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

The outcomes of patients with primary plasma cell leukemia (pPCL) after undergoing hematopoietic cell transplantation (HCT) in the novel agent era are unknown. We report outcomes of 348 patients with pPCL receiving autologous (auto-) HCT (n = 277) and allogeneic (allo-) HCT (n = 71) between 2008 and 2015. Median age was 60 years and 56 years for auto- and allo-HCT respectively. For auto-HCT, the 4-year outcomes were: non-relapse mortality (NRM) 7% (4-11%), relapse (REL) 76% (69-82%), progression-free survival (PFS) 17% (13-23%), and overall survival (OS) 28% (22-35%). Karnofsky performance status (KPS) > 90 and ≥very good partial response (VGPR) predicted superior OS in multi-variate analysis for auto-HCT. For allo-HCT, the 4-year outcomes were: NRM 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%). Compared with prior CIBMTR pPCL patients (1995-2006), inferior survival was noted in the current cohort (3-year OS, 39% vs. 38% in allo-HCT, and 62% vs. 35% in auto-HCT) respectively. However, we noted an increased HCT utilization, from 12% (7-21%) in 1995 to 46% (34-64%) in 2009 using SEER data (available till 2009). Despite modern induction translating to higher proportion receiving HCT, the outcomes remain poor in pPCL patients, mainly derived by high relapse rates post-HCT.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

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

Efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median overall survival (OS) of less than 10months. Allogeneic hematopoietic cell transplantation (allo-HCT) is commonly offered as a consolidative treatment option in RS. To our knowledge, there are no randomized controlled studies that have compared allo-HCT against other therapies in RS; available allo-HCT data are limited to small case series from single-institution or registry studies. We performed a systematic review and meta-analysis to assess the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS. We extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], complete remission [CR], OS, and progression-free survival [PFS]). For harms, data were extracted on non-relapse mortality (NRM) and relapse post-allografting. Our search strategy identified 240 studies, but only four studies (n=72 patients) met our inclusion criteria. Pooled ORR, CR, OS, and PFS rates were 79%, 33%, 49%, and 30%, respectively. Pooled NRM and relapse rates were 24% and 28%, respectively. Results of this systematic review and meta-analysis indicate that allo-HCT yields encouraging OS in RS, thus remaining a reasonable treatment option in fit patients whose disease demonstrates a chemosensitive response to pre-transplant salvage therapies. Novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients.

Abstract

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient's own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.

Abstract

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source. 646 patients were identified (MA-BM=79, MA-PB=183, RIC-BM=192, RIC-PB=192). The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD (HR 1.53, 95% CI 1.11-2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11-2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT. Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.

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

INTRODUCTION Waldenstrom macroglobulinemia (WM) is an IgM-producing lymphoproliferative disorder that remains incurable. Patients with high-risk disease have an overall survival (OS) of less than 3 years. Both autologous (AHCT) and allogeneic (allo-HCT) hematopoietic cell transplantation (HCT) are prescribed for treatment of WM despite a lack of randomized controlled studies. MATERIALS AND METHODS We performed a comprehensive literature search using PubMed/Medline and EMBASE on September 10, 2019. Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors. Fifteen studies (8 AHCT [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis. RESULTS Pooled OS, progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76% (95% confidence interval [CI], 65%-86%), 55% (95% CI, 42%-68%), and 4% (95% CI, 1%-7%), respectively. Pooled OS, PFS, and NRM rates post allografting were 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 29% (95% CI, 23%-34%), respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% (95% CI, 72%-94%) and 81% (95% CI, 69%-91%), respectively. Pooled complete response rates post AHCT and allo-HCT were 22% (95% CI, 17%-28%) and 26% (95% CI, 7%-50%), respectively. Relapse rates post AHCT and allo-HCT were 42% (95% CI, 30%-55%) and 23% (95% CI, 18%-28%), respectively. CONCLUSIONS Our results show that both AHCT and allo-HCT are effective in the treatment of WM. A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT. The role of transplant in WM needs to be addressed in the era of novel agents.

Abstract

Bone health disturbances occur commonly after hematopoietic cell transplantation (HCT) with loss of bone mineral density (BMD) and avascular necrosis (AVN) being foremost. BMD loss is related to pre-transplant chemotherapy and radiation exposures, immunosuppressive therapy for graft-versus-host-disease (GVHD), and results from deficiencies in growth or gonadal hormones, disturbances in calcium and vitamin D homeostasis, as well as osteoblast and osteoclast dysfunction. While the pathophysiology of AVN remains unclear, high-dose glucocorticoid exposure is the most frequent association. Different societal treatment guidelines for osteoporosis exist but focus mainly on menopausal-associated osteoporosis. HCT survivors comprise a distinct population with unique comorbidities, making general approaches to bone health management sometimes inappropriate. To address a core set of 16 frequently asked questions (FAQ) relevant to bone health in HCT, the American Society of Transplant and Cellular Therapy (ASTCT) Committee on Practice Guidelines convened a panel of experts in HCT, adult and pediatric endocrinology, orthopedics and oral medicine. Due to a lack of relevant prospective controlled clinical trials that specifically address bone health in HCT, the answers to the presented FAQs rely on evidence derived from retrospective HCT studies, results extrapolated from prospective studies in non-HCT settings, relevant societal guidelines, and expert panel opinion. Given heterogenous comorbidities and needs of individual HCT recipients, answers to FAQs in this article should be considered as general recommendations with good medical practice and judgment ultimately dictating care of individual patients. Readers are referred to the supplement for answers to additional FAQs that did not make the core set.