined melphalan/cyclophosphamide. Moreover, the features of cytogenetic abnormalities in our series were significantly different from those with concomitant PCM/MN who had significantly lower complex abnormalities. The latency, skewed proportion of MDS, and bias toward complex cytogenetic abnormalities/unbalanced aberrations of chromosomes 5/7 suggested an alkylating mutagenic effect on pathogenesis of secondary MN. Kaplan-Meier survival analysis demonstrated a median survival of 19 months, which was better than that for therapy-related (t)-MDS/AML. In contrast to t-MDS, the survival in our patients appeared to depend on subtypes of MDS as seen in de novo diseases.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chromosome Aberrations; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Myeloid Cells; Myeloproliferative Disorders; Neoplasms, Second Primary; Retrospective Studies

Treatment strategies for relapsed/refractory AML are limited and disappointing. Recently, high-dose melphalan (HDM) chemotherapy and autologous hematopoietic SCT (HSCT) has been proposed for AML re-induction. We investigated the impact of HDM remission induction in highly advanced relapsed/refractory AML patients planned for allogeneic HSCT. A total of 23 patients with relapsed/refractory AML were prospectively scheduled for HDM with or without stem cell support followed by myeloablative allogeneic HSCT. Patients included nine individuals with a history of previous HSCT (seven allogeneic, two autologous). A total of 18 patients (78%) achieved a leukemia-free state and an additional four had substantial reduction of the initial leukemia burden warranting treatment continuation. There were no differences between patients with or without immediate stem cell support regarding mucositis or other organ toxicity. A total of 20 patients proceeded to myeloablative allogeneic HSCT. Outcome of allogeneic HSCT was poor: 11 patients (55%) relapsed, 7 patients (35%) died from TRM and only 2 patients (10%) were alive at the last follow-up. Our study shows that HDM is effective in inducing a leukemia-free state in patients with highly advanced relapsed/refractory AML. Leukemia burden reduction with HDM, however, did not translate into improved OS.

Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Recurrence; Remission Induction; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

AML patients (total 129; median age =50 years; range 16-72) in first CR received BU and melphalan (BU/Mel) as conditioning regimen before auto-SCT. In all, 82 patients (63.6%) received PBSCs and 47 patients (36.4%) received BM cells. The distribution of cytogenetic categories was conventionally defined as favorable (15.5%), intermediate (60.1%) and unfavorable (24.3%). With a median follow-up of 31 months, the 8-year projected OS and disease-free survival (DFS) was 62 and 56% for the whole population, respectively. The relapse rate was 46% and the non-relapse mortality was 4.65%. Although PBSC transplantation led to a faster hematological recovery than BM transplantation, in univariate analysis the stem cell source, cytogenetics and different BU formulations did not significantly affect OS and DFS, whereas age and the number of post-remission chemotherapy cycles did have a significant effect on the clinical outcome. Multivariate analysis identified age <55 years as the only important independent predictor for OS and DFS. Our data suggest that BU/Mel, being associated with a low toxicity profile (mainly mucositis) and mortality, is an effective conditioning regimen even for high-risk AML patients in first CR undergoing auto-SCT.

Topics: Adolescent; Adult; Age Factors; Aged; Bone Marrow Transplantation; Busulfan; Disease-Free Survival; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Italy; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Young Adult

Specific cytogenetic alterations and changes in DNA methylation are involved in leukemogenesis. Benzene, an established human leukemogen, is known to induce cytogenetic changes through its active metabolites including hydroquinone (HQ), but the specific alterations have not been fully characterized. Global DNA hypomethylation was reported in a population exposed to benzene, but has not been confirmed in vitro. In this study, we examined cytogenetic changes in chromosomes 5, 7, 8, 11 and 21, and global DNA methylation in human TK6 lymphoblastoid cells treated with HQ for 48 h, and compared the HQ-induced alterations with those induced by two well-known leukemogens, melphalan, an alkylating agent, and etoposide, a DNA topoisomerase II inhibitor. We found that rather than inducing cytogenetic alterations distinct from those induced by melphalan and etoposide, HQ induced alterations characteristic of each agent. HQ induced global DNA hypomethylation at a level intermediate to melphalan (no effect) and etoposide (potent effect). These results suggest that HQ may act similar to an alkylating agent and also similar to a DNA topoisomerase II inhibitor in living cells, both of which may be potential mechanisms of benzene toxicity. In addition to cytogenetic changes, global DNA hypomethylation may be another mechanism underlying the leukemogenicity of benzene.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Cells, Cultured; Chromosomes, Human; DNA Methylation; Etoposide; Humans; Hydroquinones; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Lymphocytes; Melphalan; Mutagens

This study was performed to determine the feasibility of second hematopoietic stem cell transplantation (HSCT) using reduced-intensity conditioning (RIC) with fludarabine and melphalan in patients with relapsed hematologic malignancies after a prior autologous HSCT. Twelve patients (multiple myeloma [n = 7], non-Hodgkin lymphoma [n = 3], and acute myeloid leukemia [n = 2] received allogeneic HSCT using RIC with fludarabine (25 mg/m(2) for 5 days) and melphalan (140 mg/m(2) for 1 day) after a failed autologous HSCT. The graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine plus a minidose of methotrexate. All patients achieved a neutrophil and platelet engraftment in a median 13.5 days and 17.5 days, respectively. The transplant-related mortality was 2 patients (16.7%). Grade II-IV acute GVHD and chronic extensive GVHD were noted in 4 (33.3%) and 1 patient (11.1%), respectively. Over a median follow-up duration of 376 days, 5 patients were alive without evidence of disease. The estimated nonrelapse mortality at 1 year was 28.4%. The estimated overall survival rate at 1 year was 58.3%, and the estimated event-free survival rate at 1 year was 41.7%. Allogeneic HSCT using RIC with fludarabine and melphalan appears to be feasible for a second HSCT in patients with relapsed hematologic malignancies after a failed autologous HSCT.

Topics: Adult; Disease-Free Survival; Feasibility Studies; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Recurrence; Reoperation; Republic of Korea; Retrospective Studies; Salvage Therapy; Survival Rate; Time Factors; Transplantation Chimera; Transplantation Conditioning; Transplantation, Autologous; Treatment Failure; Vidarabine

Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m(2) for 4 days and Mel dose was 100-180 mg/m(2). Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was > or =90 for 45 (32%), 60-89 for 78 (55%), and <60 for 18 (13%) patients. When estimated by MDRD, GFR was > or =90 for 65 (46%), 60-89 from 66 (47%), and <60 for 10 (7%) patients. The majority of patients by both estimations had a GFR between 60 and 89 (n = 78 by CG and n = 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR <60 (P > .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.

Topics: Acute Kidney Injury; Adult; Aged; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Retrospective Studies; Transplantation Conditioning; Vidarabine; Young Adult

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome; Gaucher Disease; Humans; Immunoglobulins; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Prednisone; Thrombocytopenia

We report successful outcome in 13 children (median age 2.2 years) with high-risk AML who received SCT from an unrelated (11) or identical sibling (2) donor after a preparative regimen consisting of BU, CY and melphalan. Three children were 'poor'-risk in first CR, three in the second CR, five in PR and two had resistant disease. Immunotherapeutic strategies were employed to maximize a GVL response escalating through a reduced dose of alemtuzumab, early taper of CsA, donor lymphocyte infusion and treatment with alpha-IFN. Ten out of 13 (77%) children are alive in CR at a median of 41 months (range: 17-88) from SCT. There was no TRM, but three children relapsed and died 3, 4 and 17 months after SCT. These encouraging early results warrant further studies in children with very high-risk AML.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cyclosporine; Female; Graft vs Host Disease; Humans; Immunotherapy; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Stem Cell Transplantation; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous

Myelodysplastic syndrome (MDS) is a well-recognized complication of chemotherapy for multiple myeloma (MM). Serial bone marrow metaphase examinations were performed for MM restaging in 3,077 patients undergoing high-dose therapy (HDT). MDS-associated cytogenetic abnormalities (MDS-CAs) were observed in 105 of 2,418 patients in whom cytogenetic data were available after HDT. MDS-CAs occurred transiently in 72 patients and on 3 successive occasions (persistent MDS-CAs) in 33 patients, for 10-year estimates of 4% and 2%, respectively; only 21 patients developed overt clinical MDS and 5, acute myeloblastic leukemia (AML). MDS-CA development was linked to lower CD34 yield at collection, longer time interval from MM diagnosis to HDT, older age, and lower platelet recovery after HDT; persistent MDS-CAs were predicted by CD34 yield of less than 3 x 10(6)/kg and need for more than 2 apheresis procedures. Applying a tertile frequency distribution over time to all 105 patients with MDS-CAs, its detection early after HDT was associated with longer time interval from diagnosis and low pre-HDT platelet count (likely resulting from pre-HDT damage), whereas late-onset MDS-CAs were noted among patients treated with Total Therapy 2 and Total Therapy 3 that applied post-HDT consolidation chemotherapy (suggesting possible post-HDT damage). While the risk of MDS-CAs was low and clinical MDS occurred infrequently, monitoring after post-HDT consolidation chemotherapy appears warranted.

Topics: Age Distribution; Arkansas; Chromosome Aberrations; Databases, Factual; Follow-Up Studies; Hematopoietic Stem Cell Mobilization; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Melphalan; Metaphase; Multiple Myeloma; Myeloablative Agonists; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Factors; Transplantation, Autologous

Topics: Adolescent; Bone Marrow Transplantation; Child; Combined Modality Therapy; Fatal Outcome; Humans; Leukemia, Myeloid, Acute; Melphalan; Recurrence; Treatment Outcome

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Fatal Outcome; Humans; Leukemia, Myeloid, Acute; Melphalan; Pneumonia; Recurrence; Siblings; Treatment Outcome; Trichoderma

The purpose of this study was to assess prognostic factors and outcome of patients with relapsed/refractory Hodgkin's lymphoma (HL) who received high-dose chemotherapy and autologous stem-cell transplant (ASCT).. Data on 195 patients who received ASCT between 1985 and June 2005 were reviewed. Median time from first treatment to ASCT was 2.6 years (0.4-27.3). Demography at ASCT was 61% stage IV, median age 31 years (18-69), median prior treatment (tx) regimens 3 (2-7), median Hasenclever index 3 (0-6); 150 patients had responding disease [54 complete remission (CR), 96 partial remission (PR)], and 45 patients had untested relapse/refractory disease.. Post-ASCT, 61% (119/195) patients attained CR with an overall response (CR + PR) of 85%. Twelve patients had nonrelapse mortality. Of 119 patients attaining CR, 27 relapsed: 3 after attaining CR for >5 years and 1 after attaining CR for >10 years. Median overall survival (OS)/progression-free survival (PFS) from ASCT was 9 years/2.9 years. Five-year OS/PFS was 55% of 44% and 10-year OS/PFS was 49.4% of 37% for whole group. Twenty (10%) patients developed second cancer (seven secondary acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS)). Probability of developing second cancer at 10 years was 14.7% (95% confidence interval 8.9% to 23.8%) and 24.8% at 19 years.. These data provide the longest follow-up reported for patients receiving ASCT for relapsed/refractory HL. In addition to previously described prognostic factors, our data show that Hasenclever index <3 influences outcome favorably and attaining CR at ASCT leads to a better outcome.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Disease Progression; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multivariate Analysis; Myelodysplastic Syndromes; Recurrence; Remission Induction; Retrospective Studies; Salvage Therapy; Time Factors; Transplantation, Autologous; Treatment Outcome

We have experienced 4 cases of therapy-related leukemia (TRL) in 119 patients with multiple myeloma (MM) who had received combination chemotherapy including alkylating agents between 1988 and 1998. All 4 cases were acute myelogenous leukemia, 3 were males and 1 was female. Median age at diagnosis of MM was 60 years, and median time to TRL from diagnosis of MM was 5.5 years. The chromosome abnormalities were found in 3 of those cases. All 4 cases were resistant to antileukemic chemotherapy, and median survival time from TRL was only 5.5 months. The TRL in MM is thought to be a more important problem, because recently the treatment for this disease has become more intensive, including high-dose chemotherapy supported by autologous stem cell transplantation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Nitrosourea Compounds; Prednisolone; Prednisone; Vincristine

Recently, the standard treatments for hematological malignancies have shown dramatic improvement. For chronic myeloid leukemia, imatinib has become the treatment of choice in initial treatment, and its long-term effectiveness and safety have been confirmed. For acute myelogenous leukemia, cytarabine with anthracycline agent is believed to be the standard treatment in first remission induction therapy. To improve the efficacy of the first remission induction chemotherapy, the addition of gemutuzumab ozogamicin has been investigated intensively all over the world. However, there are many obstacles to conducting its clinical trial in Japan. The addition of rituximab to CHOP improves the survival of patients with diffuse large B-cell lymphoma. For follicular lymphoma patients, rituximab with conventional chemotherapies are considered the standard treatments, but the question of which conventional chemotherapy is better is unsolved. MP therapy had long been the standard treatment for elderly patients with multiple myeloma, but MP therapy plus thalidomide with MP therapy has been found to be superior. In patients who are candidates for autologous stem-cell transplantation, VAD therapy or high-dose dexamethasone therapy followed by autologous stem-cell transplantation is considered the treatment of choice. But the number of transplantations and the timing of second transplantation need more investigation. Considering the overall situation with regard to the standard treatments of hematological malignancies in Japan, there is little difference in practice from western countries. However, the framework of conducting clinical trials to investigate standard treatment in Japan is unsatisfactory.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Melphalan; Multiple Myeloma; Prednisone; Rituximab; Survival Rate; Vincristine

FK866 is a novel anticancer agent that was previously shown to interfere with NAD superset+ biosynthesis by inhibition of nicotinamide phosphoribosyltransferase and to initiate apoptosis in cancer cells. As NAD superset+ is involved in cellular DNA repair processes, the present in vitro study on THP-1 and K562 leukemia cells was conducted to investigate the cytotoxicity of FK866 combination treatment with various cytotoxic agents: the antimetabolite Ara-C, the DNA-intercalating agent daunorubicin and the alkylating compounds 1-methyl-3-nitro-1-nitrosoguanidinium (MNNG) and melphalan. Cell viability after drug exposure was assessed by propidium iodide (PI) staining. Non-cytotoxic concentrations of FK866 (10 superset-9 M or less), applied simultaneously or 24 hours before adding cytotoxic agents, caused a depletion in the intracellular NAD superset+ and--to a lesser extent-- NADH levels in THP-1 cells. After 48 and 72 hours treatment with daunorubicin and Ara-C, respectively, increased cell death was observed in THP-1 cells that were pretreated with FK866, as compared to cells exposed to antineoplastic drugs alone. However, this effect was transient, and there was no difference in cell survival after 72 hours incubation with daunorubicin or 96 hours with Ara-C. - Non-toxic concentrations of FK866 added 8, 16, or 24 hours before starting treatment with the PARP-activating agent MNNG synergistically decreased intracellular NAD superset+ contents, and increased MNNG-induced cytotoxicity both in THP-1 and K562 cells for at least 72 hours. This effect was less pronounced when FK866 was used in combination with another alkylating agent, melphalan. The PARP inhibitor 3-aminobenzamide delayed MNNG-induced cytotoxicity by 24 hours both in cells that were pretreated with FK866 and in non-pretreated cells. 48 hours later, the protective effect of 3-aminobenzamide could no longer be observed, but FK866-pretreated cells retained increased sensitivity to MNNG. - In conclusion, the chemosensitizing effect of FK866 on cell death induced by antineoplastic drugs was particularly obvious in combination with substances like MNNG that cause NAD superset+ depletion per se. It was less pronounced and only transiently measurable in combination with daunorubicin, Ara-C, and melphalan, respectively. These results may indicate different levels of DNA damage implicated in the action of the cytotoxic agents used.

Topics: Acrylamides; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cell Death; Cell Line, Tumor; Cell Survival; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Combinations; Humans; K562 Cells; Leukemia, Myeloid, Acute; Melphalan; Methylnitronitrosoguanidine; Monocytes; NAD; Piperidines

We report the case of a 15-yr-old girl who developed secondary acute myelogenous leukemia (AML) 4 yr after completion of therapy for metastatic Ewing sarcoma (primary right acetabulum with metastatic disease to the lungs). Peripheral blood stem cells were collected after the second cycle of chemotherapy with the plan for future consolidation with high-dose chemotherapy and autologous stem cell rescue; however, because of the patient's excellent response to chemotherapy and surgery, therapy was completed without the need for high-dose chemotherapy. No human leukocyte antigen (HLA)-matched related donor was available for a bone marrow transplant. Because of previous lung radiation, high-dose samarium [30 mCi/kg of samarium-153 ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP) day -14] and melphalan (140 mg/m(2) day -2) were chosen as the conditioning regimen to avoid potential lung complications. The patient received an infusion of 6.1 x 10(8)/kg mononuclear autologous cells on day 0. She achieved engraftment on day +23. Three years after transplantation, she continues to have complete remission. Samarium and melphalan constitute a well-tolerated regimen with potential antileukemic activity.

Topics: Adolescent; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Organometallic Compounds; Organophosphorus Compounds; Radioisotopes; Samarium; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Topics: Antineoplastic Agents, Alkylating; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Melphalan; Middle Aged; Neutrophils; Remission Induction

We present the case of a 71 year-old man with secondary acute myeloblastic leukemia, who was successfully treated with low dose melphalan plus Epo plus G-CSF. We treated the patient with 2 mg of melphalan once a day orally, G-CSF 5 mg/kg 3 times a week and Epo 10.000 ui subcutaneously 3 times a week until the maximum response was obtained. Complete remission was achieved after 16 weeks of continuous treatment. Treatment-related toxicity was not significant. We recommend the use of low dose melphalan in elderly patients with high risk MDS as a treatment option.

Topics: Aged; Anemia, Refractory, with Excess of Blasts; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Myelodysplastic Syndromes; Remission Induction; Risk Assessment

Gelatinous transformation of the marrow (GTBM) has been associated with various conditions. We present a unique case of GTBM in a patient with myeloma following treatment with Melphalan.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Atrophy; Biopsy; Bone Marrow; Gelatin; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged

An 80-year-old man with MDS-refractory anemia (RA) suffered transformation to a leukemic state after 18 months. The karyotype of the bone marrow cells was 47, XY, +8 in 8 cells among 20 dividing cells analyzed. Combination therapy of 150 micrograms of granulocyte colony-stimulating factor (G-CSF) and 250 mg of cytarabine ocfosfate (SPAC) for 3 weeks had no beneficial effect. Then, the patient was subjected to low-dose (2 mg daily) melphalan therapy. Gradual and concurrent improvement in anemia, thrombocytopenia, and neutropenia occurred, and the patient became free of transfusions at 2 weeks after the treatment began. Since then, his performance status has improved from grade 4 on his diagnosis of AML to grade 2. Cytogenetic analysis was normal in all 20 dividing cells in the bone marrow examination and melphalan had no adverse effect. Recently, several reports of low dose chemotherapy for elderly patients or high risk leukemia have been described, and have sustained for the QOL therapy. In the present case, low-dose melphalan therapy was effective and, moreover the abnormal karyotype of trisomy eight had disappeared.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chromosomes, Human, Pair 8; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Myelodysplastic Syndromes; Trisomy

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Combined Modality Therapy; Cyclophosphamide; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Melphalan; Middle Aged; Platelet Count; Recombinant Proteins; Reproducibility of Results; Safety; Survival Rate; Transplantation, Autologous

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Blood Component Removal; Combined Modality Therapy; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multiple Myeloma; Portugal; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

Twenty adult patients with high-risk leukaemia underwent allogeneic haemopoietic stem cell transplantation after melphalan, busulphan and total body irradiation followed by short-term methotrexate and low-dose cyclosporine or tacrolimus. Three patients developed veno-occlusive disease and no patient developed renal dysfunction. Seven patients experienced grade II-IV acute graft-versus-host disease (aGVHD) and five patients experienced grade III-IV. The 3-year probabilities of relapse and leukaemia-free survival were 22 +/- 11% (95% confidence interval) and 50 +/- 11%, respectively. These data suggest that this preconditioning regimen followed by a low-dose immunosuppressant provided a more anti-leukaemic effect without increased regimen-related toxicity and aGVHD.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cyclosporine; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Tacrolimus; Whole-Body Irradiation

The risk of myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) in patients with multiple myeloma has been estimated to be 10-20% after 10 years. Most myeloma patients develop MDS/AML after 3-4 years of treatment with alkylating agents, mainly melphalan; chromosomes 5 and 7 are most frequently involved. We studied 14 patients with myeloma by fluorescence in situ hybridization (FISH) with a probe to 5q31 (the critical area of deletion on chromosome 5) to verify whether deletion of 5q31 occurs during the course of stable, uncomplicated myeloma, and to assess the clinical importance of this abnormality. We found 2 patients (14%) with deletion of 5q31 in 30-40% of their peripheral white blood cells. One patient with this deletion received a high cumulative amount of melphalan, and the other patient was treated with multiple alkylating agents, including melphalan. In these patients, no clinical or laboratory evidence of transformation occurred 14 and 12 months after the finding of the aberration. These findings suggest that 5q-may occur months prior to the overt development of (t)-MDS/AML, and raise important concerns regarding the management of patients with this and similar aberrations, including modification of treatment and performance of cytogenetic evaluation prior to autologous or PSC transplantation. The clinical and biological implications of these findings should be evaluated in larger clinical and laboratory studies.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinogens; Chromosome Deletion; Chromosomes, Human, Pair 5; Female; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Time Factors

We undertook a retrospective review of all 76 patients with AML transplanted between August 1986 and March 1995 at our center. All patients received melphalan (140-160 mg/m2), etoposide (60 mg/kg) and total body irradiation. All patients had bone marrow cytogenetic analysis at regular intervals following ABMT. The primary study end point was the development of the new cytogenetic abnormalities. Secondary end points were the development of myelodysplasia (MDS) or AML. Sixty-two of 77 patients were alive at least 6 months post transplant. Cytogenetic abnormalities developed in 7/62 patients (11%) following ABMT. No patients demonstrated MDS or AML. At a median of 30 months after development of the cytogenetic abnormality, only one patient developed features suggestive but not diagnostic of MDS. All seven patients remain alive and leukemia-free up to 70 months after detection of the abnormal clone. There was no increased incidence of cytogenetic abnormalities developing in patients receiving a purged autograft. New cytogenetic abnormalities are frequent following ABMT for AML but do not appear to predict development of myelodysplasia or acute myeloid leukemia. These abnormalities may relate to use of total body radiation as part of the high-dose therapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chromosome Aberrations; Combined Modality Therapy; Etoposide; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recurrence; Retrospective Studies; Transplantation, Autologous; Whole-Body Irradiation

Thirty children with leukemia underwent allogeneic bone marrow transplantation (BMT) following a radiation-free preparative regimen, from July 1988 to January 1996. Twelve males and 18 females, ages 9 months to 15 years (median 8.5 years), received busulfan (BU, 4 mg/kg/day for 4 days by mouth), followed by melphalan (L-PAM, 60-70 mg/m2/day i.v. for 3 days), and infusion of allogeneic marrow from an HLA-matched related donor. Diagnoses included acute myelogenous leukemia (n = 20), acute lymphoblastic leukemia (n = 8) and chronic myelogenous leukemia (n = 2). Twenty-five patients were transplanted in first complete remission (CR), three in second CR, and two patients with chronic myelogenous leukemia in the first chronic phase. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (MTX) alone in 27 patients and short-term MTX and cyclosporin A in three patients. Engraftment was achieved in all patients. Toxicities were mild or moderate. Six patients developed acute GVHD: four had grade I and two had grade II. Chronic GVHD was documented in eight patients. Three patients relapsed. As of September 1997, 27 patients were alive and well at 22-110 months (median 61) of follow-up. The disease-free survival rate at 5 years after BMT was 90%. A regimen consisting of high-dose BU and L-PAM without total body irradiation is useful for conditioning for allogeneic BMT in children with leukemia.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Female; Glucocorticoids; Graft vs Host Disease; Growth; Humans; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Methylprednisolone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous

To evaluate the clinical outcome of autologous bone marrow transplantation(ABMT) in acute leukemias.. Data of 73 acute leukemia patients performed ABMT in our hospital from October 1986 to December 1997 were retrospectively analyzed. The median age was 25.5(9-48) years. Forty-three of them were ANLL [CR1 35, CR2 or early relapse (ER)8], 30 were ALL (CR1 25, CR2 or ER 5). Conditioning regimens were CTX 120 mg/kg + STBI 9-10 Gy or Bu 16 mg/kg or Mel 160-180 mg/m2 + Ara-C 4 g/m2.. All patients engrafted successfully. The median follow-up duration was 806 (32-3400) days. The 3-year probabilities of disease-free survival (DFS) for ANLL and ALL in CR1 were 54.9 +/- 7.7% and 67.0% +/- 10.6%, respectively, and the probabilities of relapse were 39.3% +/- 9.3% and 23.7% +/- 10.6%, respectively.. To decrease relapse and increase DFS, patients with acute leukemia in CR1 who have no HLA-matched related donor are recommended for ABMT.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

A case of acute nonlymphocytic leukemia (ANLL) occurring 2 years after the diagnosis of multiple myeloma (MM) that had been treated by only one course of melphalan/prednisone chemotherapy is reported. Cytogenetic and fluorescence in situ hybridization analysis of peripheral blood cells revealed trisomy 8 as the sole cytogenetic defect at the time of diagnosis of ANLL. Two years earlier, when MM was diagnosed without any cytological evidence of co-existent myelodysplasia, chromosomal analysis of bone marrow cells showed the same pathological karyotype 47, XY, +8 in 14 of 20 mitoses studied. Our interpretation of this unusual cytogenetic finding is that at the time of diagnosis of MM, in spite of lacking cytological signs of myelodysplasia, an unrecognizable myelodysplastic syndrome must have been present which then evolved to ANLL.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chromosomes, Human, Pair 8; Disease Progression; Fatal Outcome; Follow-Up Studies; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Paraproteinemias; Prednisone; Trisomy

To explore more effective and less toxic conditioning regimen without total body irradiation for autologous bone marrow transplantation (ABMT) for acute leukemia (AL).. Twenty patients with AL were treated with ABMT, including 13 cases of acute myelocytic leukemia (AML) and 7 cases of acute lymphocytic leukemia (ALL). A median of 1.06 (range, 0.69-1.75) x 10(8) nucleated BM cells/kg was harvested and stored in normal salt solution containing heparin at 4 degrees C. The conditioning regimen (MAC) consisted of high-dose melphalan (M, 140-160 mg/m2), cyclophosphamide (CY, 120 mg/kg) and cytosine arabinoside (Ara-C, 2.0 g/m2). These 3 drugs were administered within 25 hours and the unpurged autologous marrow infusion began after another 24-hour interval.. MAC regimen could result in myeloblastic efficacy in a week. All marrow cells were reinfused within 56 hours after the harvest so that hemopoietic reconstitutions could occur in all the patients. The median time to reach a neutrophil count of > 1.0 x 10(9)/L and a platelet count of > 50 x 10(9)/L was 20 and 26 days respectively. With a median observation period of 25 months, the median duration on continuous complete remission in our patients was 22 months, and the longest reached 56 months. The median survival was 33 months, and the longest was over 6 years. The event-free survival at 2 years had reached 72%. In seven patients with leukemic relapse, six (86%) relapsed within 8 months after ABMT. The relapse rate and mortality in AML patients were significantly lower than those in ALL patients. In 7 patients with M3, relapse had not yet been observed. The nonhematologic toxic effects of MAC conditioning regimen occurred mainly in the gastrointestinal tract.. The preliminary results indicated that the ABMT using MAC conditioning regimen had some advantages in stronger antileukemic efficacy, less extrahematologic toxicity and earlier recovery of platelet and could greatly prolong the duration of remission and survival in some patients with AL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Cyclophosphamide; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We studied the pharmacokinetics and toxicity of 220 mg/m2 melphalan (HDM 220) followed by autologous stem cell transplantation in 16 patients with advanced haematological malignancies. Pharmacokinetic parameters (mean values of steady-state volume of distribution 14.6 l/m2, total body clearance 313 ml/min/m2, elimination half-life 46 min) were the same as those of 140 or 200 mg/m2 melphalan in previous reports. HDM 220 was feasible. Extramedullary toxicity was mainly W.H.O. grade 4 mucositis (13/16 patients). The median duration of 41 d (10, not reached) of thrombocytopenia < 25 x 10(9)/l was long. In multiple myeloma the response rate was 89% in heavily pretreated patients, suggesting that HDM 220 could be considered earlier in the course of the disease as an alternative consolidation therapy.

Topics: Adolescent; Adult; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Multiple Myeloma; Pilot Projects; Transplantation, Autologous

A 67-year-old woman was treated with MP-P therapy and combination chemotherapy for multiple myeloma IgG-lambda type. After the therapy for about three years, pancytopenia developed. Bone marrow aspiration study revealed a few of myeloma cell and many atypical cells showing promyelocytic feature. Chromosomal abnormality was 46, X, -X, +8, -13, +mar. CD33 and CD56 were positive, but CD16 and HLA-DR were negative. We diagnosed as multiple myeloma complicated with secondary myeloid/natural killer (NK) cell acute leukemia. After she had been treated with low dose etoposide for leukemia, she obtained complete remission. But since myeloma progressed and the amount of M protein was increased, she was treated with dexamethasone and low dose etoposide, resulting in a decrease in the amount of M protein. After that, because of leukemic cell re-proliferation, she was treated with etoposide. However, she died of sepsis due to severe myelosuppression. This case was interesting one in coexist of multiple myeloma and secondary myeloid/NK cell acute leukemia, and those affecting her clinical course each other.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Etoposide; Fatal Outcome; Female; Humans; Killer Cells, Natural; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Prednisolone

Fourteen patients with acute nonlymphoblastic leukemia (ANLL) (n = 13) or juvenile chronic myelomonocytic leukemia (n = 1) were transplanted after conditioning with high-dose busulfan (4 mg/kg daily on days -7 to -4) and melphalan (180 mg/m2 on day -2). This protocol was designed for patients considered unable to receive standard conditioning regimens with cyclophosphamide and/or TBI. Five patients (4 children and 1 adult) received a second allogeneic BMT in untreated early marrow relapse after a first BMT. There were 3 procedure-related deaths (PRD), 2 during aplasia and 1 from acute GVHD. Two patients survived the procedure; 1 relapsed at 6 months and 1 is alive at 43+ months. Nine subjects (8 children and 1 adult) received an autologous BMT, 7 in first and 2 in second complete remission (CR). Of the 7 patients grafted in first CR, there was 1 PRD, 2 relapses at 3 and 15 months, and four are alive at 38 to 82+ months. One patient grafted in second CR relapsed at 7 months and 1 is alive at 67+ months. Toxicities were mild or moderate in autologous BMT recipients, mainly affecting the gastrointestinal tract. In the allogeneic BMT group, there were more moderate to severe toxicities, including 3 cases of moderate-severe renal toxicity; no cases of such toxicity were seen in ABMT recipients. Two cases of HVOD occurred, 1 in each group. These results are encouraging, although the small patient group does not allow any firm conclusions.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Melphalan

We conducted a phase II study on 19 children with AML in first (10 patients) or second (nine patients) complete remission (CR) treated with ABMT, evaluating the combination of total body irradiation (TBI, 12 Gy in six divided fractions) and high-dose melphalan (140 mg/m2 in single dose) in an attempt to improve antitumour efficacy of conditioning regimen. All patients received cryopreserved and in vitro purged (mafosfamide at a dose of 100 micrograms/ml) bone marrow. The median time from first CR to ABMT was 5 months compared with a median time of 3 months for patients in second remission. One of the 19 patients, transplanted in second CR, died of transplant-related complication 10 days after transplant and another second CR patient relapsed on day +28, before engraftment. Three further patients in second CR relapsed at 6, 6 and 18 months after marrow transplant, respectively, and this determined a relapse rate of 43% in children given ABMT in second CR and 0% for patients transplanted in first remission (P < 0.05). Seventy-two per cent of all patients are projected to be alive and disease-free at 6 years, whereas the event-free survival of patients in first and in second CR is 100 and 44%, respectively (P < 0.05). Although the number of patients does not allow us to draw any firm conclusion, our results are encouraging and suggest that the association of TBI and high-dose melphalan appears to be safe and valuable.

Topics: Adolescent; Bone Marrow Transplantation; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Over a follow-up period of ten years, nine of our 100 patients with multiple myeloma (MM), developed myelodysplastic syndrome (MDS, preleukaemia). MDS occurred 19-156 (median 35) months from the diagnosis of MM. Six patients presented with pancytopenia and no patients had active MM at the time of MDS diagnosis. Three patients were defined as having refractory anaemia (RA) and six as refractory anaemia with excess blasts (RAEB) or RAEB in transformation (RAEBT), according to the FAB classification. The clinical course is characterized by increasing red blood cell and platelet transfusion requirements, recurrent infections and bleeding episodes. All patients, except for one, died within 3 to 8 (median 5) months from MDS diagnosis. The causes of death were sepsis or bleeding; three patients underwent leukaemic transformation. Thus, the clinical course of this small group of myeloma patients who developed secondary MDS (sMDS), was similar to other series of patients with sMDS. Serial bone marrow examinations suggest an initial hypercellular phase, followed by a rapidly evolving preterminal hypocellular marrow. In an attempt to detect MM patients at risk of developing sMDS, the epidemiological (including ethnic), clinical and laboratory data of the 9 MDS patients at the time of the MM presentation were reviewed and compared to the other MM patients. No significant differences were observed between the two groups in most parameters, except for two. All MDS patients were Ashkenazi Jews and no patients of Sepharadic origin developed MDS. Also, no IgA-myeloma patient developed MDS. If these findings are confirmed in a larger series, it may point to subgroups at risk which may require a different approach.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Female; Humans; Israel; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Pancytopenia; Prednisone; Risk Factors

The aim of this paper was to present the results of bone marrow harvest followed by cryopreservation in 22 children with various malignant diseases, and the clinical course of autologous bone marrow transplantation (ABMT) performed in 10 children (three with acute lymphoblastic leukemia (ALL), three with acute myeloblastic leukemia (AML) and four neuroblastoma stage IV (NB)). In 20/22 children the harvested bone marrow contained a sufficient number of granulocyte-macrophage-colonyforming units (GM-CFU) for later marrow reinfusion. Hematological reconstitution was obtained in all 10 children who underwent ABMT. No child died of toxicity. The median time to neutrophil count > 0.5 x 10(9)/l, thrombocyte count > 50 x 10(9)/l and to discharge from hospital were 34, 49 and 29 days respectively. Five children are alive with no evidence of active disease 11-21 months after ABMT. Five children have suffered relapse and have died. It was concluded that sufficient amounts of precursor bone marrow cells may be harvested in children during a pause in cystostatic therapy. The acute toxicity of ABMT in children with malignant diseases was only moderate.

Topics: Adolescent; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Child; Cryopreservation; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Melphalan; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous

This study aimed to evaluate the effect of melphalan on both terminal divisions and self-renewal capacity of acute myeloblastic leukemia (AML) progenitors (colony-forming units, CFU-L) grown in methylcellulose. Terminal divisions and self-renewal were assayed by primary (PE1) and secondary (PE2) colony formation, respectively. Thirteen cases of AML, were tested. Melphalan induced a negative exponential dose-effect on CFU-L survival. Moreover, melphalan was equally effective in inhibiting CFU-L growth in both PE1 and PE2 assays, with D10 values of 1.53 +/- 0.17 micrograms/ml and 1.59 +/- 0.21 micrograms/ml for PE1 and PE2, respectively (p = 0.48). Cytotoxicity of melphalan on CFU-L did not differ significantly from that observed for normal hemopoietic granulocyte-macrophage colony-forming units, erythroid burst-forming units, and granulocyte-erythroid-macrophage-megakaryocyte progenitors. Mafosfamide-lysine, a stable cyclophosphamide congener, strongly inhibited primary colony formation (PE1) with a D10 value of 14.46 +/- 1.76 micrograms/ml, but was much less efficient in the PE2 assay. Our findings suggest that the self-renewal capacity of AML progenitors can be differentially affected by alkylating agents. Moreover, since it is now considered that chemotherapy should be preferentially directed against the self-renewal of leukemic progenitors, melphalan might offer a greater potential than cyclophosphamide or cyclophosphamide derivatives in the therapy of AML.

Topics: Antineoplastic Agents; Cell Division; Cell Survival; Cyclophosphamide; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Melphalan; Neoplastic Stem Cells; Tumor Cells, Cultured; Tumor Stem Cell Assay

Few studies have evaluated the late effects of adjuvant chemotherapy for breast cancer. Moreover, the relation between the risk of leukemia and the amount of drug given and the interaction of chemotherapy with radiotherapy have not been described in detail.. We conducted a case-control study in a cohort of 82,700 women given a diagnosis of breast cancer from 1973 to 1985 in five areas of the United States. Detailed information about therapy was obtained for 90 patients with leukemia and 264 matched controls. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose, 7.5 Gy).. The risk of acute nonlymphocytic leukemia was significantly increased after regional radiotherapy alone (relative risk, 2.4), alkylating agents alone (relative risk, 10.0), and combined radiation and drug therapy (relative risk, 17.4). Dose-dependent risks were observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk, 31.4 vs. 3.1). There was little increase in the risk associated with total cyclophosphamide doses of less than 20,000 mg.. Although leukemia occurs in few patients with breast cancer, significantly elevated risks were linked to treatments with regional radiation and alkylating agents. Melphalan is a more potent leukemogen than cyclophosphamide or radiotherapy. Low risks were associated with the levels of cyclophosphamide in common use today. Systemic drug therapy combined with radiotherapy that delivers high doses to the marrow appears to enhance the risk of leukemia.

Topics: Aged; Alkylating Agents; Breast Neoplasms; Case-Control Studies; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Melphalan; Middle Aged; Myelodysplastic Syndromes; Radiotherapy; Radiotherapy Dosage; Risk

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Graft vs Host Disease; Histocompatibility; Humans; Leukemia, Myeloid, Acute; Life Tables; Lymphocyte Depletion; Melphalan; Remission Induction; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

A 71-year-old man was hospitalized in November, 1983 for a back pain and a diagnosis of multiple myeloma was made, based on the Bence Jones proteinuria, The serum M-component of a IgG-kappa type (3.3 g/dl), and plasmacytosis in the bone marrow (37%). Treatment consisted of melphalan and prednisolone. A blood count in March, 1986 revealed 6000/microliters of WBC with 30% of a blast form and 8% plasma cells, and 20,000/microliters of platelets. A bone marrow aspirate revealed that 14% were myeloblasts and 26% were plasma cells. Distinguishing the myeloblasts from the immature plasma cells in the peripheral blood proved difficult. Studies by electron microscopy and an immunological inspection of phenotypes were helpful in achieving a determination. A karyotypic analysis of the bone marrow cells indicated a hypodiploid cell population, a marker chromosome, and a karyotypic instability. These findings indicate that his multiple myeloma had undergone a leukemic change associated with acute myelogenous leukemia.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunoglobulin G; Immunoglobulin kappa-Chains; Karyotyping; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Myeloma Proteins; Polyploidy; Prednisone

A 54-year-old man was admitted to our hospital for precise examination of pancytopenia in October 1988. He had been cut off his left femur and irradiated because of osteosarcoma in 1954. After 30 years, he was diagnosed as Waldenström's macroglobulinemia. Melphalan had been given 2 mg daily for 19 months until August 1988, when it was discontinued due to pancytopenia. Peripheral blood showed Hb 6.6 g/dl, platelet 40 x 10(3)/microliters, and WBC 2000/microliters with 33% blasts. Bone marrow showed normocellularity with 36% blasts. Although blasts were negative for peroxidase staining, surface marker analysis revealed myeloid (CD 13, CD 33) phenotypes. Chromosome analysis showed 45, XY, -7, inv (3). A CT scan of the liver showed a mass, 10 by 10 cm, compatible with hepatocellular carcinoma. He was treated with very low dose Ara-C without noticeable effect. Hepatic tumor gradually enlarged, and he died of hepatic failure. This is a rare case of quadruplicate malignancies. The chromosomal abnormality suggests that AML was secondary leukemia which might be associated with immunosuppression due to macroglobulinemia and/or melphalan therapy.

Topics: Carcinoma, Hepatocellular; Femoral Neoplasms; Humans; Leukemia, Myeloid, Acute; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Osteosarcoma; Waldenstrom Macroglobulinemia

We followed up 153 patients with biopsy-proven primary systemic amyloidosis to determine their risk for acute nonlymphocytic leukemia or a dysmyelopoietic syndrome. In 10 patients cytogenetic abnormalities developed consistent with alkylator-induced damage to hematopoietic cells. In this group, the total melphalan dose ranged from 476 to 2450 mg (median, 1764 mg) administered over 21 to 92 months (median, 38 months). Eight of the 10 patients died as a direct result of pancytopenia, 1 died of progressive renal amyloid, and 1 remains alive with persistent complex cytogenetic abnormalities. Four patients had acute nonlymphocytic leukemia; 5 had a dysmyelopoietic syndrome; and 1 had a nondiagnostic bone marrow examination. Although only 6.5% of the entire group had leukemia or a dysmyelopoietic syndrome, the actuarial risk in patients surviving 3.5 years was 21%. Median survival from onset of dysmyelopoietic syndrome or acute leukemia was 8.1 months.

Topics: Aged; Amyloidosis; Chromosome Aberrations; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Risk Factors; Survival Rate; Time Factors

We report three pregnancies with successful outcomes in two women following allogeneic bone marrow transplantation (BMT) for acute leukaemia using high dose melphalan alone as conditioning therapy. The increasing application and success of BMT together with the instigation of conditioning regimens that do not include total body irradiation should increase such cases. These and previous cases document that a normal outcome of pregnancy is likely in these patients.

Topics: Adult; Bone Marrow Transplantation; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Pregnancy; Pregnancy Complications, Neoplastic; Remission Induction

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Ovarian Neoplasms

The cytogenetic findings in 11 patients with multiple myeloma in whom a myelodysplastic syndrome or an acute nonlymphocytic leukemia developed are reported. All patients were treated with oral melphalan for 2-9 years in a total dose of 0.5-4.1 g. When examined during the myelodysplastic or leukemic phase, all patients had an abnormal bone marrow karyotype, hypodiploid in nine of the 11 cases. The chromosome abnormalities were clearly nonrandom and comprised a 5q deletion in three cases, monosomy 5 in four cases, deletion 7q--in two cases, and monosomy 7 in three cases. Loss of material from the long arm of chromosomes 5, 7, or both was found in eight patients. The different chromosome abnormalities were not associated with any specific morphological or clinical features.

Topics: Aged; Chromosome Aberrations; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes

A 40-year-old man who developed acute myelomonoblastic leukemia (M4) after 7 years of treatment for multiple myeloma with the alkylating agent melphalan and steroids is presented. Leukemia was treated with courses of adriblastin, cytosine arabinoside, and thioguanin (DAT protocol), with a 8 months' survival.

Topics: Adult; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma

Five cases of hypoplastic acute myelocytic leukemia were treated with an IgG-melphalan conjugate, K-18. Eight tablets of K-18, containing 30 mg per tablet, were given daily. One patient, a 68-year-old female, obtained complete remission with a duration of 1.5 + months. Among the four remaining patients without remission, one showed a decrease in leukemic cells in the peripheral blood. No side effects of K-18 were observed except in one patient, showing a slight increase in serum GOT and GPT levels. Further studies with a large group will be necessary to clarify the effect of this drug on hypoplastic leukemia.

Topics: Administration, Oral; Aged; Drug Combinations; Female; gamma-Globulins; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Remission Induction; Tablets

Eleven children between the ages of 1 and 16 years with acute non-lymphoblastic leukemia (ANLL) in first remission were included in a study of double unpurged autologous bone marrow transplantation (ABMT). Prior to each ABMT patients received massive chemotherapy with melphalan at a dosage of 140 mg/m2. The first ABMT was done within a median of 4 months after the achievement of complete remission. As soon as the children had adequate hematologic recovery, a second marrow collection was done, followed by a second course of melphalan and a second ABMT. The duration of aplasia was significantly longer after the second ABMT than after the first, but the non-hematologic toxicity was relatively mild in each case and no patient died from the procedure. Four patients relapsed and seven are alive in unmaintained complete remission with a median duration of leukemia-free survival of 29 months (range 15-56 months) after the first ABMT. These data demonstrate the feasibility of repeating ABMT after melphalan in children with ANLL. The eventual impact of such therapy needs to be demonstrated in prospective randomized studies.

Topics: Adolescent; Bone Marrow; Bone Marrow Transplantation; Child; Child, Preschool; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoiesis; Humans; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Recurrence; Remission Induction; Transplantation, Autologous

A form of liver injury characterized by bile ductule-like transformation of hepatocytes, prominent hemosiderin deposition and fibrosis, was occasionally encountered in autopsy cases we examined during the period from 1973 to 1981. It was found that this liver injury was irreversible and intimately related to combination chemotherapy with the DCMP regimen (daunorubicin, cytosine arabinoside, 6MP and prednisolone) for acute non-lymphocytic leukemia (ANLL). Its correlation was reconfirmed by the fact that this liver injury disappeared after withdrawal of the DCMP regimen in 1981. After 1978, the regimen of combination chemotherapy for adult ANLL was partly changed, 6-thioguanine being utilized (DCTP) instead of the 6MP in the DCMP regimen. The hepatic injury occurring after the change in the regimen was different from that produced with DCMP, showing reversible intrahepatic cholestasis. These facts indicated that substitution for one drug in a combination chemotherapy regimen could cause a different type of hepatic change.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Liver; Melphalan; Prednisolone; Prednisone; Thioguanine

Clinical effects of a low dose of behenoyl ara-C (LD-BHAC) and K-18, an IgG-melphalan conjugate, were studied in hypoplastic leukemia (HL). Among 8 cases of HL treated with LD-BHAC regimen, in which 50 mg BHAC was administered daily by one-hour drip infusion for 14 days, 4 achieved complete remission (CR) and 2, partial remission (PR). The response rate (CR + PR) was 75%. Hematological toxicities were observed in most of the cases. The peak level of serum ara-C concentration, 3.62-18.9 ng/ml (mean: 11.74 ng/ml), was observed at cessation of infusion, and an ara-C level of 2.75-48.9 ng/ml (mean: 3.45 ng/ml) was still present in the blood 6 hours after cessation of infusion. Six cases of HL were treated with K-18. Eight tablets of K-18, containing 30 mg per tablet, were given daily. Two of 6 cases achieved CR with little hematological toxicities. LD-BHAC and K-18 can be expected in the treatment of hypoplastic leukemia and its related diseases such as hypoplastic preleukemia in the aged.

Topics: Adult; Aged; Antineoplastic Agents; Cytarabine; Drug Evaluation; Humans; Immunoglobulin G; Immunotoxins; Infusions, Intravenous; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Preleukemia

The sensitivity of myeloid leukaemic colony forming cells (AML-CFC), to five cytotoxic drugs has been compared in two culture systems with the sensitivity of normal myeloid progenitor cells (GM-CFC). No increased sensitivity was found for AML-CFC to any of the chemotherapeutic agents studied. AML-CFC were significantly less sensitive than normal GM-CFC to mafosfamide at the doses commonly used to purge bone marrow autografts. It is suggested that AML cells probably display similar sensitivity to cytotoxic agents as normal myelopoietic cells at a similar stage of differentiation. Hence complete elimination of the leukemic clone by pharmacological purging may be incompatible with bone marrow re-engraftment. We conclude that purging AML autografts with any of the agents examined has little scientific basis.

Topics: Antineoplastic Agents; Bone Marrow; Bone Marrow Transplantation; Cell Survival; Clone Cells; Cyclophosphamide; Cytarabine; Etoposide; Granulocytes; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Melphalan; Transplantation, Autologous; Tumor Cells, Cultured

Three cases of secondary leukemia developing after chemotherapy and/or radiotherapy for myeloma, mycosis fungoides, and non-Hodgkin's lymphoma are reported. The first case was a 51-year-old man with IgG-lambda myeloma, treated with melphalan and prednisolone, who developed acute myelomonocytic leukemia 54 months after the diagnosis of myeloma. The second case was a 54-year-old woman with mycosis fungoides treated with radiation, predonine, and cyclophosphamide, who developed acute megakaryoblastic leukemia 298 months after the diagnosis of mycosis fungoides. The third case was a 35-year-old woman with stage IV non-Hodgkin's lymphoma treated with VEMP who developed acute myelogenous leukemia 26 months after the diagnosis of malignant lymphoma. All cases showed pancytopenia and two of three cases had morphologic abnormality in several hemopoietic cell lineages in the leukemic stage. There is a possibility that second malignancies are an increasingly recognized complication in the patients treated with a large amount of chemo-radiotherapy.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Megakaryoblastic, Acute; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Lymphoma, Non-Hodgkin; Male; Melphalan; Mercaptopurine; Middle Aged; Multiple Myeloma; Mycosis Fungoides; Pancytopenia; Prednisolone; Vincristine

Topics: Animals; Hematopoietic Stem Cells; Leukemia, Myeloid, Acute; Melphalan; Mice; Mice, Inbred BALB C; Neoplasms, Multiple Primary; Plasmacytoma

Several large cohorts of patients treated with alkylating agents served as a means to review the clinical and pathologic features of 55 cases of myelopathic disorders that resulted. The incidence was 1.8% overall and consisted of five patients (9.9%) who developed bone marrow hypoplasia or aplasia, 15 (27.2%) who developed a myelodysplastic syndrome, and 35 cases of acute myeloid leukemia (62.9%). The median time to recognition of MPD was 14 months, following cessation of chemotherapy. The distribution of the treatment-related MDS cases was different than "de novo" MDS with a high percentage of RAEB-T, and with the treatment related AMLs, there were a higher percentage of patients with FAB M6 (erythroleukemia), and no cases of FAB M3 (hypergranular promyelocytic). The median survival of all patients was very brief.

Topics: Adolescent; Adult; Aged; Alkylating Agents; Anemia, Aplastic; Child; Child, Preschool; Chlorambucil; Cyclophosphamide; Female; Gastrointestinal Neoplasms; Humans; Infant; Karyotyping; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Ovarian Neoplasms

We report in a 40 year-old woman a bifocal mammary and vertebral plasmocytoma attended by surgery and "preventive" chemotherapy. Eight years later, an acute and apparently non secondary myeloblastic leukemia is observed without sign of diffuse myelomatosis. Plasma cell tumors of the breast are uncommon. Eleven cases have been published, combining solitary plasmocytoma and infiltration occurring in multiple myeloma.

Topics: Adult; Breast Neoplasms; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Neoplasms, Multiple Primary; Plasmacytoma; Spinal Neoplasms; Time Factors

Experience with 19 autologous bone marrow transplantations shows that this approach may produce a high proportion of complete remissions in otherwise resistant tumours. Although most responses are of short duration, they suggest that longterm disease-free survival may be achieved in patients with poor prognosis if treated earlier in the course of disease.

Topics: Adult; Bone Marrow Transplantation; Child; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Melphalan; Middle Aged; Postoperative Complications; Remission Induction

Topics: Alkylating Agents; Chromosome Aberrations; Ethics, Medical; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Prognosis

Topics: Adult; Female; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Time Factors

High-dose melphalan followed by "rescue" with autologous marrow stored for 12-24 hours at room temperature was used in the treatment of 14 patients with advanced tumors refractory to conventional treatment. Twelve patients were evaluable, with three complete responses (25%), five partial responses (42%), and two minimal responses (16%). Response durations ranged from 4 to 38 weeks (median, 7). There were two treatment-related deaths and one patient developed acute nonlymphocytic leukemia 3 months after a second course of high-dose melphalan.

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Neoplasms; Neutropenia

Dissociated cancer cells are exposed to antineoplastic drugs (5 X 10(4) viable cells/drug for 1 hr or continuously) and cultured for 4 to 6 days in liquid medium. Cells are then stained with Fast green dye, sedimented onto slides with a Cytospin centrifuge, and counterstained with a modified hematoxylin and eosin technique. Dead cells stain with Fast green, and living cells stain with hematoxylin and eosin. Cell kill is calculated as percentage of control based on the relative numbers of living tumor cells, living non-tumor cells, and dead cells. Drug sensitivity could be assayed in 125 of 162 specimens of human neoplasms obtained from malignant effusions (16 of 18), excisional biopsies (31 of 44), needle biopsies (34 of 47), endoscopic biopsies (18 of 23), peripheral blood samples (19 of 20), and bone marrow aspirates (five of seven). The assays were successful (median of ten drugs tested) in: 46 of 64 adenocarcinomas; four of 11 squamous cell carcinomas; five of seven lymphomas; six of seven melanomas; two of four sarcomas; 18 of 20 transitional-cell carcinomas; 14 of 15 small-cell carcinomas; seven of eight myelomas; 12 of 12 chronic lymphocytic leukemias; seven of nine acute leukemias, and four of five "undifferentiated" carcinomas. The assay results demonstrated a strong correlation between the in vitro chemosensitivity of different types of tumors and the known clinical response patterns of these tumors. This assay can be used to determine which specific cells are killed in a heterogeneous cell population. Further work is needed to determine if this assay may be useful in blind screening trials for antineoplastic agents or if it may be of clinical use in predicting response to agents which are not cycle specific.

Topics: Antineoplastic Agents; Cell Line; Cell Survival; Doxorubicin; Drug Evaluation, Preclinical; Eosine Yellowish-(YS); Etoposide; Fluorouracil; Hematoxylin; Humans; Leukemia, Myeloid, Acute; Mechlorethamine; Melphalan; Neoplasms; Staining and Labeling

Therapy of solid and hematologic tumors with alkylating agents appears to increase the frequency of acute non-lymphocytic leukemia (ANLL), as indicated by the cases reported in the literature. The carcinogenetic mechanism of alkylating agents seems related to their ability to damage DNA, and this is supported by the findings of multiple cytogenetic abnormalities in these patients. We report a case of ANLL secondary to therapy with melphalan, which was utilized on an adjuvant basis for breast cancer. ANLL developed 24 months after chemotherapy was discontinued. Results of the cytogenetic analysis in our patient showed multiple rearrangements and marker chromosomes. Among these was a large metacentric chromosome, identified in 6 of 8 karyotypes, in the size range of group A, which probably resulted from a translocation t(7;14) (7qter leads to 7p11::14p11 leads to 14qter). The natural history of the underlying disease and of the ANLL in our patient and data from chromosomal analysis seem to confirm the hypothesis that alkylating agents are potentially leukemogenic in man, probably through genetic damage. This possibility should be considered when such cytotoxic drugs are used in an adjuvant setting.

Topics: Breast Neoplasms; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Melphalan; Middle Aged

Topics: Adult; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Time Factors

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Leukopenia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Vincristine

The patients entered into the Medical Research Council's First Myelomatosis Trial (MRCI) have been followed up for a minimum of 12 years, and an attempt has been made to define features recorded at presentation that might predict long-term survival and to estimate the risk of acute myeloid leukaemia (AML) induced by treatment with either of the alkylating agents, melphalan or cyclophosphamide. In this series, the chance of a patient surviving 5 years was strongly related to the haemoglobin, blood urea concentration (BUC) and performance status at presentation. Other features, including paraprotein levels, type of heavy or light chain, bone lesions and recovery of polyclonal immunoglobulin added little useful information. Six patients died of AML, all after more than 4 years in the trial; the incidence of AML among 4-year survivors was 10%. All six patients had been treated with continuous melphalan and the implications of this for future chemotherapy for myelomatosis are discussed.

Topics: Aged; Bence Jones Protein; Cyclophosphamide; Female; Hemoglobins; Humans; Immunoglobulin G; Kidney Failure, Chronic; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Paraproteins; Prognosis; Time Factors; Urea

Topics: Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Multiple Myeloma

Topics: Aged; Bone Marrow; Humans; Leukemia, Myeloid, Acute; Male; Melphalan

A 67-year-old woman suffered from an ovarian carcinoma with lymph nodes metastasis. During 3 years, she was treated with alkylating agents (Melphalan). At the end of therapy, no recurrence was observed. Two years later, she developed concomitantly pyoderma gangrenosum and acute myelomonocytic leukaemia. Death occurred rapidly. The association between pyoderma gangrenosum and acute leukaemia is discussed in the light of 16 cases previously reported in the literature. In this case, an induction of leukaemia by cytostatic drugs seems likely. The authors conclude that pyoderma gangrenosum may be considered as a cutaneous signs of acute leukaemia.

Topics: Aged; Cystadenocarcinoma; Female; Humans; Leukemia, Myeloid, Acute; Lymphatic Metastasis; Melphalan; Ovarian Neoplasms; Pyoderma

During the years 1966-1973 474 patients with ovarian carcinoma were treated with melphalan. Of these, 48 patients received at least 300 mg melphalan and survived at least 3 years; four cases of acute leukemia were found among these 48 patients. All cases belonged to a group of 12 cases receiving 800 mg melphalan or more.

Topics: Acute Disease; Aged; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Ovarian Neoplasms; Time Factors

Topics: Aged; Breast Neoplasms; Diagnostic Errors; Female; Humans; Leukemia, Myeloid, Acute; Mastectomy; Melphalan

Topics: Adult; Breast Neoplasms; Female; Humans; Leukemia, Myeloid, Acute; Mastectomy; Melphalan; Recurrence

Topics: Bone Neoplasms; Cyclophosphamide; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Time Factors

The unsaturated B12 binding capacity (UBBC) of the serum and the binding capacity of each of the 3 vitamin B12 binders--the transcobalamins (TC) I, II and III were determined in 21 patients with polycythaemia vera (PV) during the course of the disease and following treatment, using the recently described charged cellulose filter technique. High serum UBBC due to elevated serum TCIII was found in all patients. TCI was moderately elevated in patients who had leucocytosis with a shift to the left. The changes in serum TCIII and UBBC correlated with the activity of the disease. Chemotherapy resulted in a decrease in TCIII and UBBC. The decrease in TCIII and UBBC folowing chemotherapy may be observed before a decrease in the haematocrit and the leucocyte count occurs. Activation of the disease may be assessed by the elevation of TCIII and UBBC. The onset of acute myeloblastic crisis in 1 patient was associated with a decrease in TCIII and TCI levels and a rise in serum TCII. The determination of TCIII and UBBC may be helpful in differentiating true from secondary polycythaemia.

Topics: Blood Proteins; Busulfan; Humans; Leukemia, Myeloid, Acute; Melphalan; Polycythemia Vera; Protein Binding; Transcobalamins; Vitamin B 12

Of 476 patients with multiple myeloma treated during a 9-year period, 11 developed acute myelogenous leukemia or sideroblastic anemia. In all, the myeloma was in remission from chemotherapy with melphalan-prednisone combinations that had been continued for a median duration of 3 years. The incidence of acute leukemia or sideroblastic anemia was about 100 times higher than found in normal individuals of the same age. In all patients studied, major cytogenetic abnormalities were present, with hypodiploidy and evidence of chromosomal damage being noted most frequently. The frequency and nature of the chromosome changes were attributed to effects resulting from the prolonged drug therapy. These findings supported the long-term follow-up of selected patients with myeloma without any chemotherapy when marked degrees of remission followed the initial treatment courses.

Topics: Aged; Chromosomes; Diploidy; Female; Humans; Leukemia, Myeloid, Acute; Long-Term Care; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission, Spontaneous

To estimate the leukemogenic potential of alkylating agents, we surveyed 70 institutions using these drugs for the frequency of second cancers in patients with advanced ovarian cancer. Thirteen cases of acute nonlymphocytic leukemia occurred among 5455 patients, as compared to 0.62 cases expected (relative risk = 21.0). All 13 had received alkylating agents. Nine also received radiotherapy. The relative risk for patients given chemotherapy was 36.1 and rose to 171.4 for those surviving for two years (rate = 13.75 per 1000 patients per year). To evaluate the role of therapy versus underlying disease, a historical control of 13,309 patients with ovarian cancer in the National Cancer Institute's End Results Program was analyzed. No excess of leukemia was noted in this group, even among 6596 women receiving radiation. The excess of acute nonlymphocytic leukemia, therefore, appears attribute to alkylating agents, although the effect may be enhanced by exposure to radiation, as previously suggested for Hodgkin's disease.

Topics: Acute Disease; Alkylating Agents; Altretamine; Chlorambucil; Cyclophosphamide; Female; Fluorouracil; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Risk; Thiotepa; Time Factors; Uracil Mustard

Topics: Aged; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Thalassemia

Topics: Asparaginase; Child; Cyclophosphamide; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous; Rhabdomyosarcoma; Teniposide; Thioguanine; Vincristine; Wilms Tumor

A patient with multiple myeloma died of an acute myeloid leukaemia 15 years after onset of the former. At time of diagnosis the 39 year-old-patient had bone marrow infiltration of maximally 32 plasma cells/100 white bone marrow cells, a paraprotein (IgG, light-chain type lambda), osteoporosis of late onset and occasional osteolysis. The long survival time, as well as the acute myeloid leukaemia, are probably due to the effective treatment, first with cyclophosphamide (198 g over four years), later melphalan (3000 mg over eight years).

Topics: Cyclophosphamide; Humans; Immunoglobulin G; Leukemia, Myeloid, Acute; Long-Term Care; Male; Melphalan; Middle Aged; Osteoporosis; Plasmacytoma; Time Factors

Topics: Adult; Female; Humans; Leukemia, Myeloid, Acute; Melanoma; Melphalan; Neoplasms, Multiple Primary

Report on a 74-year-old patient who developed acute myeloid leukemia 16 months after diagnosis of IgA paraproteinemia. He had received a total dose of 1.4-1.5 g melphalan. The possible etiologic role of melphalan in the development of acute leukemia is discussed.

Topics: Aged; Blood Protein Disorders; Blood Protein Electrophoresis; Humans; Immunoglobulin A; Leukemia, Myeloid, Acute; Male; Melphalan; Time Factors

Topics: Carmustine; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Prednisone

Topics: Aged; Anemia, Sideroblastic; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma

Chromosomal findings are reported in three patients with acute myelomonocytic leukemia and in one with reticulosarcoma leukemia who had been treated for multiple myeloma with melphalan and X-ray. All four patients had striking chromosomal anomalies. An iatrogenic causation of aneuploidy is suggested. This is supported by chromosomal findings in patients with acute leukemia following polycythemia vera and Hodgkin's disease; practically all of the leukemias have been aneuploid. A comparison is made of such "secondary" acute leukemias with "primary" acute leukemias that are aneuploid in only 40% of the cases. Chromosomal changes are not considered to be the initial event in leukemogenesis.

Topics: Aneuploidy; Chromosome Aberrations; Female; Humans; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Multiple Myeloma; X-Rays

Topics: Aged; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Prednisolone; Procarbazine; Vincristine

Topics: Bone Marrow Examination; Humans; Immunoglobulins; Leukemia, Myeloid, Acute; Leukocytes; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins

Topics: Animals; Antineoplastic Agents; Biological Assay; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Models, Animal; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Fluorouracil; Hodgkin Disease; Humans; Leukemia; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Mechlorethamine; Melphalan; Mice; Mice, Inbred AKR; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Remission, Spontaneous; Vinblastine; Vincristine

Topics: Adult; Aged; Alkylating Agents; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma

Topics: Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma

Topics: Amyloidosis; Blood Cell Count; Blood Platelets; Blood Transfusion; Bone Marrow Examination; Cephalothin; Cytarabine; Erythrocytes; Gentamicins; Hemoglobins; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Proteinuria; Thioguanine

Topics: Anemia, Sideroblastic; Bone Marrow Examination; Cytarabine; Female; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulins; Iron; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Mercaptopurine; Middle Aged; Multiple Myeloma; Muramidase; Precancerous Conditions; Prednisone; Staining and Labeling; Vincristine

Topics: Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Mercaptopurine; Middle Aged; Multiple Myeloma

Topics: Female; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Multiple Myeloma; Urethane

Topics: Aged; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma

Topics: Bence Jones Protein; Cyclophosphamide; Humans; Immunoglobulin A; Immunoglobulin G; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Sarcoma

Topics: Adult; Aged; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Urethane

Topics: Antineoplastic Agents; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Radiotherapy

Topics: Cytarabine; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Remission, Spontaneous

Topics: Acute Disease; Aged; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Multiple Myeloma

Topics: Adult; Bronchopneumonia; Cytarabine; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Plasmacytoma; Thioguanine

Topics: Aged; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma

Topics: Aged; Autopsy; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged

Topics: Aged; Amyloidosis; Bone Marrow; Bone Marrow Examination; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Time Factors

Topics: Bone Marrow; Cyclophosphamide; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma

Topics: Antineoplastic Agents; Asparaginase; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Cytarabine; Dactinomycin; Daunorubicin; Female; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Melphalan; Mercaptopurine; Methotrexate; Prednisone; Pregnancy; Vincristine; Wilms Tumor