melphalan and Leukemia--Myeloid

The incidence of secondary myelodysplasia/acute myeloid leukemia (AML) was retrospectively assessed in an international joint study in 305 node-positive breast cancer patients, who received mitoxantrone-based high-dose chemotherapy (HDCT) followed by autologous stem cell support as adjuvant therapy. The median age of the patients was 57 years (range 22-67). In all, 268 patients received peripheral blood stem cells, and 47 patients received autologous bone marrow. After a median follow-up of 57 months (range 10-125), three cases of secondary AML (sAML) were observed, resulting in a cumulative incidence of 0.94%. One case of sAML developed 18 months after HDCT (FAB M3) The karyotype was translocation 15;17 and, after induction therapy, the patient underwent autologous stem cell transplantation, and is in complete remission (CR) of both breast cancer and AML. The second patient developed AML (FAB M4eo with inversion 16) 5 months after HDCT. This patient achieved CR after induction therapy, but died of infectious complication. A third patient developed AML (FAB M4) 6 months after HDCT. She achieved CR after induction therapy, but relapsed and expired 28 months after diagnosis of AML. sAML after mitoxantrone-based HDCT is a possible, but rare complication in breast cancer patients.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Epirubicin; Female; Humans; Incidence; Leukemia, Myeloid; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Leukemia, Radiation-Induced; Lymphatic Metastasis; Melphalan; Middle Aged; Mitoxantrone; Neoplasms, Second Primary; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Radiotherapy, Adjuvant; Thiotepa; Transplantation Conditioning; Transplantation, Autologous

Topics: Anemia, Aplastic; Benzene; Benzene Derivatives; Bone Marrow; Bone Marrow Cells; Chloramphenicol; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid; Melphalan; Mutation; Occupational Diseases; Oxymetholone; Phenylbutazone

Topics: Adenocarcinoma; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Hodgkin Disease; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Melanoma; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Vincristine

Topics: Bence Jones Protein; Blood Protein Electrophoresis; Bone Marrow Cells; Cell Count; Clone Cells; Cyclophosphamide; DNA; gamma-Globulins; Humans; Immunoglobulin G; Immunoglobulins; Leukemia, Myeloid; Melphalan; Middle Aged; Multiple Myeloma; Mutation; Plasmacytoma; Ribosomes

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

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

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

Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (P<0.0001). For transplantation in first remission, 8 year EFS and OS were 55% (95% CI, 44-64%) and 62% (95% CI, 50-72%), respectively. By multivariate analysis, only age (P=0.04) and cytogenetic risk group (P=0.006) influenced OS. For patients transplanted in second remission, 8 year EFS and OS were 30% (95% CI, 9-55%) and 36% (95% CI, 13-60%), respectively. No pre-transplant variables significantly predicted outcome. None of the seven patients who underwent ABMT beyond second remission or in early relapse were long-term survivors. ABMT can provide long-term antileukemic control for patients with AML in first remission. For patients in second remission approximately 30% can achieve cure with ABMT, and this option may be preferable to alternate donor allogeneic stem cell transplantation.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Data Collection; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Longitudinal Studies; Melphalan; Middle Aged; Remission Induction; Risk Factors; Survival Analysis; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

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

To improve outcome for older patients with poor-prognosis myeloid malignancies by using allogeneic hematopoietic stem-cell transplantation (alloHSCT) from unrelated and sibling donors after reduced-intensity conditioning (RIC).. Nineteen older patients (median age, 64 years; range, 60 to 70 years) with active myeloid malignancies were treated with an RIC regimen that was based on fludarabine, melphalan, and carmustine followed by alloHSCT from matched unrelated (n = 12) or sibling donors (n = 7). Before transplantation, patients had a median of 50% bone marrow blasts (range, 0% to 70%). Graft-versus-host-disease (GvHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil or methotrexate. Eleven of 12 patients with an unrelated donor also received anti-T-lymphocyte globulin (ATG).. Engraftment was successful for all 19 patients. Seventeen assessable patients achieved complete response (CR). Four patients experienced relapse; three achieved CR again after donor lymphocyte infusion (n = 1) or a second alloHSCT (n = 2). Six patients died as a result of relapse (n = 2), GvHD-associated complications (n = 2), or fungal infections (n = 2), resulting in a 1-year nonrelapse mortality rate of 22%. With a median follow-up of 825 days (range, 595 to 1,028 days), 13 of 19 patients are alive, resulting in a 1-year survival rate of 68% (95% confidence interval, 48% to 89%).. In older patients with untreated poor-prognosis leukemia, this RIC regimen combined with alloHSCT sufficiently reduces the leukemic burden, resulting in a high CR rate. When ATG is added, matched unrelated donor transplantation can be performed safely in older patients. For these patients, early transplantation after diagnosis offers a fair chance of cure.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Chemotherapy, Adjuvant; Female; Hematopoietic Stem Cell Transplantation; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid; Living Donors; Male; Melphalan; Middle Aged; Prognosis; Siblings; Survival Analysis; 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

Leukemic relapse remains a major problem after both autologous and allogeneic transplantation. In the single-arm ALL autograft study our results were very encouraging and suggest that Melph/TBI can produce disease-free survival results at least as good as with other conditioning regimens. The role of postautograft maintenance remains unclear, but we feel our results are sufficiently encouraging to justify a randomized study, particularly as we studied a group of patients with relatively poor prognoses. In our study comparing Cy and TBI with Melph and TBI in AML, we have shown a significant increase in antileukemic activity after transplantation following the latter conditioning regimen. The retrospective study of Melph/TBI in autologous versus allogenic transplantation suggested that in AML this antileukemic effect may derive from increased GvHD and is not present in the autologous setting. We hope that by increasing the intensity of our GvHD prophylaxis we can reduce the toxicity of Melph/TBI and preserve its antileukemia effect. Our experience with GM-CSF has been a little disappointing: despite facilitating neutrophil recovery, we were unable to demonstrate a clinical benefit in the treatment arm. We hope to further investigate the use of cytokine combinations in the transplant setting.

Topics: Acute Disease; Adolescent; Adult; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; England; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation, Autologous; Whole-Body Irradiation

Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown.. We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria.. A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25%) patients in RIC and 125 (32%) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92%; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29%, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR ≥ 1.4, p ≤ 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94).. These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning; Treatment Outcome

A pilot study of a novel, reduced-toxicity, myeloablative conditioning regimen using intravenous busulfan 12.8 mg/kg, fludarabine 180 mg/m(2), and melphalan 80 mg/m(2) for single cord blood transplantation (CBT) was conducted at our institution. Fifty-one patients with myeloid malignancies not in remission were included in this study. Their median age was 59 years (range, 19 to 70 years), with a median hematopoietic cell transplantation-specific comorbidity index score of 3. With a median observation period of 39.6 months (range, 24.3 to 90.8 months) among the survivors, overall survival and progression-free survival at 2 years were both 54.9%. Forty-six of 51 achieved neutrophil engraftment at a median of 19.5 days (range, 13 to 38 days) after transplantation, with a cumulative incidence of 90.2%. No patient developed graft rejection in this study. All patients who achieved engraftment showed hematological complete remission with complete donor chimerism. Eleven patients relapsed at a median of 4.9 months (range, .5 to 26.7 months). Cumulative incidences of nonrelapse mortality (NRM) at 100 days and 2 years were 11.8% and 25.5%, respectively. In conclusion, the present results show that the novel conditioning regimen for single CBT provided durable engraftment and remission with acceptable NRM leading to excellent survival, even for a relatively older population with myeloid malignancies not in remission.

Topics: Adult; Aged; Busulfan; Female; Graft Survival; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myeloablative Agonists; Recurrence; Remission Induction; Survival Analysis; Transplantation Conditioning; Vidarabine; Young Adult

Busulfan, fludarabine, and melphalan as hematopoietic cell transplant conditioning, was used in 6 patients aged 1 to 19 years with very high-risk myeloid malignancies. This dose regimen had an acceptable toxicity profile resulting in complete donor engraftment even following transplantation of small 2/6 antigen disparate umbilical cord blood grafts. It provided excellent disease control as all patients had high-risk features in terms of cytogenetics, therapy-related leukemia, and/or significant measurable disease before transplant. All patients remain in remission, without acute or chronic graft-versus-host disease with a median follow-up of 24 months. A larger study is indicated to confirm the efficacy and safety of this regimen.

Topics: Adolescent; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid; Male; Melphalan; Myeloablative Agonists; Myeloproliferative Disorders; Remission Induction; Tissue Donors; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult

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

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

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

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

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Myeloablative Agonists; Neoplasms; Neoplasms, Germ Cell and Embryonal; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antifungal Agents; Antilymphocyte Serum; Antineoplastic Agents; Aspergillosis, Allergic Bronchopulmonary; Base Sequence; Bone Marrow Transplantation; DNA, Mitochondrial; Electron Transport; Female; Genetic Diseases, Inborn; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid; Melphalan; Mitochondrial Diseases; Myeloablative Agonists; Sequence Deletion; Syndrome; Transplantation Conditioning; Transplantation, Homologous; Treatment Failure; Vidarabine

Therapy-related acute myeloid leukemias arise as a result of cytotoxic chemotherapy and/or radiation therapy. The most common types of acute myeloid leukemia arising in this setting are acute myeloid leukemia with maturation, and lesser numbers of acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, or acute megakaryocytic leukemia. We present a patient with multiple myeloma who was treated with melphalan and 4 years later developed acute erythroid leukemia. The morphologic diagnosis of pure erythroid leukemia developing in the setting of multiple myeloma may be challenging.

Topics: Acute Disease; Aged, 80 and over; Antineoplastic Agents, Alkylating; Epistaxis; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Male; Melphalan; Multiple Myeloma; Muscle Weakness

Relapsed acute myeloid leukemia (AML) in adults has a poor prognosis if treated with chemotherapy alone. Case series have previously supported the role of myeloablation and autologous transplantation as a potentially curative treatment. This study aimed to use the large numbers and extended follow-up data in the British Society of Blood and Marrow Transplantation (BSBMT) registry database to establish long-term outcomes and relate these to biological and procedural factors. The BSBMT registry database was used to retrospectively identify 152 adult patients (age, 16-69 years) with AML in second remission treated with autologous transplantation in 1982-2003. Cytogenetic data were available for 68% of the patients; of these, at diagnosis, 42% had good risk features, 57% had standard risk features, and 1% had poor risk features. Conditioning regimens varied; autologous rescue was provided with bone marrow (BM) (71%), peripheral blood stem cells (PBSCs) (18%), or both (11%), which were harvested during first complete remission (CR1) and/or second CR (CR2). Median follow-up was 84 months (range, 2-200 months). At 10 years, actuarial overall survival (OS) was 32%, progression-free survival (PFS) was 28%, and relapse rate (RR) was 57%. The 100-day nonrelapse mortality (NRM) was 7%, rising to 11% at 1 year and to 14% at 10 years. OS was significantly related to M3 subtype (5-year OS, 66%; P = .005), patient age at diagnosis (P = .005) and transplantation (P = .026), and length of CR1, with greatest significance if the patient was dichotomized at CR1 duration of < 8 months or > or = 8 months (P = .0001). There was no difference in OS between regimens containing total body irradiation (TBI) and chemotherapy alone (P = .7). In relation to the nature of autologous graft material, there was improved OS (P = .025) and PFS (P = .009) with the use of cells harvested entirely in CR1 compared with cells harvested in CR2 or in both CR1 and CR2. Engraftment times were significantly shortened with the use of PBSCs alone or in combination with BM compared with BM alone (P = .0001), but there was no significant long-term impact on OS, PFS, RR, or NRM. This study provides long-term follow-up data in one of the largest series of patients with standard-risk and good-risk AML in CR2 treated with autologous transplantation and supports earlier observations that long-term survival is achievable in about 1/3 of patients overall and in about 2/3 of patients with M3 with a relatively low

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Etoposide; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Registries; Remission Induction; Retrospective Studies; Risk Factors; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; United Kingdom; Whole-Body Irradiation

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

Eight children developed osteochondroma (OS) at a mean of 88 months after hematopoietic stem cell transplantation (HSCT). The mean age at HSCT was 56 months (12-84). This represents a cumulative incidence of 20% among patients less than 18 years of age transplanted from 1981 to 1997. These eight patients underwent allogeneic (n = 2) or autologous (n = 6) transplantation for either acute leukemia (n = 6) or neuroblastoma (n = 2) after a conditioning regimen including TBI (n = 7) or a combination of Bu and CY. OS was multiple in seven patients and solitary in one. Eight lesions were resected and all were benign. Four children received growth hormone before diagnosis of OS, but there was no clinical, radiological or histological difference between those who did not. Univariate analysis showed an increased rate associated only with autologous HSCT, with a 31.7% probability of a new OS at 12 years after HSCT. Osteochondroma should be added to the other adverse effects of HSCT in children.

Topics: Actuarial Analysis; Acute Disease; Bone Neoplasms; Busulfan; Child; Child, Preschool; Cranial Irradiation; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid; Male; Melphalan; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Neuroblastoma; Osteochondroma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Whole-Body Irradiation

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

Topics: Acute Disease; Aged; Antineoplastic Agents, Alkylating; Bone Marrow; Chromosome Painting; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 20; Dose-Response Relationship, Drug; Female; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myeloid; Male; Melphalan; Recurrence; Translocation, Genetic; Treatment Outcome

Quantitative expression of neutrophil CD11b/CD18 following chemotherapy (either conventional dose consolidation chemotherapy or high dose chemotherapy with autologous stem cell transplantation) was investigated during the early recovery phase (neutrophil count 0. 5-1.0x109/l) and at full recovery (neutrophil count 1.0-2.5x109/l) following treatment. CD11b/18 expression was normal in stem cell transplantation supported patients during both early and full neutrophil recovery. By contrast CD11b/CD18 expression was markedly decreased in patients who received chemotherapy without stem cell support. These results suggest that recovery of neutrophil count may not always coincide with recovery of neutrophil function and that G-CSF stimulated peripheral stem cell transplantation enhances neutrophil function post chemotherapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; CD18 Antigens; Combined Modality Therapy; Cytarabine; Etoposide; Female; Filgrastim; Gene Expression Regulation, Leukemic; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Macrophage-1 Antigen; Male; Melphalan; Middle Aged; Neoplasm Proteins; Neutropenia; Recombinant Proteins; Remission Induction

Topics: Antineoplastic Agents, Alkylating; Female; Fluorodeoxyglucose F18; Humans; Leukemia, Myeloid; Melphalan; Meningeal Neoplasms; Middle Aged; Neoplasms, Second Primary; Thrombocytosis; Tomography, Emission-Computed

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

Causes of treatment-related death were studied amongst 138 patients with acute myeloid (n = 90) or lymphoblastic (n = 48) leukemia allografted from HLA-identical siblings in first (n = 107) or second (n = 31) remission after a conditioning regimen comprising 110 mg/m2 melphalan and 1050 cGy single-fraction total-body irradiation (TBI) prescribed as maximum lung dose. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (n = 78) or cyclosporine-methotrexate (n = 60). Eighty-one patients died of causes other than relapse 16-2917 days (median 77) after transplantation. The actuarial probability of non-relapse mortality was 62% at 5 years. The major primary causes of death were pneumonitis (n = 38, 47%), GVHD (n = 18, 22%), and sepsis (n = 11, 14%). Pneumonitis contributed to 42 of the deaths (52%), and its etiology was infective (n = 27), idiopathic (n = 14), or a combination of the two (n = 1). On multivariate analysis, GVHD prophylaxis with cyclosporine alone was associated with a higher overall toxic death rate. The use of cyclosporine alone and a low infused cell dose (<2.5 x 10(8) total nucleated cells/kg or <0.6 x 10(8) mononuclear cells/kg) were associated with a higher risk of death from pneumonitis. We conclude that the use of cyclosporine alone as GVHD prophylaxis is associated with increased transplant-related toxicity, and the addition of methotrexate and infusion of a higher number of cells decrease the incidence of fatal pneumonitis.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Child; Child, Preschool; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid; Lung Diseases, Interstitial; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sepsis; Transplantation Conditioning; Whole-Body Irradiation

Forty-four adults with AML (n = 18) or ALL (n = 26) beyond first remission underwent unpurged (n = 39) or purged (n = 5) autografting after 110-140 mg/m2 melphalan and 1050 cGy TBI. ALL patients were eligible to receive maintenance chemotherapy with 6-mercaptopurine and methotrexate for 2 years after hematologic recovery. The duration of first remission was 1-167 months (median 11). The median time to 50 x 10(9)/I platelets was 76 days, and that to 0.5 x 10(9)/I neutrophils 31 days. Eight patients died of transplant-related toxicity; seven within 1 year. Twenty-two patients relapsed at 1-20 months (median 2.5 months). The 3-year probabilities (95% CI) of relapse and disease-free survival are 58% (43-75%) and 31% (17-45%), respectively. The duration of the first remission (< 1 year vs > or = 1 year) and the stage of transplant (second remission vs other) had no effect on relapse or disease-free survival. There was a trend towards higher relapse rates (76 vs 34%) and poorer disease-free survival (19 vs 49%) among ALL patients compared with AML which did not reach significant levels due to small patient numbers. We conclude that melphalan-TBI is a suitable conditioning regimen for autografting in advanced leukemia. The outcome of AML patients is comparable to standard regimens, but the outcome of ALL patients is poor and measures to enhance the anti-leukemic efficacy are necessary.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Leukemia; Leukemia, Myeloid; Male; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

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

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Esophageal Stenosis; Esophagitis; Etoposide; Fatal Outcome; Female; Humans; Immunocompromised Host; Leukemia, Myeloid; Melphalan; Middle Aged

We report our experience with 67 patients with myeloid malignancies (acute myeloid leukaemia (AML) or chronic myelogenous leukaemia (CML) conditioned with busulphan and melphalan as preparation for autologous haemopoietic cell transplantation. The major non-haematological toxicities were severe mucositis, nausea and vomiting, but the marrow aplasia was delayed and of short duration. The anti-tumor effect was appreciable with subsequent chronic phase (CP) obtained in 30/31 CML in transformation and complete remission (CR) obtained in 2/3 refractory AML. Among 32 patients treated while they had no evidence of active disease, 12 remained in CR or CP with a median follow-up of 54.7 months.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Melphalan; Middle Aged

Peripheral blood stem cells (PBSC) were used to augment autologous bone marrow transplantation (ABMT), aiming to hasten engraftment after high dose treatment in a group of heavily pretreated patients. PBSC were obtained by leukapheresis during the rebound after standard chemotherapy. In 11 patients aged 7-17 years, high dose chemotherapy consisted of busulphan 16 mg/kg orally with melphalan 160 mg/m2 intravenously for seven patients, and melphalan 200 mg/m2 intravenously alone for four. The median number of granulocyte-macrophage colony forming units in the reinfused PBSC was 3.42 x 10(4)/kg (3.03-18.01) and bone marrow 12.4 x 10(4)/kg (4.16-28.6). Neutrophil recovery to > or = 0.5 x 10(9)/l and platelet transfusion independence occurred at a median of 14 days (11-18) and 22 days (9-84) respectively. In five patients the early engraftment was transient with neutrophils again dropping below 0.5 x 10(9)/l then slowly recovering. There was one toxic death due to sepsis. PBSC harvesting in these children was undertaken without interrupting routine chemotherapy and without the use of bone marrow growth factors. In some patients PBSC failed to influence engraftment and the use of combined chemotherapy and growth factor priming for PBSC collection may give improved results.

Topics: Acute Disease; Adolescent; Bone Marrow Transplantation; Busulfan; Child; Combined Modality Therapy; Cryopreservation; Female; Hemangiosarcoma; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Leukapheresis; Leukemia, Myeloid; Male; Melphalan; Rhabdomyosarcoma; Sarcoma, Ewing

Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum cytoreduction was achieved by intensive early chemotherapy. Final intensification, with autologous BMT was offered to all those remaining in first complete remission (CR). Patients received two induction and two consolidation courses of intensively scheduled chemotherapy. Cytoreduction was assessed on day 14 and remission was assessed after courses 2 and 4. Bone marrow was harvested after recovery from the second consolidation course or after the first maintenance course and separated on a discontinuous percoll gradient before cryopreservation. Twenty-eight of 31 consecutively enrolled patients achieved CR. Three relapsed early and, of the 25 eligible, 24 underwent autologous BMT. Twenty-three patients received high-dose melphalan and 1 received busulphan and cyclophosphamide before autologous BMT at a median of 113 days (range, 86 to 301) after initial CR. Trilineage engraftment occurred in all. Neutrophil recovery to greater than 0.5 x 10(9)/L occurred at a median of 46 days (range, 13 to 92) after autologous BMT. Platelet recovery was delayed, with a median time to achieve greater than 20 x 10(9)/L of 42 days (range, 18 to 215). With a minimum follow up of 25 months following autologous BMT only 3 children have relapsed. The 5-year event-free survival rate (EFS) from diagnosis is 68% (95% confidence interval, 46% to 90%). Five-year EFS following autologous BMT is 87% (95% confidence interval, 67% to 100%). Autologous BMT with high-dose melphalan administration after intensive chemotherapy has produced EFS equivalent to allogeneic BMT and is associated with a strikingly low relapse rate. High-dose melphalan appears to be a valuable agent for conditioning therapy in AML.

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Infant; Leukemia, Myeloid; Male; Melphalan; Probability; Remission Induction; Survival Analysis; Time Factors; Transplantation, Autologous

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has been used in two clinical studies at the Christie Hospital in Manchester, United Kingdom. Short daily "bolus" injections (over 30 min) were associated with serious toxicity which included bone pain, pruritus and pericarditis. In contrast, continuous infusions did not cause any toxicity and produced significantly higher increments of the peripheral neutrophil counts. rhGM-CSF reduced the period of life-threatening neutropenia following high-dose i.v. melphalan (120 mg/m2). Also, rhGM-CSF shortened the duration of thrombocytopenia induced by this chemotherapy to less time than has been seen historically in conjunction with autologous bone marrow rescue.

Topics: Adult; Colony-Stimulating Factors; Dose-Response Relationship, Drug; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Leukemia, Myeloid; Leukocyte Count; Melphalan; Neutropenia; Neutrophils; Recombinant Proteins

This report describes the development of acute myeloblastic leukemia in a patient after long-term alkylator therapy for multiple myeloma. Despite chromosome deletions -5, -7, the patient lacked the histochemistry and clinical findings characteristic of therapy-induced leukemia. In double-labeled surface marker studies by flow cytometry, the leukemic blast cells co-expressed myeloid and plasma cell surface markers. The findings may support the hypothesis of a single stem cell abnormality's being responsible for both the malignant plasma cells and the myeloid leukemic cells.

Topics: Acute Disease; Antigens, Neoplasm; Antigens, Surface; Bone Marrow; Chromosome Aberrations; Chromosome Disorders; Female; Flow Cytometry; Humans; Leukemia, Myeloid; Melphalan; Middle Aged; Multiple Myeloma; Plasma Cells; Prednisone; Time Factors

A previously untreated 31-yr old female with Ph-positive chronic myeloid leukaemia (CML) received busulphan and melphalan at high dosage followed by an autograft of peripheral blood stem cells collected 4 weeks earlier. Though recovering haemopoiesis was at first mainly Ph-positive, Ph-negative haemopoiesis predominated at 12 months and has persisted until the most recent study (24 months post-autograft). Her haemopoietic cells now show no rearrangement of the bcr gene, unlike the cells collected at diagnosis. Autografting carried out soon after diagnosis could be valuable for obtaining cytogenetic remissions in other patients with CML.

Topics: Adult; Busulfan; Female; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Melphalan; Transplantation, Autologous

We report the case of a patient with scleromyxedema with abnormal monoclonal gamma globulin of the kappa type who was treated with melphalan (Alkeran), an alkylating agent. After nine and one-half years of therapy, the patient showed myelomonocytic leukemia. The risk of secondary malignancies must be considered when weighting the benefits and risks of melphalan treatment.

Topics: Adult; Diabetes Mellitus, Type 1; Humans; Leukemia, Myeloid; Male; Melphalan; Paraproteinemias; Scleroderma, Systemic

K 18, an IgG-Melphalan conjugate was administered to 30 patients, who had recurrent hematopoietic malignancy. Ten out of the 30 patients received single doses of 1 to 20 enteric tablets containing 10 mg of K 18, as a phase I study. No side effects were observed. K 18 was administered every day to the remaining 20 patients in order to evaluate the side effects and therapeutic effects, as a phase II study. One patient attained partial remission. Although no remission effect was obtained in 14 of the 20 patients, antitumor effects such as a decrease in leukemia cells, were observed in 4 of 20 patients. As to side effects, neither recurrence of tumor nor cumulative toxicity were shown in one patient with NHL who received only K 18 for 14 months as maintenance therapy. Evaluation of antitumor effect was difficult in the case of the remaining 4 patients. In the 20 cases who entered the phase II study, a decrease in neutrophils was observed in 2 patients, a slight decrease in platelets in 3 patients and increased transaminase activity in one patient as side effects of K 18. In brief, compared with Melphalan, K 18 has between 1.3 and 2 times a more potent therapeutic effect, with extremely low side effects.

Topics: Administration, Oral; Adolescent; Adult; Drug Administration Schedule; Drug Evaluation; Female; Humans; Immunoglobulin G; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Multiple Myeloma

Dose-effect relationships of high-dose melphalan were evaluated in 37 patients with measurable relapsed or refractory acute leukemias. Thirteen patients (Group 1) received 70-100 mg/m2 of melphalan without marrow rescue and 24 patients (Group 2) received 140-180 mg/m2 of melphalan followed by marrow transplantation. Patients in both groups were comparable with respect to age, sex, diagnosis, and status of the leukemia. The complete remission rate was 23% in Group 1 versus 75% in Group 2 (P less than 0.01). Hematological recovery of remission patients was not statistically different in either group. Nonhematological toxicity was comparable in the two dose ranges examined. These results demonstrate the existence of a dose-response effect of high-dose melphalan regimens in relapsed acute leukemias, without marked increases in nonhematological toxicity with these doses.

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Transplantation; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Hematologic Diseases; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Retrospective Studies

Topics: Anemia, Pernicious; Humans; Hydroxyurea; Leukemia, Myeloid; Male; Melphalan; Middle Aged

Even patients with chronic myelogenous leukemia (CML) in blast crisis were treated with chemotherapy, followed by infusion of autologous bone marrow that had been collected during the chronic phase of the disease and cryopreserved at -198 degrees C. The mean age of the nine females and two males in this study was 34 years with an average duration of the chronic phase of the disease of 5.5 years. Seven out of the 11 patients had a splenectomy prior to intensive chemotherapy. The median survival of the first four patients who received 6-thioguanine, cytosine arabinoside, daunorubicin (TAD) chemotherapy was 2.6 weeks and no patient reachieved the chronic phase of CML. The second group of seven patients received more intensive chemotherapy (MAdHAT), which included melphalan 30 mg/m2 days 1, 2, and 3; Adriamycin 50 mg/m2 intravenously (iv) day 1, hydroxyurea 1500 mg/m2 by mouth for 5-7 days, cytosine arabinoside 100 mg/m2 continuous infusion for 5-7 days, and VM-26 100 mg/m2 iv on day 3. Six out of these seven patients reachieved chronic phase CML after bone marrow reinfusion. The median survival was 29.9 weeks for all patients and 33 weeks for the six patients who reachieved chronic phase CML. All patients subsequently died of recurrent blast crisis. There was no correlation between the time of bone marrow storage and the duration of subsequent chronic phase CML. These studies have shown that autologous bone marrow transplantation after high-dose chemotherapy can result in bone marrow engraftment with reestablishment of chronic phase CML, and prolongation of survival.

Topics: Adult; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Doxorubicin; Female; Freezing; Humans; Hydroxyurea; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Teniposide; Thioguanine; Tissue Preservation; Transplantation, Autologous

Chronic granulocytic leukemia (CGL) developed in a 31-year-old man after he underwent a third renal transplant. The leukemia was initially controlled with azathioprine sodium and prednisone therapy, but eventually it entered blast cell crisis. This was controlled with an adult acute lymphocytic leukemia protocol with an excellent response. Despite discontinuing treatment with azathioprine and with the use of busulfan to control the peripheral WBC count, the patient maintained stable renal function for one year following treatment of the blast cell crisis and subsequently died of sepsis. We suggest that CGL after renal transplantation is similar to that observed in the general population and can be treated with the usual chemotherapeutic agents for the disorder without sacrificing renal function.

Topics: Adult; Allopurinol; Azathioprine; Humans; Hydroxyurea; Kidney Transplantation; Leukemia, Myeloid; Male; Melphalan; Postoperative Complications; Prednisone

We report a 59-year-old patient with chronic myeloid leukemia, who developed severe interstitial lung fibrosis after short term and sequential treatment with melphalan and busulfan. The probable additive toxicity of both agents on the pulmonary tissue is discussed.

Topics: Busulfan; Drug Synergism; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Pulmonary Fibrosis

Eighteen months after the occurrence of Waldenström's macroglobulinemia, Philadelphia (Ph1) chromosome-positive chronic myeloid leukemia developed in a 69-year-old woman. The coexistence of the two disorders was characterized by an initial reduction of paraproteinemia at the time that leukemia occurred, a long-lasting remission of the two disorders, and a final parallel increase of paraproteins and WBCs. Since leukemia occurred 15 months after the interruption of melphalan therapy, the potential mutagenic role of chemotherapy was considered irrelevant. Therefore, Waldenström's macroglobulinemia might favor the occurrence of chronic myeloid leukemia.

Topics: Aged; Bone Marrow; Chromosomes, Human, 21-22 and Y; Female; Humans; Leukemia, Myeloid; Melphalan; Time Factors; Waldenstrom Macroglobulinemia

The case histories of 4 patients who developed bone marrow damage after therapy with melphalan are described. In 3 patients bone marrow damage manifested initially as a sideroblastic anaemia which was later followed by acute myeloid leukaemia. The last patient developed a dyserythropoietic anaemia with leucopenia, but thus far there has been no further progression. None of the 4 patients had any haematological abnormality prior to the melphalan therapy. Two were suffering from carcinoma of the breast and 2 had ovarian neoplasms. The fact that melphalan was given as adjuvant therapy in all 4 patients prior to the development of the haematological abnormalities supports the concept that it was of aetiological importance. These findings are in line with a number of reports in the literature in which acute leukaemia has developed in subjects treated for malignant tumours (especially multiple myeloma and ovarian cancer) with melphalan.

Topics: Acute Disease; Aged; Antineoplastic Agents; Bone Marrow Diseases; Female; Humans; Leukemia; Leukemia, Myeloid; Melphalan; Middle Aged

Topics: Bone Marrow; Cystadenoma; Female; Humans; Leukemia, Myeloid; Melphalan; Middle Aged; Ovarian Neoplasms; Radiotherapy

Topics: Adult; Aged; Antineoplastic Agents; Busulfan; Chlorambucil; Female; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Multiple Myeloma; Pleural Effusion; Pulmonary Fibrosis

Thirty-three patients with newly diagnosed chronic granulocytic leukemia (CGL) were treated with melphalan between 1968 and 1976. Within 3 mo of beginning therapy subjective and objective disease parameters improved. Disease control was easily maintained with this agent until hematologic exacerbation occurred. The median duration of disease control was 25.3 mo, and the median duration of survival was 28.6 mo. Serious side effects were not produced. Thus melphalan appears to be another agent that may be used to control the manifestations of CGL prior to hematologic exacerbation.

Topics: Adolescent; Adult; Aged; Female; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Splenic Diseases

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

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

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

Rapidly fatal acute myelomonocytic leukemia developed in five patients with multiple myeloma who were treated with melphalan for 28 to 54 months. In each patient, multiple myeloma responded to therapy and progress was satisfactory until the development of acute leukemia. At postmortem examination, leukemic infiltration of organs was seen, and there was little or no evidence of myeloma. Consideration of these cases and a review of the literature suggest that these circumstances represent the development of acute myelomonocytic leukemia rather than plasma cell leukemia; there also appears to be an increased incidence of acute leukemia in multiple myeloma, probably related to the alkylating agent.

Topics: Acute Disease; Aged; Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Bone Neoplasms; Hemoglobins; Humans; Leukemia, Myeloid; Leukemia, Plasma Cell; Leukocyte Count; Male; Melphalan; Microscopy, Electron; Middle Aged; Multiple Myeloma; Plasma Cells; Prednisone; Testosterone; Time Factors

Topics: Antineoplastic Agents; Breast Neoplasms; Busulfan; Carcinogens; Cyclophosphamide; Humans; Leukemia, Myeloid; Lung Neoplasms; Melphalan; Methotrexate; Neoplasms; Pancreatic Neoplasms; Rectal Neoplasms; Triaziquone; Urinary Bladder Neoplasms

Topics: Agranulocytosis; Antineoplastic Agents; Busulfan; Cyclophosphamide; Humans; Leukemia, Myeloid; Melphalan; Multiple Myeloma

Topics: Antineoplastic Agents; Benzene; Bone Marrow Diseases; Chloramphenicol; Cyclophosphamide; Dose-Response Relationship, Radiation; Humans; Immunosuppressive Agents; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Leukemia, Radiation-Induced; Melphalan; Multiple Myeloma; Phenylbutazone; Phenytoin; Polycythemia Vera

Topics: Aged; Agranulocytosis; Bone Marrow; Bone Marrow Cells; Cell Survival; Child; Creatinine; Cyclophosphamide; Female; Humans; Leukemia, Myeloid; Leukocyte Count; Male; Melphalan; Methotrexate; Middle Aged; Muramidase; Neutrophils; Phosphorus Isotopes; Time Factors; Vinblastine

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

Topics: Aged; Autopsy; Blood Cell Count; Blood Protein Disorders; Blood Protein Electrophoresis; Bone Marrow; Bone Marrow Cells; Cytarabine; Daunorubicin; Humans; Immunoelectrophoresis; Immunoglobulin G; Leukemia, Myeloid; Male; Melphalan; Multiple Myeloma; Prednisone

Topics: Adult; Aged; Esterases; Female; Histocytochemistry; Humans; Immunosuppression Therapy; Leukemia, Myeloid; Male; Melphalan; Microscopy, Electron; Middle Aged; Multiple Myeloma; Myeloma Proteins; Peroxidases; Plasma Cells

Topics: Agammaglobulinemia; Antibodies; Antigens, Bacterial; Blood Protein Disorders; Blood Proteins; Busulfan; Chlorambucil; Electrophoresis, Paper; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulins; Immunosuppression Therapy; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mannomustine; Melphalan; Primary Myelofibrosis; Radiation Effects; Saliva; Skin Tests; Spleen; Time Factors

Topics: Adult; Antibody Formation; Bence Jones Protein; Female; Humans; Immunoglobulin G; Leukemia, Myeloid; Male; Melphalan; Monocytes; Multiple Myeloma; Muramidase; Plasma Cells

Topics: Blood Protein Disorders; Cryoglobulins; Cyclophosphamide; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Melphalan

Topics: Autopsy; Bone Marrow Diseases; Female; Humans; Leukemia, Myeloid; Melphalan; Middle Aged; Radiography

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

Topics: Adolescent; Antineoplastic Agents; Busulfan; Child; Cyclophosphamide; Drug Therapy; Humans; Infant; Leukemia; Leukemia, Myeloid; Melphalan; Mercaptopurine; Multiple Myeloma; Neoplasms; Phosphorus Isotopes; Prednisone