Abstract

Reduced-intensity conditioning (RIC) has been facilitating allogeneic hematopoietic cell transplantation (allo-HCT) for patients originally considered ineligible for HCT with myeloablative conditioning. Fludarabine (Flu) with reduced doses of busulfan (Bu) (Flu + Bu) and Flu with reduced doses of melphalan (Mel) (Flu + Mel) are widely used RIC regimens for acute myeloid leukemia (AML). A nationwide retrospective study comparing clinical outcomes of adult patients with AML receiving first allo-HCT after RIC between 2001 and 2010 was performed. Cumulative incidences of relapse were not significantly different among the Flu + ivBu-based (FBiv), Flu + poBu-based (FBpo), and Flu + Mel-based (FM) groups (p = 0.29). Non-relapse mortality (NRM) was significantly lower in patients receiving FBiv compared with FBpo (p = 0.003) and FM (p < 0.001). On multivariate analysis, there was no significant difference in overall survival, but FM was associated with a significantly lower risk of relapse (hazard ratio (HR) = 0.65, 95% confidence interval (CI): 0.50-0.85, p = 0.002), higher NRM (HR = 1.60, 95% CI: 1.10-2.33, p = 0.013) and better leukemia-free survival (HR = 0.77, 95% CI: 0.63-0.95, p = 0.015) compared with FBiv. These results suggest that Flu + Mel has a more intense disease control potential and Flu + ivBu is less toxic than the other. Both RIC regimens provide similar survival outcomes and are effective and useful regimens for patients with AML who received allo-HCT.

Abstract

The long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC) remain inconclusive. To address this issue, we conducted a nationwide registry-based study of patients with acute myeloid leukemia (AML) age 50 years or older who underwent allogeneic HCT in complete remission using RIC (n = 284) or myeloablative conditioning (MAC, n = 190) between 2002 and 2007. The median follow-up period for surviving patients was 10.1 years for RIC recipients and 10.4 years for MAC recipients. The 10-year probabilities of overall survival, relapse, and non-relapse mortality were 36.4%, 30.0%, and 35.7% for RIC recipients, and 39.8%, 26.3%, and 35.5% for MAC recipients, respectively. Multivariate analysis revealed that the conditioning intensity did not affect overall mortality (P = 0.184), relapse (P = 0.904), or non-relapse mortality (P = 0.387). For the 218 patients qualifying for propensity score-matched pairing (109 pairs), RIC was found to be associated with similar survival (P = 0.095) and relapse (P = 0.467), and significantly lower non-relapse mortality (P = 0.046) compared with MAC. Our results confirm the long-term efficacy of RIC allogeneic HCT for older patients with AML and mitigate concerns over an increase in late relapse.

Abstract

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Abstract

To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P < 0.01) than did FM-TBI regimen due to higher non-relapse mortality (HR, 1.72; P = 0.02). In addition, mycophenolate mofetil-containing GVHD prophylaxis was associated with better OS than methotrexate-containing GVHD prophylaxis among patients who received FM-TBI (HR, 0.65; P = 0.03) and FC-TBI (HR, 0.25; P < 0.01) regimens due to a decreased relapse risk. In summary, our results suggest that all three RIC/RTC regimens have comparable clinical outcomes in ALL, while the FM-TBI or FC-TBI regimens combined with mycophenolate mofetil-containing GVHD prophylaxis is preferable in RIC/RTC-UCBT for ML. Large prospective studies are warranted to confirm these results.

Abstract

CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by non-myeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than one prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m(2)). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m(2)/day IV on days -7 through -3) and cyclophosphamide (1 g/m(2)/day IV on days -4 through -3). The primary objective was to determine the six-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host (GVHD), disease-free survival (DFS) and overall survival (OS). Sixty patients were enrolled, of which 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49, 90% CI 0.10-9.3%). Moderate to severe (grade 2-3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of non-protocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate.

Abstract

Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L x h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

Abstract

Importance: Reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimens are frequently used in allogeneic hematopoietic cell transplant (HCT) for non-Hodgkin lymphoma. However, the optimal RIC-NMAC regimen in allogeneic HCT for non-Hodgkin lymphoma is not known. Objective: To investigate whether RIC-NMAC regimens at a higher end of the intensity spectrum are associated with increased nonrelapse mortality and lower overall survival compared with RIC-NMAC regimens at the lower end of the intensity spectrum in patients with non-Hodgkin lymphoma undergoing allogeneic HCT. Design, Setting, and Participants: This cohort study used data from 1823 adult patients with non-Hodgkin lymphoma in the Center for International Blood and Marrow Transplant Research registry. Included patients underwent allogeneic HCT using matched related or unrelated donors between January 2008 and December 2016. Statistical analysis was performed from June 1, 2019, to February 10, 2020. Interventions: Patients received 1 of 4 RIC-NMAC regimens: fludarabine-intravenous busulfan (Flu-Bu), approximately 6.4 mg/kg (n = 458); fludarabine-melphalan (Flu-Mel140), 140 mg/m2 (n = 885); fludarabine-cyclophosphamide (Flu-Cy) (n = 391); or Flu-Cy with 2 Gy total body irradiation (Flu-Cy-2GyTBI) (n = 89). Main Outcomes and Measures: The primary outcome was overall survival. Secondary outcomes were nonrelapse mortality, incidence of relapse, progression-free survival, and the incidence of acute and chronic graft-vs-host disease (GVHD). Results: Of 1823 patients, 1186 (65%) were male, with a mean (SD) age of 54.8 (9.9) years. The 4-year adjusted OS was 58% in the Flu-Bu cohort, 67% in the Flu-Cy-2GyTBI cohort, 49% in the Flu-Mel140 cohort, and 63% in the Flu-Cy cohort (P < .001). After adjustment for age, Karnofsky performance score, HCT comorbidity index, NHL subtype, remission status at HCT, and the use of antithymocyte globulin or alemtuzumab, the regression analysis showed a significantly higher mortality risk associated with Flu-Mel140 compared with Flu-Bu (hazard ratio [HR], 1.34; 95% CI, 1.13-1.59; P < .001). Compared with the Flu-Cy cohort, the Flu-Mel140 cohort had a higher risk of chronic GVHD (HR, 1.38; 95% CI, 1.15-1.65; P < .001). The Flu-Mel140 regimen was associated with a higher nonrelapse mortality risk (HR, 1.78; 95% CI, 1.37-2.31; P < .001) compared with the Flu-Bu regimen. Conclusions and Relevance: The findings suggest that use of the more intense RIC-NMAC regimen, Flu-Mel140, may have a negative association with overall survival and may be associated with higher nonrelapse mortality. The Flu-Bu and Flu-Cy regimens with or without 2GyTBI regimens appeared to provide comparable overall survival.

Abstract

BACKGROUND Reduced-intensity conditioning (RIC) regimens are frequently used for allogeneic hematopoietic cell transplantation (allo-HCT) in diffuse large B-cell lymphoma (DLBCL). However, the RIC regimen with the best risk/benefit profile for allo-HCT in DLBCL is not known. This is particularly important, as patients with DLBCL undergoing allo-HCT in the future would be enriched for those whose lymphoma has failed chimeric antigen receptor T-cell (CAR-T) therapy or other novel immunotherapies, with potentially more advanced disease and suboptimal performance scores. Using the CIBMTR database, we report the outcomes of the three most commonly used allo-HCT RIC regimens in DLBCL. METHODS 562 adult DLBCL patients in the CIBMTR registry undergoing allo-HCT using matched related or unrelated donors, between 2008-2016 were included in the analysis. Patients received one of the three RIC regimens: fludarabine/i.v. busulfan (~6•4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m(2)) (Flu/Mel140) or BCNU/etoposide/cytarabine/melphalan (BEAM). FINDINGS The study cohort was divided into three groups: Flu/Bu (n=151), Flu/Mel140 (n=296) and BEAM (n=115). Relative to Flu/Bu, the Flu/Mel140 (HR=2.33, 95%CI=1.42-3.82; p=0.001) and BEAM (HR=2.54, 95%CI=1.34-4.80; p=0.004) regimens were associated with a higher non-relapse mortality (NRM) risk. Although the risk of relapse with Flu/Mel140 was lower compared to Flu/Bu (HR=0.70, 95%CI=0.52-0.95; p=0.02), this did not translate in an improvement in progression-free (HR=1.04) or overall survival (HR=1.30). There was a significantly higher risk of grade 3-4 acute graft-versus-host disease with BEAM (HR=2.19, 95%CI=1.10-4.35; p=0.03) compared to Flu/Bu. In the chemosensitive subset, multivariate analysis showed a significantly higher mortality risk with Flu/Mel140 (HR=1.48, 95%CI=1.07-2.04, p=0.02) relative to Flu/Bu conditioning. CONCLUSIONS In the largest analysis comparing the impact of various RIC conditioning regimens on the survival of DLBCL patients undergoing allo-HCT, our results suggest that Flu/Bu is a better RIC choice in less fit or heavily pretreated patients due to lowest NRM risk.

Abstract

Reduced-intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo-HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)-matched sibling or unrelated donor allo-HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0.01. There were no significant differences between regimens in risk for non-relapse mortality (NRM) (P = 0.54), relapse/progression (P = 0.02) or progression-free survival (PFS) (P = 0.14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo-HCT (HR = 0.28; 95% CI = 0.10-0.73; P = 0.009), but beyond 11 months post allo-HCT it was associated with a significantly higher risk of mortality, (HR = 2.46; 95% CI = 0.1.32-4.61; P = 0.005). Four-year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0.64), respectively. These data confirm the choice of RIC for allo-HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo-HCT (possibly due to late NRM events).