Impact of type of reduced-intensity conditioning regimen on the outcomes of allogeneic haematopoietic cell transplantation in classical Hodgkin lymphoma.
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ABSTRACT:
SUBMITTER: Ahmed S
PROVIDER: S-EPMC7575614 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine-fludarabine-melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine-fludarabine-melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.
| S-EPMC5193224 | biostudies-literature
Project description:We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan (FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM-TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission [CR1] 72%, median follow-up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60.8 years, AML 62%, CR1 69%, median follow-up: 22.4 months) RIC regimen. In multivariate analysis, FB2A2 was associated with significant lower overall survival (OS, HR: 2.14; 95%CI: 1.05-4.35, P = 0.04) and higher relapse incidence (RI, HR: 2.17; 95%CI: 1.02-4.61, P = 0.04) and a trend for lower leukemia-free survival (LFS, HR: 1.75; 95%CI: 0.94-3.26, P = 0.08). These results were confirmed using a propensity score-matching strategy. However, when considering AML and MDS patients separately, the benefit of the CLOB2A2 regimen was restricted to AML patients (2-year OS FB2A2: 38% [14.5-61.6] vs. CloB2A2: 79.2% [62.9-95.4], P = 0.01; 2-year LFS FB2A2: 38% [16-59.9] vs. CloB2A2: 70.8% [52.6-89], P = 0.03). The better survivals were due to the lower risk of relapse in this CloB2A2 AML subgroup (2-year RI FB2A2: 41.2% [19-62.4] vs. CloB2A2: 16.7% [5-34.2], P = 0.05). This retrospective comparison suggests that the CloB2A2 RIC regimen can likely provide longer survival than that awarded by a FB2A2 RIC regimen and may become a new standard of care RIC regimen for allotransplanted AML patients. A prospective phase 3 randomized study is warranted.
| S-EPMC5119961 | biostudies-literature
Project description:ImportanceReduced-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.ObjectiveTo 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 participantsThis 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.InterventionsPatients 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 measuresThe 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).ResultsOf 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 relevanceThe 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.
| S-EPMC7273311 | biostudies-literature
Project description:Reduced-intensity conditioning (RIC) regimens are frequently used for allogeneic hematopoietic cell transplantation (allo-HCT) in patients with 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 because 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 Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report the outcomes of the 3 most commonly used allo-HCT RIC regimens in patients with DLBCL. Our analysis included a total of 562 adult DLBCL patients in the CIBMTR registry undergoing allo-HCT using matched related or unrelated donors, between 2008 and 2016. Patients received 1 of 3 RIC regimens: fludarabine/i.v. busulfan ~6.4 mg/kg (Flu/Bu), fludarabine/melphalan 140 mg/m2 (Flu/Mel140), or BCNU/etoposide/cytarabine/melphalan (BEAM). Accordingly, the study group was divided into 3 groups: Flu/Bu (n = 151), Flu/Mel140 (n = 296), and BEAM (n = 115). Relative to Flu/Bu, the Flu/Mel140 (hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.42 to 3.82; P = .001) and BEAM (HR, 2.54; 95% CI, 1.34 to 4.80; P = .004) regimens were associated with a risk of higher nonrelapse mortality (NRM). Although the risk of relapse with Flu/Mel140 was lower than that with Flu/Bu (HR, .70; 95% CI, .52 to .95; P = .02), this did not translate to improved progression-free survival (HR, 1.04) or overall survival (HR, 1.30). There was a significantly higher risk of grade III-IV acute graft-versus-host disease with BEAM compared with Flu/Bu (HR, 2.19; 95% CI, 1.10 to 4.35; P = .03). In the chemosensitive subset, multivariate analysis showed a significantly higher mortality risk with Flu/Mel140 (HR, 1.48; 95% CI, 1.07 to 2.04; P = .02) relative to Flu/Bu conditioning. In the largest analysis comparing the impact of various RIC 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.
| S-EPMC7972998 | biostudies-literature
Project description:Reduced intensity conditioning (RIC) regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients and up to 2 years for 311 patients who underwent a RIC HCT at two institutions from January 2008 to December 2010. Multiple linear regression was used to analyze the association between clinical variables, center effect, and costs. Patient and transplant characteristics were comparable between the sites, although differences were seen in pretransplant performance scores. Significant predictors for lower costs for the first 100 days included a diagnosis of lymphoma/myeloma and use of human leukocyte antigen-matched related donors. Grade II-IV acute graft-versus-host disease (GVHD) was associated with higher costs. The overall short-term costs between the two institutions were comparable when adjusted for clinical variables (p = .43). Late costs between 100 days and 2 years after HCT were available for one cohort (n = 311); median costs during this period were $39,000 and accounted for 39% of costs during the first 2 years. Late costs were not associated with any pretransplant variables, but were higher with extensive chronic GVHD and death. After adjustment for clinical characteristics, the overall costs of the RIC transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/alternative donors, transplant for diseases other than lymphoma or myeloma, and acute GVHD were predictors for higher early costs, and extensive chronic GVHD and death were associated with higher late costs.
| S-EPMC4041670 | biostudies-literature
Project description:Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunodeficiency characterized by severe systemic hyper-inflammatory responses to infectious or other triggers of the immune system. In many patients, the underlying cause of HLH is a genetic defect leading to defective CD8(+) T cell and natural killer cell granule-mediated cytotoxicity. The treatment of HLH consists principally of immune suppression followed by allogeneic haematopoietic cell transplantation (HCT) to cure the underlying defect and prevent relapse of HLH. Initial treatment regimens consist of steroids coupled with either etoposide or antithymocyte globulin, ± ciclosporin. Complete responses are observed in only 50-75% of patients and even after a complete response, relapse and death still occur. The only definitive, long-term cure for patients with genetic forms of HLH is allogeneic HCT. Unfortunately, allogeneic HCT for patients with HLH is often complicated by critical illness, extensive organ involvement, active infections, or refractory HLH. For these reasons, patients are unusually prone to developing transplant-related toxicities and complications. In recent years, great strides have been made with regard to the care and transplantation of patients with HLH. Here we review the current state of the treatment of patients with HLH with allogeneic HCT, highlighting the important steps forward that have been made with reduced-intensity conditioning.
| S-EPMC3155668 | biostudies-literature
Project description:We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3-111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29%-41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16%-27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach.
| S-EPMC3376237 | biostudies-literature
Project description:Large, multicenter studies comparing commonly used reduced-intensity conditioning (RIC) approaches in follicular lymphoma (FL) have not been performed. Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) versus fludarabine, cyclophosphamide, and rituximab (FCR) in FL patients. We evaluated 200 FL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received RIC with either Flu/Bu (n = 98) or FCR (n = 102) during 2008 to 2014. All patients received peripheral blood grafts, and graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches. Median follow-up of survivors in the Flu/Bu and FCR groups was 48 months and 46 months, respectively. On univariate analysis in the Flu/Bu and FCR groups, the 3-year rates of nonrelapse mortality (11% versus 11%, P = .94), relapse/progression (18% versus 15%, P = .54), progression-free survival (PFS) (71% versus 74%, P = .65), and overall survival (OS) (73% versus 81%, P = .18) were not significantly different. On multivariate analysis no difference was seen between the FCR and Flu/Bu cohorts in terms of grades II to IV (relative risk [RR], 1.06; 95% confidence interval [CI], .59 to 1.93; P = .84) or grades III to IV (RR, 1.18; 95% CI, .47 to 2.99; P = .72) acute GVHD, nonrelapse mortality (RR, .83; 95% CI, .38 to 1.82; P = .64), relapse/progression (RR, .99; 95% CI, .49 to 1.98; P = .97), PFS (RR, .92; 95% CI, .55 to 1.54; P = .76), or OS (RR, .70; 95% CI, .40 to 1.23; P = .21) risk. However, RIC with FCR was associated with a significantly reduced chronic GVHD risk (RR, .52; 95% CI, .36 to .77; P = .001). RIC with either Flu/Bu or FCR in patients with FL undergoing allo-HCT provides excellent 3-year OS, with acceptable rates of nonrelapse mortality. FCR-based conditioning was associated with a lower risk of chronic GVHD.
| S-EPMC5743624 | biostudies-literature
Project description:Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.
| S-EPMC6234373 | biostudies-literature
Project description:Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m(2)), melphalan (140 mg/m(2)), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.
| S-EPMC3998675 | biostudies-literature