Impact of Postgrafting Immunosuppressive Regimens on Nonrelapse Mortality and Survival after Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplant Using the Fludarabine and Low-Dose Total-Body Irradiation 200-cGy

Abstract

The development of nonmyeloablative (NM) hematopoietic cell transplantation (HCT) has extended the potential curative treatment option of allografting to patients in whom it was previously contraindicated because of advanced age or comorbidity. Acute and chronic graft versus host disease (GVHD) and its consequent nonrelapse mortality (NRM), remains the major limitation of NM HCT. In this report, we analyzed the outcome of 67 patients (median age, 45 years) with hematologic diseases receiving NM conditioning with fludarabine 90 mg/m(2) and total body irradiation (TBI) 200-cGy, followed by filgrastim-mobilized peripheral blood stem cell transplant from HLA identical (n = 61), 5/6 antigen-matched related (n = 1), 6/6 antigen-matched unrelated (n = 3), and 5/6 antigen-matched unrelated (n = 2) donors. The first cohort of 21 patients were given cyclosporine (CSP) and mycophenolate mofetil (MMF) as postgrafting immunosuppression, whereas the subsequent cohort was given additional methotrexate (MTX) and extended duration of CSP/MMF prophylaxis in an attempt to reduce graft-versus-host disease (GVHD). Sixty-four (95%) patients engrafted and 3 (5%) had secondary graft failure. Myelosuppression was moderate with neutrophil counts not declining below 500/microL in approximately 25% of patients, and with more than half of the patients not requiring any blood or platelet transfusion. The 2-year cumulative interval (CI) of grade II-IV, grade III-IV acute GVHD and chronic GVHD were 49%, 30%, and 34%, respectively. The 2-year probability of NRM, overall (OS), and progression-free (PFS) survival were 27%, 43%, and 28%, respectively. GVHD-related death accounted for 85% of NRM. Compared with patients receiving CSP/MMF, patients receiving extended duration of CSP/MMF with additional MTX in postgrafting immunosuppression had a significantly lower risk of grade III-IV acute GVHD (CI 20% versus 52%; P = .009) and NRM (CI at 2 years: 11% versus 62%; P < .001), without any significant adverse impact on the risk of relapse (CI at 2 years: 59% versus 33%; P = .174) Subgroup analysis of a cohort of patients given MTX/CSP/MMF showed that patients with "standard risk" diseases (n = 21) had a 3-year OS and PFS of 85% and 65%, respectively. This compares favorably to the 41% (P = .02) and 23% (P = .03) OS and PFS, respectively, in patients with "high-risk" diseases (n = 25). In conclusion, the addition of MTX onto the current postgrafting immunosuppression regimen with extended CSP/MMF prophylaxis duration provides more effective protection against severe GVHD, and is associated with more favorable outcome in patients receiving NM fludarabine/TBI conditioning than in patients receiving fludarabine/TBI conditioning with CSP and MMF without MTX.

Favorable impact of pre-transplant ATG on outcomes of reduced-intensity hematopoietic cell transplants from partially mismatched unrelated donors

“…7 The best outcomes with allogeneic transplantation are achieved through transplantation of hematopietic progenitor cells from an HLA-matched related or unrelated donor; however, even in this setting grades II-IV acute GVHD (aGVHD) occur in 30-50% of patients. 6,8 Further, for any degree of HLA disparity, OS generally decreases as a consequence of nonrelapse mortality from GVHD and complications arising from its management. 9,10 The use of antithymocyte globulin (ATG) as in vivo T-cell depletion for the prevention of GVHD has been studied in the unrelated donor (URD) transplant setting, primarily following myeloablative conditioning.…”

“…[1][2][3][4][5] In principle, use of a RIC reduces immediate toxicities of the transplant maneuver, but the patient remains subject to morbidity and mortality associated with GVHD. 6 The ultimate efficacy of the transplant therefore depends on successful achievement of a balance between graft versus tumor effects necessary for eradication of the malignancy and complications associated with GVHD and immune incompetence. 7 The best outcomes with allogeneic transplantation are achieved through transplantation of hematopietic progenitor cells from an HLA-matched related or unrelated donor; however, even in this setting grades II-IV acute GVHD (aGVHD) occur in 30-50% of patients.…”

Mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced-intensity conditioning

“…Recently, Koh et al [34] reported that the post-grafting MTX combined with cyclosporine and MMF significantly reduced the risk of grade III-IV acute GVHD as compared with a combination of cyclosporine and MMF. Consistent with their experience, the cumulative incidence of severe acute GVHD after our triple combination was 5%, encouragingly lower than those previously reported in the analysis of unrelated BMT through the Japan Marrow Donor Program, while the incidence of extensive chronic GVHD was apparently similar [27,35].…”

The hematopoietic stem cell transplantation in Indonesia: an unsolved dilemma

“…2 During mid-1990s when neighbouring countries started their allogeneic BMT programme, patients were referred to Singapore and Malaysia. [3][4][5][6][7][8][9][10] There was a hope at that time that allogeneic BMT would also be performed in Indonesia, that is, in Semarang and Jakarta but was later stopped after having been done in small number of patients.…”