Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant

Abstract

Summary:Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count Ͼ0.5 × 10 9 /l and to platelet count of Ͼ20 × 10 9 /l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine-and melphalan-based conditioning promotes full donor chimerism, even following Hematopoietic stem cell (HSC) transplantation has improved the likelihood of disease-free survival for many patients with hematological disorders. Nevertheless, relapse remains the major cause of treatment failure following HSC transplantation performed in patients with advanced hematological malignancies. 1,2 The prospects for patients relapsing after an HSC transplant are limited. Donor leukocyte infusion (DLI) has been demonstrated to be effective in patients with chronic myelogenous leukemia (CML), but has met with limited success in highly proliferative malignancies, such as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). 3,4 Second HSC transplants using allogeneic donors are often attempted, but are fraught with complications. Regimen-related toxicity is usually prohibitive and outcomes are adversely affected by high rates of infection and graft-versus-host disease (GVHD). 2,5-14 Moreover, relapse is common following a second HSC transplant, particularly for patients not in remission at the time of transplantation. Outcomes are particularly poor for patients ...

Cyclosporine and mycophenolate mofetil prophylaxis with fludarabine and melphalan conditioning for unrelated donor transplantation: a prospective study of 22 patients with hematologic malignancies

“…We did not observe any cases of veno-occlusive disease of the liver (VOD) in the seven patients who received Mylotarg before URD HSCT, in contrast to the experience recently reported with this drug, describing a 17% incidence of VOD after HSCT, 11% fatal. 14 Mucositis was observed in 45% of our patients (Bearman grade 2); again, indirect comparison with MTX-based regimens in this respect is difficult due to intrinsic problems with mucositis grading systems, but one study using Flu/Mel and FK-506/MTX reported Bearman grade 2 stomatitis in nine of 11 patients (82%), 15 suggesting that the avoidance of MTX is important in minimizing regimen-related toxicity.…”

“…Recent reports confirm this observation. 3,15 It is expected that RIC regimens will allow a growing number of older and sicker patients with hematological malignancies to benefit from the life-saving potential of URD HSCT. Our encouraging 1-year DFS of 55% for the entire group, and 71% for patients with advanced AML or MDS seems comparable or better than standard dose regimens for younger patients.…”

Long-term remission of APL with a second allogeneic BMT after CNS relapse following HLA-identical allogeneic BMT

“…Bone Marrow Transplantation (2003) 32, 843-846. doi:10.1038/sj.bmt.1704225 Keywords: AML; APL; CNS-relapse; GvL Published data on second allogeneic transplants after leukaemia relapse indicate high treatment related mortalities (TRM) and relapse rates. [1][2][3][4] . In the most recently published series, a 2-year disease-free survival of 21% was found.…”

“…2 Other studies found even higher incidences of fatal complications. 4 The high rate of TRM can be attributed to heavy pretreatment in most patients. For leukaemia relapse, the main reasons may be resistant disease and an insufficient graft-versus-leukaemia (GvL) effect.…”

“…[1][2][3][4] . In the most recently published series, a 2-year disease-free survival of 21% was found.…”