High-dose melphalan and allogeneic peripheral blood stem cell transplantation for treatment of early relapse after allogeneic transplant

Abstract

Summary:Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m 2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66-206). The melphalan dose was 90 mg/m 2 intravenously on days −4 and −3 with PBSC infusion on day 0. GVHD prophylaxis consisted of cyclosporine and methylprednisolone. The median time to an absolute neutrophil count Ͼ0.5 × 10 9 /l and to a platelet count Ͼ20 × 10 9 /l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II-III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56-614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6-614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for shortterm disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence. Bone Marrow Transplantation (2000) second myeloablative conditioning with allograft, 5 and enhancement of the graft-versus-leukemia effect by discontinuation of immunosuppressive therapy or addition of immunocompetent donor cells. [6][7][8][9][10][11][12][13][14][15][16][17][18] Other studies have involved stimulation of donor-derived immune responses or inhibition of the leukemic clone using cytokines such as interferon, G-CSF or interleukin-2. [19][20][21][22][23] Early relapses occurring during the first year post transplant carry an ominous prognosis with few patients responding to immune manipulation, chemotherapeutic maneuvers or second myeloablative therapies, which are associated with an extremely high risk of toxicity and treatment-related mortality.Immunological approaches such as interferon or donor lymphocyte infusion have been generally successful in chronic myelogenous leukemia (CML) relapsing in chronic phase, but not in acute leukemia or CML in transformed phases. The failure of immunological approaches in these diseases may be due in part to the proliferative rate of malignant cells and the long interval required for buffy coat infusions to exert an immune therapeutic effect. Cytoreduction with chemotherapy followed by reinfusion of both immunocompetent and hematopoietic progenitor cells could reinduce remissions in this setting. Cytoreduction with chemotherapy would allow donor-derive...

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

“…This is likely related to the refractory nature of disease in most of our patients, given the early time to relapse following the first transplant procedure. [6][7][8]31 This low intensity conditioning regimen by itself, while having some antileukemic activity, is unlikely to sustain a remission in patients with advanced AML, as has been suggested previously by de Lima et al 31 Others have also suggested that employing a less intensive pretransplant conditioning may increase the risk of relapse in patients with AML. 32 Four of the five patients who suffered relapse never developed acute or chronic GVHD prior to the onset of relapse.…”

Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia

“…All other regimens were categorized as reduced-intensity regimens. 10 Myeloablative preparative regimens included cyclophosphamide in combination with intravenous busulfan (seven patients) or total body radiation7thiotepa (five patients); 11,12 decitabine (eight patients); 13 single agent melphalan (13 patients); 14 intravenous busulfan in combination with fludarabine (two patients), or cyclophosphamide and thiotepa (three patients). 15,16 Reduced-intensity regimens included fludarabine, cytarabine, and idarubicin or cisplatin (two patients), fludarabine and melphalan with/without antithymocyte globulin (19 patients); [17][18][19] fludarabine plus antithymocyte globulin (six patients); fludarabine plus intravenous busulfan (one patient); gemtuzumab ozogamicin, fludarabine, and cytarabine (four patients) or melphalan (one patient).…”

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies

“…5 Melphalan (MEL) is an alkylating agent with demonstrated activity in acute leukemia. 6 A reduced-intensity preparative regimen of FLU and MEL leads to durable engraftment in sibling and unrelated HSCT in adult patients. [7][8][9] However, this approach has not been evaluated in childhood leukemia.…”