Regimen-related toxicity after fludarabine–melphalan conditioning: a prospective study of 31 patients with hematologic malignancies

Abstract

Summary:A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/ m 2  5 days and melphalan 70 mg/m 2  2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m 2 and ATG 30 mg/kg  4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabinemelphalan has considerable activity and leads to durable remission in a proportion of patients. Bone Marrow Transplantation (2003) 32, 471-476. doi:10.1038/sj.bmt.1704166 Keywords: fludarabine; melphalan; nonmyeloablative; transplantation Patients with advanced hematologic malignancies are considered incurable with conventional chemotherapy, but can occasionally be cured with allogeneic transplantation. The impact of allogeneic transplantation is unfortunately limited because of high recurrence rates and due to treatment-related complications in patients with considerable comorbidities. A number of new preparative regimens have been evaluated, which avoid the use of full-dose TBI.1-3 For patients considered ineligible for TBI, we studied the fludarabine-melphalan preparative regimen and report our experience in 31 consecutive patients. This regimen was developed specifically for patients with advanced hematologic malignancies. 1 We confirmed its ability to induce engraftment but observed considerable regimen-related toxicity associated with this regimen that could not be explained solely by patient selection. Patients and methods Patients and protocolPatients were eligible if they had hematologic malignancies including acute and chronic leukemia and myeloproliferative disorders, non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma. Patients with acute leukemia in first remission were enrolled only if they had unfavorable cytogenetics.Additional eligibility criteria included, Karnofsky performance status greater than or equal to 60%, bilirubin less than or equal to 2 mg/dl, creatinine less than 1.5 times normal.Patients were enrolled on this protocol only if they were considered ineligible for TBI, because o...

Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from veno-occlusive disease

“…1,23,24 In addition, our series reports no cases of VOD. This observation is in contrast to previous studies where, although the incidence and severity was less than in full intensity regimens, morbidity 25 and mortality 26 from VOD were still reported.…”

Cardiac toxicity of high-dose chemotherapy

“…68 Surprisingly, after an initial report 59 of about 2.5% incidence of grade IV/V cardiac toxicity with this combination, this unexpected side effect has been confirmed in three other reports, with incidence up to 14% and outcomes variable from complete reversibility with standard medical treatment 69 to toxic deaths. 70,71 These data clearly contrast with the reported rarity of cardiotoxicity with either agent individually. The mechanism of this unique toxicity is not known, as none of the patients had a history of cardiac disease and all of them had normal pre-transplant cardiac function and limited, if any, previous exposure to anthracyclines.…”

“…Some authors have found that older age represents a risk factor for the development of cardiovascular side effects, 28,80 while others have not. 17,70,97,98 It should be noted, however, that studies in which a positive correlation was found are those in which older patients (up to 65 years old) were included. Finally, an association of risk of CHF with age has been proposed for patients receiving anthracycline-based chemotherapy.…”

Outcomes of patients with AML and MDS who relapse or progress after reduced intensity allogeneic hematopoietic cell transplantation

“…Occasionally for sex-mismatched donor/recipient pairs, fluorescence in situ hybridization for X and Y chromosomes was used. 12,13 No lineage-specific engraftment analysis (e.g. T-cell chimerism) was available.…”