melphalan and Myelodysplastic-Syndromes

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

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.

Topics: Adult; Aged; Allografts; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Predictive Value of Tests; Stem Cell Transplantation; Survival Rate; Telomere; Telomere Homeostasis; Transplantation Conditioning

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

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

Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.

Topics: Aged; Aged, 80 and over; Biomarkers; Endothelial Cells; Humans; Lenalidomide; Leukemia, Myelomonocytic, Chronic; Melphalan; Middle Aged; Myelodysplastic Syndromes; Neovascularization, Pathologic; Prospective Studies; Thalidomide; Vascular Endothelial Growth Factor A

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

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

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

To observe the efficacy and side-effects of low-dose melphalan for the treatment of intermediate- to high-risk myelodysplastic syndromes (MDS) patients.. Thirty patients with intermediate- to high-risk MDS received oral melphalan at a daily dose of 2 mg. The melphalan therapy was continued until marrow blasts increased or severe cytopenia attributed to melphalan. Patients achieved complete remission (CR) or partial remission (PR) were still maintained with melphalan until disease relapse.. Among the 30 patients, 9 (30.0%) achieved CR, 3 (10.0%) PR, 3 (10.0%) bone marrow complete remission and hematology improvement (MCR + HI), 1 (3.3%) MCR, 4 (13.3%) stable disease and 10 (33.3%) no response, the overall response rate being 66.7% according to the Modified International Working Group Response Criteria for MDS. The CR plus PR rate (60.0%) and total response rate (80.0%) in patients with normocellular or hypocellular bone marrow were significantly higher than in those with hypercellular bone marrow (0.0%, 40%, respectively) (P = 0.002 and 0.045, respectively). Median overall survival (OS) and median relapse-free survival (RFS) were 18 (95% CI 14-22) and 11 (95% CI 3-19) months, respectively. There was no side-effect except for slight marrow suppression in 3 patients and one patient died from brain hemorrhage on inefficacy of platelet transfusion.. Low-dose melphalan therapy for intermediate- to high-risk MDS patients is safe and effective, especially suitable for elderly patients with hypocellular marrow.

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Treatment Outcome; Young Adult

We investigated the hypothesis that gemtuzumab ozogamicin (GO), an anti-CD33 immunotoxin would improve the efficacy of fludarabine/melphalan as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. Toxicity was defined as grades III-IV organ damage, engraftment failure or death within 30 days. 'Response' was engraftment and remission (CR) on day +30. We sought to determine the GO dose (2, 4 or 6 mg m(-2)) giving the best trade-off between toxicity and response. All patients were not candidates for myeloablative regimens. Treatment plan: GO (day -12), fludarabine 30 mg m(-2) (days -5 to -2), melphalan 140 mg m(-2) (day -2) and HSCT (day 0). GVHD prophylaxis was tacrolimus and mini-methotrexate. Diagnoses were AML (n=47), MDS (n=4) or CML (n=1). Median age was 53 years (range, 13-72). All but three patients were not in CR. Donors were related (n=33) or unrelated (n=19). Toxicity and response rates at 4 mg m(-2) were 50% (n=4) and 50% (n=4). GO dose was de-escalated to 2 mg m(-2): 18% had toxicity (n=8) and 82% responded (n=36). 100-day TRM was 15%; one patient had reversible hepatic VOD. Median follow-up was 37 months. Median event-free and overall survival was 6 and 11 months. GO 2 mg m(-2) can be safely added to fludarabine/melphalan, and this regimen merits further evaluation.

Topics: Adolescent; Adult; Aged; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Gemtuzumab; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Sialic Acid Binding Ig-like Lectin 3; Survival Rate; Transplantation, Homologous; Vidarabine

In the current study, we have analyzed the efficacy of cyclosporine A (CSA) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis in the fludarabine plus melphalan or busulfan reduced intensity regimen (RIC) setting in a series of 44 patients receiving allogeneic transplantation from an unrelated donor. Only 23% were in the first complete remission at the time of transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD (aGVHD) was 53% and 23%, respectively. Fifty-six percent had equal to or greater than grade 2 gut involvement. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 93% and 63%, respectively. Ninety-two percent of patients who were evaluable +100 days after transplant were in complete remission. Relapse rate was 25% at 2 years. Event free (EFS) and overall survival (OS) at 2 years were 52%. Pharmacokinetic assays of mycophenolic acid (MPA) showed a therapeutic area under the curve (AUC) at the dosage of 3 g daily, although a large inter- and intraindividual variations of MPA plasma levels were found. In conclusion, the combination of CSA plus MMF in the fludarabine plus melphalan or busulfan RIC setting is feasible. Regarding GVHD, this combination allowed to control aGVHD but lead to a high incidence of cGVHD, so that newer strategies are required, especially in trying to decrease gastrointestinal involvement.

Topics: Adolescent; Adult; Antineoplastic Agents; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Cyclosporine; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Myelodysplastic Syndromes; Peripheral Blood Stem Cell Transplantation; Survival Analysis; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

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

Myeloablative conditioning followed by T-cell depletion of grafts and reduced intensity conditioning (RIC) has both been shown to decrease treatment related mortality (TRM). However in RIC the incidence of graft vs. host disease (GvHD) is high and patients with aggressive diseases tend to relapse. Following myeloablative conditioning, patients with chemotherapy-responsive hematological malignancies underwent transplantation from HLA identical siblings. GvHD prophylaxis was by ex viva T-cell depletion with alemtuzumab. The outcome of these patients was analysed. At transplantation, the median age of 81 consecutive individuals was 45 years (range 15-60). GvHD was seen in 10% and was commonly associated with infections resulting in one and 3 year TRM of 15 and 20.5%. Fifteen patients relapsed, 10 who had myeloproliferative syndromes or lymphoma and two with myeloma responded to DLI. For the whole group, median follow up is 777 (range 7-2702) days and 73% remain disease free. Cox regression analysis for survival showed that only occurrence of GvHD was a significant adverse factor. Age order than median was not associated with worse outcome. By reducing the incidence and severity of GvHD, T-cell depletion of grafts leads to greater tolerance to myeloablative chemotherapy, resulting in acceptable TRM. This strategy should be compared with the RIC approaches.

Topics: Adolescent; Adult; Alemtuzumab; Antibiotic Prophylaxis; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Busulfan; Cyclophosphamide; Female; Graft vs Host Disease; Hematologic Neoplasms; Humans; Lymphocyte Depletion; Male; Melphalan; Myeloablative Agonists; Myelodysplastic Syndromes; Myeloproliferative Disorders; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Risk; Survival Analysis; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation

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

This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).. Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors.. After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics.. Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

Topics: Acute Disease; Adolescent; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Prospective Studies; Remission Induction; Stem Cell Transplantation; Transplantation Conditioning; Vidarabine

In a phase I-II study for patients aged 55-65 years, we employed radioimmunotherapy using an anti-CD-66 antibody as part of a dose-reduced conditioning regimen, which was followed by a T-cell-depleted graft. 20 patients with a median age of 63 years suffering from acute leukaemia (n=17) or myelodysplastic syndrome (n=3) received the antibody labelled either with 188Rhenium (n=8) or with 90Yttrium (n=12) during conditioning. Radioimmunotherapy provided a mean dose of 21.9 (+/-8.4) Gy to the bone marrow with a significantly higher dose when 90Yttrium was used. Additional conditioning was fludarabine-based plus anti-thymocyte globulin in matched related donor transplants (n=11), or plus melphalan in matched unrelated donor transplants (n=9). Regimen-related toxicity was low, with two patients developing three episodes of grade III organ toxicity. All patients engrafted, grade II-IV acute graft-versus-host disease (GvHD) was observed in one patient (5%) and chronic GvHD in three patients (15%). The cumulative incidence of non-relapse mortality was 25%, the cumulative incidence of relapse 55%. The probability of survival was estimated to be 70% at 1 year and 52% at 2 years post-transplant, although no plateau was reached afterwards. In conclusion, radioimmunotherapy using the anti-CD66 antibody was feasible and safe in our elderly patient group and provided a high marrow dose.

Topics: Aged; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation; Antilymphocyte Serum; Antineoplastic Agents; Cell Adhesion Molecules; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Leukemia; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Radioimmunotherapy; Radioisotopes; Radiometry; Rhenium; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Yttrium Radioisotopes

The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural.. Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years).. The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation.. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Recurrence; Risk Factors; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous; Treatment Outcome; Vidarabine

We report the use of reduced-intensity conditioning (RIC)-matched sibling allogeneic bone marrow stem cell transplantation as a method of establishing a graft-vs.-leukaemia (GvL) effect against myeloid disorders using a fludarabine-melphalan protocol without the use of T-lymphocyte-depleting antibodies. The 16 patients in this group had predominantly poor-risk acute myeloid leukaemia (AML) (n=10), AML/myelodysplasia (MDS) (n=2) and MDS (n=4). All but one patient achieved full haematopoietic engraftment. Thirteen of 16 patients are alive and in continued complete remission on completion of this study with a median follow-up of 426 d (range 83-1524). The actuarial 4 yr disease-free and overall survival is 79% for both. Only one patient relapsed following transplant, giving a relapse rate of 6% during the study period. The treatment-related mortality was 13% (n= 2). Overall, acute graft-vs.-host disease (GvHD) occurred in 53% (8/15), with acute GvHD grade II or above occurring in 47% (7/15). In the 13 evaluable patients, chronic GvHD occurred in 46% (6/13), with this being extensive in three patients. These results suggest that a GvL effect can be delivered against poor-risk myeloid disorders with a low non-relapse mortality using this fludarabine-melphalan RIC protocol.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Disease-Free Survival; Female; Graft Survival; Graft vs Host Disease; Graft vs Leukemia Effect; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Siblings; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

A cohort of 76 patients with previous chemotherapy for Hodgkin's disease and non-Hodgkin lymphomas received high-dose carmustine, etoposide, cytosine-arabinoside and melphalan (BEAM) followed by autologous stem cell transplantation (ASCT) and was followed for relapse and development of leukemic complications. Six patients, four with Hodgkin's disease and two with non-Hodgkin lymphomas, developed leukemic complications, myelodysplasia (MDS) in four cases and overt acute myeloid leukemia (AML) in two. All six showed an abnormal karyotype, in four of them highly characteristic of therapy-related MDS (t-MDS) and therapy-related AML (t-AML). The cumulative risk of t-MDS and t-AML increased from 16 months after start of the primary chemotherapy for lymphoma and reached 17.3% (s.e. 8.5%) after 74 months. If calculated from start of BEAM and ASCT, the cumulative risk increased as early as 4 months and reached 24.3% (s.e. 12.9%) after 43 months. For the whole course of the disease, the relative risk (RR) of AML was 357 (95% CI: 43-1290), as two overt leukemias were observed vs 0.0056 expected cases of de novo AML. In the present cohort the risk of t-MDS and t-AML although high, did not differ from our previous experience in patients treated conventionally for Hodgkin's disease and non-Hodgkin lymphomas, and did not differ for patients receiving stem cells isolated from the bone marrow as compared to patients receiving stem cells isolated from peripheral blood. Antecedent chemotherapy seems to be the critical factor for the development of t-MDS and t-AML rather than the BEAM and ASCT regimen, which however may accelerate the evolution of the disease.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Podophyllotoxin; Risk Factors

Four consecutive children with myelodysplastic syndromes (MDS) underwent matched allogeneic bone marrow transplantation (BMT). Ages ranged from 3.2 to 6.3 years. Diagnosis was assessed according to FAB classification: refractory anemia-RA (n = 1), RA with excess of blasts (RAEB) (n = 1), and juvenile chronic myelogenous leukemia (JCML) (n = 2). Initial treatment included transfusions for all of them, splenectomy (n = 2) and chemotherapy (n = 1). Patients were all prepared with busulfan 21 mg/kg (480 mg/m2), cytosine arabinoside 24,000 mg/m2, melphalan 140 mg/m2. Graft-versus-host disease (GVHD) prophylaxis associated cyclosporine-methotrexate. Engraftment was prompt and complete in all children. Toxicity included severe mucositis (n = 3), moderate veno-occlusive disease (n = 2), acute GVHD (n = 3), chronic GVHD (n = 1). Sequelae have not yet been seen. All patients are alive and disease-free with a follow-up ranging from 7 to 35 months, with a Karnofsky score of 90-100%. Combined busulphan conditioning can offer an alternative to total body irradiation-based regimens in order to avoid late side-effects in children.

Topics: Anemia, Refractory; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclosporine; Cytarabine; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Methotrexate; Myelodysplastic Syndromes; 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

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

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

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

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

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m

Topics: Aged; Busulfan; Graft vs Host Disease; Humans; Melphalan; Middle Aged; Myelodysplastic Syndromes; Survival Analysis; Transplantation Conditioning; Vidarabine

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

Topics: Abnormal Karyotype; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Erythroblasts; Erythropoietin; Female; Humans; Immunoglobulin D; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neutrophils; Proto-Oncogene Proteins c-myc

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

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

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

In the present study we compared outcomes of patients with myeloid neoplasms undergoing allogeneic hematopoietic stem cell transplantation after fludarabine-based regimens with melphalan (FM140) or 3-day busulfan (FB3). The FM140 and FB3 combinations were administered to 21 and 27 patients, respectively. Efforts for early reduction (from day +30 to 60) and discontinuation (until day +100 to 130) of prophylactic immunosuppression were a component of the post-transplant approach. Following FB3 patients suffered from more severe stomatitis (P = 0.013). In contrast, other manifestations of regimen-related toxicity were more frequent in the FM140 group (P = 0.048). There were no statistically significant differences in the development of graft-versus-host disease, non-relapse mortality, post-transplant remission rate, or relapse incidence. Two-year disease-free survival rates were comparable in the two cohorts (66 vs. 55 %; P = 0.751), and so were the overall survival rates (64 vs. 62 %; P = 0.715). The outcomes of allografted patients with myeloid neoplasms were comparable after the FM140 and FB3 regimens. Relatively high therapeutic response in both groups may have been influenced by early reduction and discontinuation of prophylactic immunosuppression followed by effective immunological control of the malignant clone.

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

Risk factors associated with the development of aGVHD in the gastrointestinal tract have not been studied in depth. We retrospectively assessed 25 pediatric patients with MDS and JMML and compared the treatment outcome of two different conditioning regimens. Seventeen children (68%) underwent conditioning with busulfan (Bu), cyclophosphamide (Cy), and melphalan (Mel) and eight children (32%) with Bu and Cy. Gastrointestinal aGVHD stages II-IV (day 0-100) were observed in 47% (eight of 17) of the patients in the BuCyMel group and in none (0 of 8) in the BuCy group (p < 0.05). In patients who developed gastrointestinal aGVHD stages III-IV, a 24-h variation in the Bu concentration with a nighttime peak was noted. HC and liver aGVHD stages II-IV were observed in 47% (eight of 17) and 35% (six of 17) after BuCyMel conditioning and in 0% (0 of 17) and 12.5% (one of eight) after BuCy conditioning. The overall survival rate was 53% (nine of 17) in the BuCyMel group and 62.5% (five of eight) in the BuCy group. In conclusion, the addition of melphalan to the BuCy conditioning regimen resulted in severe gastrointestinal complications and did not improve overall survival.

Topics: Adolescent; Busulfan; Child; Child, Preschool; Cyclophosphamide; Female; Gastrointestinal Tract; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myelomonocytic, Acute; Male; Melphalan; Myelodysplastic Syndromes; Retrospective Studies; Risk Factors; Transplantation Conditioning; Treatment Outcome

Defining the role of high-dose therapy with autologous stem cell rescue in the therapeutic algorithm of follicular lymphoma remains a major challenge. In contrast to the acknowledged poor outcome associated with cyclophosphamide/total body irradiation conditioning in heavily pretreated patients, the prognostic impact of the number of previous therapy lines in patients treated with the chemotherapy-only containing regimen, BEAM, is unknown. From 1997 to 2008 80 patients (41 males, 39 females; median age, 51 years; range, 31-67) received high-dose therapy with autologous stem cell rescue with BEAM for relapsed follicular lymphoma at our center. Overall survival and time-to-progression were analyzed according to the number of prior treatment lines. The median number of previous treatment lines was three, with 61% of the patients having received more than three lines (including rituximab in 47%). After a median follow-up of 76 months (range, 14-160), three patients developed secondary myelodysplastic syndrome. The 5-year overall survival rate was 71% and 5-year time-to-progression was 44%. There were no differences in time-to-progression or overall survival according to the number of previous treatment lines or episodes of disease. In conclusion, high-dose therapy with autologous stem cell rescue with BEAM appears to be equally effective in second or third remission of follicular lymphoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; In Situ Hybridization; Kaplan-Meier Estimate; Lymphoma, Follicular; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Prognosis; Remission Induction; Time Factors; Transplantation, Autologous; Treatment Outcome

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 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 report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II-IV acute GVHD was 35.4%; grade III-IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD; of these 35 were extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result.

Topics: Adult; Aged; Chemoprevention; Dose-Response Relationship, Drug; Drug Combinations; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Sirolimus; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult

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

To obtain accurate incidence data for myelodysplasia in the Wellington Region of New Zealand (NZ), to analyse the treatment these patients received and to review their outcome.. Patients diagnosed with myelodysplasia between 1 January 2002 and 1 September 2007 were identified. Their bone marrow biopsy, clinical record, cytogenetic analysis and transfusion record were analyzed.. Seventy myelodysplastic patients were identified yielding an incidence of 2.75 per 100,000 per year. Median survival was 23 months, and transformation to acute leukaemia occurred in five patients (7.1%). Three patients (4.3%) received an allogeneic bone marrow transplant, and five patients (7.1%) received disease modifying treatment. Fifty-six of 70 patients (80%) received a blood transfusion, a mean of 32.9 red blood cell (RBC) units were transfused to each transfusion recipient during the study period of 68 months. One of 70 patients developed a clinical syndrome of iron overload.. The incidence of myelodysplasia in Wellington, NZ is similar to incidence figures from previously published studies. The treatment these patients received was predominantly supportive through RBC transfusion. Effective iron chelation therapy measures were not used although there appeared to be a low incidence of clinical iron overload in the study population. The data in this study will be available for comparison with future studies to assess trends in incidence, treatment and outcome in myelodysplastic patients in NZ.

Topics: Aged; Aged, 80 and over; Bone Marrow Examination; Erythrocyte Transfusion; Ethnicity; Female; Ferritins; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; New Zealand; Pyridoxine; Transplantation, Homologous; Treatment Outcome

Topics: Antineoplastic Agents; Humans; Lenalidomide; Leukemia, Myeloid; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Probability; Risk Assessment; Thalidomide

Topics: Adolescent; Adult; Age Factors; Aged; Anemia, Refractory, with Excess of Blasts; Cytogenetics; Female; Humans; Karyotyping; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Treatment Outcome

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

Survival of patients with plasma cell disorders has increased. However, the expanding use of melphalan in patients with longer survival suggests that myelodysplasia may become increasingly important. The objective of this study was to determine the risk of myelodysplasia after treatment with melphalan for patients with amyloidosis. We reviewed the long-term follow-up data (more than 12 years) from 101 patients with immunoglobulin light-chain amyloidosis. We identified 10 patients with myelodysplasia or acute nonlymphocytic leukemia that directly caused death for 8 and transfusion dependency for 2. Two of the 10 patients did not have development of myelodysplasia until 144 months after first exposure to alkylating agents. The actuarial risk of myelodysplasia development at ten years was 18%. As the survival of patients with plasma cell disorders improves, myelodysplasia may be a more common cause of morbidity and mortality for this group.

Topics: Adult; Aged; Amyloidosis; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Risk Factors; Time Factors

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

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 retrospectively evaluated the outcome of reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic stem cell transplantation (HCT) in 43 patients with myelodysplastic syndrome (MDS) or AML arising from MDS. All patients received fludarabine plus melphalan followed by an allogeneic HCT from an HLA-identical sibling (SIB: n=19) or unrelated donor (MUD: n=24). Median age was 58 years (range: 30-71). Diagnoses at transplantation were RA (n=8), RARS (n=1), RAEB (n=13), RAEB-T (n=6), or AML arising from MDS (n=15). Of 28 patients with MDS, two patients had low, 10 had intermediate-1, nine had intermediate-2 and seven had high-risk MDS by IPSS criteria. All patients initially engrafted with the median neutrophil recovery of 15 days (range: 9-27). The 2-year overall survival, disease-free survival, relapse and transplant-related mortality were 53.5% (CI 45.2-61.1), 51.2% (CI 43.3-58.5), 16.3% (CI 7.9-30.7) and 35.2% (26.4-45.7), respectively. Grade II-IV acute graft-versus-host disease occurred in 27 (63%) patients. There was no significant survival difference between SIB and MUD-HCT, but the relapse rate was higher among SIB donor recipients when compared to MUD (38.5 versus 7%, P=0.02). RIC with fludarabine plus melphalan was associated with durable disease control and acceptable toxicity in this high-risk cohort.

Topics: Adult; Aged; Graft Survival; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Allogeneic hematopoietic stem cell transplantation is the treatment of choice in young patients with severe aplastic anemia. The main causes of failure after this procedure are graft versus host disease, infections and graft failure, often exacerbated by large numbers of transfusions and prolonged disease duration before transplant.. We report the results of allografting following conditioning with fludarabine, alemtuzumab and melphalan in: five patients with severe aplastic anemia and one with hypoplastic myelodysplastic syndrome. All patients had matched sibling donors. Source of hematopoietic stem cell was: bone marrow-2, blood-3, bone marrow and blood-1. The age of recipients was 18-26 years. Four patients received their graft as the first line therapy and two after failure of cyclosporine and antithymocyte globulin treatment. Number of transfused units including red blood cells and platelets before transplantation was 8-100 (median: 22) and 10-32 (median: 11), respectively. All donors and recipients were CMV-seropositive. Conditioning consisted of: alemtuzumab 30 mg/d (day -7 to -5), fludarabine 30 mg/m(2) (days -7 to -3) and melphalan 140 mg/m(2) at the day -2.. The time to granulocytes and platelets recovery was 15 and 25 days, respectively. All patients achieved full donor chimerism on day +60. Only two patients needed ganciclovir as preemptive therapy. Recurrent parvovirus B19 infection with pure red cell aplasia and acute viral B hepatitis was observed in one case. Pure red cell aplasia was successfully treated with immunoglobulins and cyclosporine discontinuation. With a follow-up of 16-39 (median: 29) months all patients are alive, and neither graft failure nor graft versus host disease, or any no other severe complications, was observed.. Our study suggests that transplantation of hematopoietic stem cell using alemtuzumab, fludarabine and melphalan as a conditioning therapy is safe, inexpensive and effective treatment for patients with severe aplastic anemia, including multi-transfused adults having their disease for a long time.

Topics: Adolescent; Adult; Alemtuzumab; Anemia, Aplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Bone Marrow Transplantation; Costs and Cost Analysis; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Living Donors; Melphalan; Myelodysplastic Syndromes; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Therapy-related myelodysplastic syndrome (MDS) is a major problem in long-term cancer survivors, therefore early detection and prevention of therapy-related secondary neoplasia is an important issue. We searched for therapy-related MDS and analyzed cytogenetic changes in 155 patients with multiple myeloma (MM) from a single institution. Of the total 155 MM patients with cytogenetic results, 7 patients showed de novo appearance of myeloid-related cytogenetic changes, and 5/7 had -7/7q-, including 3 with der(1;7)(q10;p10): 3 patients developed MDS (i.e. 2 patients with der(1;7)(q10;p10) and 1 with a complex abnormality including -5 and 7q-). Among five patients receiving more than 2 g of melphalan, three developed MDS, and two of them showed der(1;7)(q10;p10) before or at the time of MDS diagnosis. Although morphologic identification of MDS was difficult in some cases, we concluded that the presence of 7q-, specifically der(1;7)(q10;p10), during chemotherapy involving melphalan for MM patients might indicate hidden MDS status and appropriate therapeutic options should be considered for such patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chromosome Aberrations; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 7; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes

Cytogenetic abnormalities (CA), especially of chromosome 13, have been used to identify a subgroup of previously untreated multiple myeloma (MM) patients with very poor prognosis despite high-dose therapy (HDT). We examined the prognostic implications of CA in 1000 MM patients receiving melphalan-based tandem autotransplants (median follow-up, 5 years). Negative consequences for both overall survival (OS) and event-free survival (EFS) in the presence of any CA were confirmed, especially when detected within 3 months of HDT. In the context of standard prognostic factors (SPF), 'MM-MDS' (MM karyotype that contains, in addition, CA typical of MDS) imparted a poor OS and EFS, after adjusting for any CA and all individual CA. One-year mortality was also high, especially for the MM-MDS subgroup with trisomy 8 within a MM signature karyotype (87%vs 34% in its absence, P < 0.001). No patient remained event free 5 years post transplant in the presence of these baseline high-risk CA. However, certain trisomies (e.g. chromosomes 7 and 9) and del 20 had favourable clinical consequences. The higher risk that is associated with CA compared with SPF justifies routine cytogenetic studies in all patients with MM at diagnosis and whenever additional treatment decisions are considered, such as in planning HDT either for initial response consolidation, at the time of primary unresponsiveness to induction therapy, or at relapse.

Topics: Antineoplastic Agents, Alkylating; Chromosome Aberrations; Cluster Analysis; Cytogenetic Analysis; Disease-Free Survival; Follow-Up Studies; Gene Deletion; Humans; Melphalan; Monosomy; Multiple Myeloma; Myelodysplastic Syndromes; Proportional Hazards Models; Risk Assessment; Survival Rate; Translocation, Genetic; Transplantation, Autologous; Trisomy

Effective therapy of myelodysplatic syndromes and acute myeloid leukemia originating from myelodysplastic syndrome has remained an unresolved problem. Advanced age of the patients and persistent pancytopenia make the treatment difficult. Despite large number of therapeutic options none of them is satisfactory. Recently palliative treatment with low-dose melphalan has been reported to have certain activity. The aim of the study was to evaluate the efficacy of low-dose melphalan in high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia with multilineage dysplasia (AML). Twenty three patients were eligible for the study: 8 with MDS and 15 with AML with multilineage dysplasia. All of them received oral melphalan in a daily dose of 2 mg. Median total dose of the drug was 120 mg (40-840 mg). Ten patients responded to the therapy. We observed complete remission (CR) in 4, partial remission (PR) in 3 and stabilization of the disease in 3 patients. Thirteen patients did not respond to the therapy. The survival time of the patients from the day of diagnosis and from the beginning of the treatment with melphalan was longer in patients responding to the therapy (median 15 and 10 months, respectively) than in non-responders (4.5 and 4 months, p=0.003 and p=0.008, respectively). Low-dose melphalan shows significant activity in high-risk MDS and AML with multilineage dysplasia with acceptable toxicity.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Cell Lineage; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Risk Factors; Safety

The apparent contradiction between clonal expansion and marrow failure encountered in myelodysplastic syndromes (MDS) is more evident in hypocellular forms at presentation. Hypoplastic MDS (hMDS) appears to be a distinct clinicopathologic entity, accounting for about 15% from all MDS. The pathogeny is supposed to result from immunosupressive mechanisms and some observations on successful treatment with Cyclosporine A (CsA) are reported. The case of a young female patient diagnosed by bone marrow core biopsy with hMDS - refractory anemia (FAB and WHO classification) with normal karyotype and scarce CD34(+) cells by immunohistophenotyping is presented. She was treated with androgens followed by CsA for a few months and shortly after she developed an acute myeloid leukemia (M4) which responded to low-doses of daily oral melphalan. This is one of the first few reports on such an event during the immunosuppressive therapy in MDS and the possible explanations for this unusual evolution are discussed.

Topics: Acute Disease; Adult; Antineoplastic Agents, Alkylating; Cyclosporine; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid; Melphalan; Myelodysplastic Syndromes; Treatment Failure

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

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

We treated 21 elderly patients with high-risk myelodysplasia (n = 14) or secondary acute myeloid leukaemia (n = 7) with 2 mg of melphalan orally once a day until a complete peripheral response was obtained or until there was evidence of treatment failure. We observed seven (30%) complete and two (10%) partial peripheral responses occurring within 4-16 weeks and lasting for 12 + to 55 weeks. In relapse, retreatment was successful in most of the patients. Responses were associated with the absence of complex cytogenetic abnormalities and with a normal or reduced bone marrow cellularity.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Female; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Risk Factors

We report an adult case of reactive hemophagocytic syndrome (RHS) associated with myelodysplastic syndrome (MDS) who received emergency bone marrow transplantation (BMT). Despite methylprednisolone pulse therapy, high-dose gamma-globulin, and chemotherapy containing etoposide, the pancytopenia progressed. After informed consent, the patient underwent syngeneic BMT using melphalan as the conditioning regimen. The patient has been well without relapse of RHS and MDS for more than 2 years after BMT. This result suggests that the above strategy, including BMT, should be considered for the treatment of adult RHS associated with hematological malignancy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Disease-Free Survival; Histiocytosis, Non-Langerhans-Cell; Humans; Japan; Male; Melphalan; Myelodysplastic Syndromes; Pancytopenia; Transplantation, Isogeneic

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

Hodgkin's disease is curable in the majority of patients, although a proportion of patients are resistant to or relapse after initial therapy. High-dose therapy with autologous stem cell support has become the standard salvage therapy for patients failing chemotherapy, but there have been reports of a high incidence of myelodysplasia/acute myeloid leukaemia (MDS/AML) following such treatment. Patients who receive such therapy form a selected group, however, who have already been subjected to other leukaemogenic factors, such as treatment with alkylating agents. In order to ascertain the true risk of MDS/AML, comparison must be made with other patients subjected to the same risks but not undergoing transplantation. We report a retrospective comparative study of 4576 patients with Hodgkin's disease from the BNLI and UCLH Hodgkin's databases, which includes 595 patients who have received a transplant. Statistical analysis including Cox's proportional hazards multivariate regression model with time-dependent covariates was employed. This analysis reveals that the risk of developing MDS/AML was dominated by three factors, namely quantity of prior therapy (relative risk [RR] 2.01, 95% confidence intervals [CI] 1.49-2.71, for each treatment block, P < 0.0001) and whether the patient had been exposed to MOPP (RR 3.61, 95% CI 1.64-7.95, P = 0.0009) or lomustine chemotherapy (RR 4.53, 95% CI 1.96-10.44, P = 0.001). Following adjustment for these factors in the multivariate model the relative risk associated with transplantation was 1.83 (95% CI 0.66-5.11, P = 0.25). This study provides no evidence of a significantly increased risk of MDS/AML associated with BEAM therapy and autologous transplantation in Hodgkin's disease. Concern over MDS/AML should not mitigate against the timely use of this treatment modality.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Child; Child, Preschool; Chlorambucil; Cohort Studies; Combined Modality Therapy; Cytarabine; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Incidence; Infant; Leukemia, Myeloid; Life Tables; Lomustine; Male; Mechlorethamine; Melphalan; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Podophyllotoxin; Prednisolone; Prednisone; Procarbazine; Retrospective Studies; Risk; Salvage Therapy; Vinblastine; Vincristine

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

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

A 42-year-old male patient with a history of occupational exposure to benzene presented with pancytopenia. His bone marrow showed evidence of trilineage dysplasia and cytogenetic analysis revealed a unique t(9;13)(q34;q12) translocation. Five months after diagnosis he developed secondary AML. He was treated with four courses of chemotherapy and an autologous bone marrow transplantation (BMT). Four years post-transplantation he remains in haematological and morphological remission though the cytogenetic abnormality is still present in all metaphases examined.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Benzene; Bone Marrow; Bone Marrow Transplantation; Carmustine; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 9; Combined Modality Therapy; Etoposide; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Melphalan; Myelodysplastic Syndromes; Neoplastic Stem Cells; Occupational Diseases; Occupational Exposure; Pancytopenia; Remission Induction; Solvents; Translocation, Genetic; Transplantation, Homologous

A 42-year-old woman with Crow-Fukase syndrome developed acute myeloid leukemia (M6: FAB classification) following treatment with alkylating agents (a total of 2,500 mg of melphalan and 9,800 mg of cyclophosphamide). Chromosome analysis of the bone marrow showed 49,XX,der(1;7)(q10;p10), +8, +19, +21 in therapy-related myelodysplastic syndrome with additional chromosomes 8, and 12 and two additional chromosomes 21 in acute leukemia. Because of the risk of therapy-related leukemia, alkylating agents should be used with caution in the treatment of Crow-Fukase syndrome.

Topics: Adult; Alkylating Agents; Chromosome Aberrations; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 7; Cyclophosphamide; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Myelodysplastic Syndromes; POEMS Syndrome; Translocation, Genetic; Trisomy

Multiple myeloma (IgG kappa + IgA kappa type, clinical stage IA) was diagnosed in a 82-year-old woman in January 1986. Chemotherapy (melphalan, prednisolone, vindesine, cyclophosphamide), caused prolonged myelosuppression. Therefore she was given other treatment. In October 1992, her peripheral blood examination demonstrated 2% blastic cells and 12% eosinophils. Bone marrow aspiration showed dysplastic features of trilineage blood cells with 4.8% myeloblasts. The karyotype of bone marrow cells from this patients was 47, XX, +der(1)t(1;7) (p11;p11), -7, +8. A diagnosis of therapy-related myelodysplastic syndrome (refractory anemia) was established. Eleven months after diagnosis of myelodysplastic syndrome, she is alive without leukemic transformation.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 7; Cyclophosphamide; Eosinophilia; Female; Humans; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Prednisolone; Translocation, Genetic; Vindesine

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

A 35-year-old male presented with chronic myelomonocytic leukemia (CMMoL) after 6.5 years of alkylating agent therapy for IgG-kappa type multiple myeloma. The total dose of melphalan was 0.648 g. CMMoL was stable with weekly injection of alpha-interferon for one year. Thereafter, monocytosis and thrombocytopenia aggravated, and the patient died of disseminating intravascular coagulation. Prolonged drug therapy can induce CMMoL, as well as other myelodysplastic syndromes.

Topics: Adult; Disseminated Intravascular Coagulation; Humans; Leukemia, Myelomonocytic, Chronic; Male; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary

As typical disorders of the elderly, myelodysplastic syndromes (MDSs) are relatively unusual in childhood. Nevertheless, up to 17% of cases of pediatric acute myeloid leukemia may have a preleukemic phase. In young patients, the goal of treatment is eradication of the preleukemic malignant clone and reconstitution of normal hematopoiesis. Allogeneic bone marrow transplantation (BMT) has proved to be capable of this, but the optimal conditioning treatment to achieve eradication remains to be defined. Between May 1989 and June 1993, eight consecutive pediatric patients with MDS received a marrow transplant from an HLA-identical, mixed lymphocyte culture (MLC) non-reactive sibling. Diagnosis at time of presentation was refractory anemia with excess of blasts (RAEB) in two patients, RAEB in transformation (RAEB-t) in three, and juvenile chronic myelogenous leukemia (JCML, the pediatric counterpart of adult chronic myelomonocytic leukemia) in the remaining three children. Conditioning regimen consisted of busulfan, cyclophosphamide and melphalan, three alkylating agents potentially capable of killing also dormant preleukemic stem cells. The preparative regimen was very well tolerated, and all patients engrafted promptly. Six out of eight patients (75%) are alive and well with a median observation time of 20 months (range 8-34 months). Serial karyotype monitoring and molecular analyses have demonstrated a full chimerism of donor cells and the complete disappearance of trisomy 8 detected before transplant in three cases. All surviving patients have a Karnofsky score of 100%. One boy, affected by RAEB-t with monosomy 7 resistant to treatment with low-dose ara-C, relapsed 11 months after BMT, evolved in AML and died from progressive leukemia. Another patient with RAEB died on day +95 after BMT due to interstitial pneumonia of unclear etiology. This study confirms that allogeneic BMT is the treatment of choice in pediatric patients with MDS, and suggests that the employed conditioning regimen is a safe and effective means for eradicating the preleukemic malignant clone. Particularly noteworthy is that the three children with JCML obtained a complete remission and one of them is now a long-term survivor.

Topics: Adolescent; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Melphalan; Myelodysplastic Syndromes; Preleukemia; Remission Induction; Transplantation, Homologous

A multiple myeloma patient presented for cytogenetic analysis at diagnosis of secondary MDS, which followed cytotoxic treatment including melphalan. Two abnormal unrelated clones were detected, one of them had 5q-, 7q- with clonal evolution of an additional aberration, t(12;13); in the second clone there was a translocation between the two homologues of chromosome 1 as the only aberration. We suggest that the clone with 5q- and 7q- represented the secondary MDS cells, whereas the abnormal clone with t(1;1) represented the plasmablasts of the multiple myeloma.

Topics: Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Humans; Karyotyping; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Translocation, Genetic

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

From 1980 to 1987, three cases of chronic myelomonocytic leukemia (CMML) were encountered among 68 cases of multiple myeloma who survived more than three years from the diagnosis. The incidence (4.8%) of secondary myelodysplastic syndrome (MDS) is almost identical to previous reports, but case reports of chronic myelomonocytic leukemia were rare. In Japan, there are few reports of multiple myeloma patients who later developed secondary MDS or acute myelogenous leukemia (AML). In our cases, none of the 31 patients treated with cyclophosphamide developed secondary MDS, while three of 37 patients treated with melphalan developed CMML. This difference is not statistically significant.

Topics: Aged; Female; Humans; Leukemia, Myelomonocytic, Chronic; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes

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

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

Topics: Acute Disease; Female; Humans; Leukemia; Melphalan; Middle Aged; Myelodysplastic Syndromes; Thrombocythemia, Essential

Topics: Aged; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 7; Female; Humans; Male; Melphalan; Middle Aged; Monosomy; Multiple Myeloma; Myelodysplastic Syndromes; Uterine Cervical Neoplasms

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