melphalan and Leukemia--Myelomonocytic--Chronic

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

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

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

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

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