Abstract

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years, the field has not only seen an improvement in transplantation technology thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells including chimeric antigen receptor T-cell (CART-cell) and T-cell receptors (TCRs) has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established multi-stakeholder task force consisting of transplant experts, payer representatives and a patient advocate to provide guidance on indications for HCT and IECT. This manuscript presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence, (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but has been shown to be effective therapy, (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exist but large clinical trials and observational studies are not feasible, (4) Developmental, for diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option, and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.

Abstract

INTRODUCTION Disease relapse is the most common cause of therapy failure in non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM). Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either fludarabine (Flu)/2Gy TBI vs. Flu/4Gy TBI. METHODS In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008-2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression and progression-free survival (PFS). RESULTS At baseline the Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients had a higher HCT-CI. On multivariate analysis the two conditioning cohorts were not significantly different in terms of risk of grade 3-4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11-2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03-2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47-1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78-1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively. Relapse was the most common cause of death in both cohorts. CONCLUSIONS In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.

Abstract

In a systematic review and meta-analysis, we compared allogeneic transplant outcomes after myeloablative (MAC) vs. reduced-intensity (RIC) conditioning in patients with MDS. Only two published randomized clinical trials were found, with a pooled sample size of 183 (RIC: 92; MAC: 91). Both studies suggested an overall survival advantage after RIC, with a pooled hazard ratio (HR) of 0.67 (95% confidence interval [CI] 0.41-1.09) for RIC vs. MAC. Relapse results were also concordant, with a pooled HR of 1.55 (95%CI 0.74-3.25) for RIC vs. MAC. Neither result was statistically significant. Comparisons for other outcomes were unremarkable. In conclusion, the evidence for the optimal conditioning intensity in MDS is weak. Post-transplant maintenance strategies and incorporation of genomic information into decision-making may improve post-transplant outcomes.

Abstract

Many patients with multiple myeloma (MM) eventually relapse even after curative intent allogeneic hematopoietic cell transplantation (HCT). Over the past decade, outcomes for patients with MM have significantly improved with the availability of new therapies, including next generation proteasome inhibitors, immunomodulatory agents, and more recently, monoclonal antibodies. While several published studies have evaluated the outcomes of allogeneic HCT for MM, the data on survival outcomes in MM subjects experiencing disease relapse following an allogeneic HCT are limited. In addition, the predictors for post-relapse survival in these patients are not known. In this study, the outcomes of a single-center cohort of MM patients who experienced relapse or progression after allogeneic HCT (n=60) were examined. In addition, we evaluated the utilization of salvage regimens for treatment of relapsed MM and analyzed the predictors for improved post-relapse survival. After a median follow up of 2.2 years from the time of relapse, the median post-relapse survival was 1.8 years (95% Confidence Interval [CI], 1.2-5.0 years). Patients received a median of 3 lines of therapy (range, 0-10) for treatment of MM beyond the post allogeneic HCT relapse/progression. Multivariate analysis demonstrated cytogenetic risk (standard vs. high-risk; HR 0.34, P=0.01), time to relapse after allogeneic HCT (>12 vs. ≤12; HR 0.41, P=0.04) and occurrence of acute graft-versus-host disease (GVHD) before relapse (GVHD vs. no GVHD; HR 2.89, P=0.01) significantly affected post-relapse survival. These data illustrate that long-term myeloma control and survival is attainable in those relapsing/progressing after allogeneic HCT and suggest that the synergism between novel therapies and the allogeneic immune platform is the key to improved survival in this high-risk patient population.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment modality for primary myelofibrosis (MF) and related myeloproliferative neoplasms. Older age at diagnosis and age-related comorbidities make most patients ineligible for alloHCT, given concerns for non-relapse mortality (NRM). Herein, we report the outcomes of 37 consecutive recipients of allogeneic HCT for MF performed at a single center between 2009 and 2018 with a standardized institutional protocol. Most patients received ruxolitinib prior to HCT (n=32), and those with splenomegaly >22 cm received pre-transplant splenic irradiation. Median age at HCT was 60 years (range, 40-74): 68% carried JAK2 driver mutation. All patients received fludarabine/busulfan-based conditioning: 22 patients (59%) received reduced intensity conditioning. All patients received peripheral blood grafts. Sixteen (43%) patients had matched sibling donor, and others had unrelated (n=20) or haploidentical-related donor (n=1). Sixty one percent had an HCT-CI score ≥3, 40% had KPS <90 and 24% had a high-risk DIPSS Plus score. With a median follow-up of 40.2 months (range, 16.9-115), the 3-year overall and relapse-free survival were 81.1% (95% Confidence Interval [95%CI], 64.4-90.5%) and 78.4% (95% CI, 61.4-88.5%), respectively. Only two patients relapsed/progressed after transplant. NRM at 2 years was 16.2% (95% CI, 6.5-29.9%). All patients engrafted. Sixteen patients were treated with ruxolitinib post-transplant for treatment of GVHD, graft rejection/relapse and persistent MF. These results suggest that pre-transplant ruxolitinib, fludarabine/busulfan-based conditioning and splenic management are keys to improved transplant outcomes in MF.

Abstract

INTRODUCTION The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserve grafts before the start of pretransplant conditioning. Post-transplant cyclophosphamide (ptCY), is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. METHODS We analyzed 274 patients with hematologic malignancy undergoing allo-HCT from 2013-2018 with cryopreserved grafts and ptCY. Eighteen received bone marrow and 256, peripheral blood grafts. These were matched for age, graft type, disease risk index (DRI) and propensity score to 1,080 patients that underwent allo-HCT with a fresh graft. The propensity score, which is an assessment of the likelihood of receiving a fresh versus cryopreserved graft, was calculated logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT-comorbidity index, conditioning regimen intensity, donor type and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease GVHD, non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only p-values <0.01 were considered statistically significant. RESULTS The two cohorts (cryopreserved versus fresh) were similar in patient age, KPS, diagnosis, DRI, HCT-comorbidity index, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval, 68.3-73.8%) with fresh grafts and 70.3% (64.6-75.7%) with cryopreserved grafts (p=0.81). Corresponding probabilities of OS survival at two years were 60.6% (57.3-63.8%) and 58.7% (51.9-65.4%) (p=0.62). In matched pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (Hazard Ratio for cryopreserved versus fresh [HR] =1.05, 95% confidence interval, 0.86-1.29, p=0.60). Similarly, rates neutrophil recovery (HR=0.91, 0.80-1.02, p=0.12), platelet recovery (HR=0.88, 0.78-1.00, p=0.05), grade 3-4 acute GVHD (HR=0.78, 0.50-1.22, p=0.27), NRM (HR=1.16, 0.86-1.55, p=0.32) and relapse/progression (HR=1.21, 0.97-1.50, p=0.09) were similar with cryopreserved versus fresh grafts. There were somewhat lower rates chronic GVHD (HR=0.78, 0.61-0.99, p=0.04) and DFS (HR for treatment failure=1.19, 95%CI=1.01-1.29, p=0.04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. CONCLUSIONS Graft cryopreservation does not significantly delay hematopoietic recovery, increase acute GVHD risk or NRM, or decrease overall survival after all-HCT using ptCY.

Abstract

Preclinical research shows that stress-induced activation of the sympathetic nervous system can promote hematopoietic malignancies via beta-adrenoreceptor-mediated molecular pathways. Hematopoietic cell transplant (HCT) recipients exposed to conditions of chronic stress show activation of a conserved transcriptional response to adversity (CTRA) gene expression profile, which in turn is associated with increased relapse and decreased disease-free survival. We conducted a randomized controlled phase 2 biomarker trial testing the impact of the nonselective beta-antagonist propranolol on CTRA-related gene expression of 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected at baseline, day -2, and day +28. Intention-to-treat analyses controlling for demographic characteristics, high-risk disease (International Myeloma Working Group risk score), and tumor stage tested effects on a 53-gene CTRA indicator profile and measures of CTRA-related cellular processes in peripheral blood mononuclear cells. Twelve participants were randomized to the intervention and 13 to the control. Relative to the control group, propranolol-treated patients showed greater decreases from baseline to HCT day -2 and day +28 for both CTRA gene expression (P = .017) and bioinformatic measures of CD16- classical monocyte activation (P = .005). Propranolol-treated patients also showed relative upregulation of CD34+ cell-associated gene transcripts (P = .011) and relative downregulation of myeloid progenitor-containing CD33+ cell-associated gene transcripts (P = .001). Ancillary analyses identified nonsignificant trends toward accelerated engraftment and reduced posttransplant infections in propranolol-treated patients. Peri-HCT propranolol inhibits cellular and molecular pathways associated with adverse outcomes. Changes in these pathways make propranolol a potential candidate for adjunctive therapy in cancer-related HCT.

Abstract

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P=.01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P=.0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.

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

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.