Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up

Abstract

Reduced-intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative conditioning. We prospectively analyzed the outcomes of 292 consecutive patients, median age 58 years (range, 19 to 75) with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total body irradiation (200 cGy) with or without antithymocyte globulin and cyclosporine and mycophenolate mofetil graft-versus-host disease (GVHD) prophylaxis followed by allogeneic HCT at the University of Minnesota from 2002 to 6. Probability of 5-year overall survival was 78% for patients with indolent non-Hodgkin lymphoma, 53% for chronic myelogenous leukemia, 55% for Hodgkin lymphoma, 40% for acute myelogenous leukemia, 37% for myelodysplastic syndrome, 29% for myeloma, and 14% for myeloproliferative neoplasms. Corresponding outcomes for relapse were 0%, 13%, 53%, 37%, 39%, 75%, and 29%, respectively. Disease risk index (DRI) predicted both survival and relapse with superior survival (64%) and lowest relapse (16%) in those with low risk score compared with 24% survival and 57% relapse in those with high/very-high risk scores. Recipient cytomegalovirus (CMV)-positive serostatus was protective from relapse with the lowest rates in those also receiving a CMV-positive donor graft (29%). The cumulative incidence of 2-year nonrelapse mortality was 26% and was lowest in those receiving a matched sibling graft at 21%, with low (21%) or intermediate (18%) HCT-specific comorbidity index, and was similar across age groups. The incidence of grades II to IV acute GVHD was 43% and grades III to IV 27%; the highest rates were found in those receiving an unrelated donor (URD) peripheral blood stem cell (PBSC) graft, at 50%. Chronic GVHD at 1 year was 36%. Future approaches incorporating alternative GVHD prophylaxis, particularly for URD PBSC grafts, and targeted post-transplant antineoplastic therapies for those with high DRI are indicated to improve these outcomes.

Weight‐based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation

“…Although the association between higher MMF dose and lower rates of acute GVHD has been previously reported by our group and others, there was a large interstudy variability on the approach used for MMF dosing for GVHD prophylaxis. [4][5][6]9,11,12,[24][25][26] While some transplant centers use fixed dose of MMF, 4,5,11,15,26 others use weight-based guided MMF dosing approach. 5,12,13 We previously showed that MMF dose of 3g/d vs. two prior studies that reported favorable effect of ≥30 mg/kg MMF dose on acute GVHD did not show increased risk of relapse.…”

“…MMF was continued in patients who developed acute GVHD before day + 30 until 7 days after resolution of all GVHD symptoms. Supportive care and UCB graft selection criteria have been previously reported 2‐4,6,15 …”

“…2,14 RIC regimen uniformly consisted of cyclophosphamide, fludarabine, and low-dose TBI for both MSD and UCB alloHCT. 3,14,15 Equine antithymocyte globulin (ATG) was used as part of conditioning regimen for those patients who had not received immunosuppressive chemotherapy within 3 months or prior autologous transplantation within 12 months of alloHCT. 3,14 MMF was administered at total dose of to day + 30 of alloHCT.…”

Transfusion burden following reduced intensity allogeneic hematopoietic cell transplantation: Impact of donor type

“…All were adults with a diagnosis of hematological malignancy who received their first allogeneic HCT using RIC conditioning with cyclophosphamide/fludarabine/total body irradiation (Cy/Flu/TBI), a modification including low dose melphalan and post HCT Cy or Cy/Flu/TBI plus anti‐thymocyte globulin (ATG) for those without multidrug intensive chemotherapy in the preceding 3 months 1 …”

“…All were adults with a diagnosis of hematological malignancy who received their first allogeneic HCT using RIC conditioning with cyclophosphamide/fludarabine/ total body irradiation (Cy/Flu/TBI), a modification including low dose melphalan and post HCT Cy or Cy/Flu/TBI plus anti-thymocyte globulin (ATG) for those without multidrug intensive chemotherapy in the preceding 3 months. 1 We enumerated the complete and detailed transfusion data from day À10 to day 100 post HCT linked to the patient demographics including age, sex, race/ethnicity, and diagnosis. The donor and graft type, disease risk index (DRI), conditioning regimen, GvHD prophylaxis, Karnofsky performance score (KPS), and HCTcomorbidity index (HCT-CI) and extent of ABO match (ABO match/ minor mismatch / major mismatch / bidirectional) were considered as potential covariates that might influence blood product utilization.…”