Farhadfar, Nosha

Abstract Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

Abstract Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P < .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features.

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 Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)‐Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.

Introduction: Cryopreservation of peripheral blood stem cell (PBSC) or bone marrow (BM) grafts is rarely performed, thus information about the effect of cryopreservation on graft characteristics and HCT outcomes is limited. Given the global pandemic leading to changing practices for donor graft collection and increasing utilization of cryopreservation, we evaluated the outcomes of HCT recipients who received either fresh or cryopreserved allogeneic BM or PBSC grafts. The primary endpoint was engraftment. Secondary endpoints were incidence of acute graft-vs.-host disease (aGVHD), relapse, transplant related mortality (TRM), disease free survival (DFS), and overall survival (OS). Methods: We included 7397 patients transplanted between 2013 and 2018. 1883 cryopreserved graft recipients were divided into three cohorts based on graft source and donor type: matched related (MRD) PBSC (n=1,051), matched unrelated (MUD) PBSC (n=678), and matched related or unrelated bone marrow donors (n=154). All patients received conventional calcineurin-based GVHD prophylaxis strategies. Patients who received cryopreserved grafts were matched with 5514 patients who received fresh adjusting for graft type (BM vs. PB), donor source (MRD vs. 8/8 MUD), Disease Risk Index (DRI, low risk vs. intermediate risk vs. high risk), recipient age (within 5-years) and propensity score (within 1 standard deviation from pooled sample). The propensity score was based on age, Karnofsky score, diagnosis, disease risk index, HCT-comorbidity index, and conditioning intensity. The level of statistical significance for the main analyses was p&lt;0.01 due to multiple comparisons. The reason for cryopreservation was available on a subset of URD product recipients. Results: Baseline characteristics for all cohorts are shown in Table 1. CD34+ doses reflect enumeration at infusion. In univariate analyses, rates of graft failure and neutrophil recovery at day 28 were similar for cryopreserved and fresh grafts for BM or related PBSC recipients but differed in cryopreserved vs. fresh MUD PBSC (5% vs 2%, p&lt;0.001 and 87 vs 94%, p&lt;0.001, respectively). Rates of platelet recovery within 28 days were similar in marrow cohorts, but lower with cryopreserved related (92% vs 96%, p&lt;0.001) and MUD PBSC (87 vs 94%, p&lt;0.001) grafts. In matched pair multivariable analyses, there were no significant differences in any outcomes with cryopreserved vs fresh BM grafts, irrespective of donor type. With related donor PBSC, cryopreservation was associated with decreased platelet recovery (HR=0.73, CI=0.68-0.78, p&lt;0.001) and an increased risk of both grade II-IV (HR=1.27, CI=1.09-1.48, p=0.002) and grade III-IV (HR=1.48, CI=1.19-1.84, p&lt;0.001) aGVHD, but had no impact on other outcomes. In contrast, with MUD PBSC grafts, cryopreservation was associated with delayed engraftment of neutrophils (HR=0.77, CI=0.71-0.84, p&lt;0.001) and platelets (HR=0.61, CI=0.56-0.66, p&lt;0.001), an increased risk of TRM (HR=1.4, CI=1.18-1.66, p&lt;0.001) and relapse (HR=1.32, CI=1.11-1.58, p=0.002), and decreased DFS (HR=1.36, CI=1.20-1.55, p&lt;0.001) and OS (HR=1.38, CI=1.22-1.58, p&lt;0.001) but did not affect the incidence of aGVHD. In a subset analysis of 299 URD recipients, the most common reason for cryopreservation was delays due to patient-related events, eg., additional chemotherapy, infection. These recipients had decreased OS compared to products cryopreserved for non-patient reasons (HR=0.65, CI=0.44-0.96, p=0.029). Conclusions: The retrospective nature of this analysis, and the fact that cryopreservation is likely to have been performed in recipients with a different (higher) risk profile compared to those receiving fresh products limits our ability to draw firm confusions. Despite these limitations, we conclude that cryopreservation in some patient populations may have a negative impact on engraftment and transplant outcomes. The decision to cryopreserve donor grafts, particularly PBSC grafts, should be carefully considered and highlights the need for further investigation of the effect of cryopreservation of allogeneic grafts where patient factors can be controlled for. Disclosures Farhadfar: CSL Behring: Research Funding; Incyte pharmaceutical: Other: Member of GVHD advisory forum. Frey:Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Syntax: Consultancy, Honoraria. Devine:Magenta Therapeutics: Consultancy. Shaw:Orca Bio: Consultancy. Wingard:Shire: Other: Personal Fees - serve on data monitoring committee for clinical trial; Ansun: Other: Personal Fees - serve on data monitoring committee for clinical trial; Merck: Other: Personal Fees - serve on data monitoring committee for clinical trial; Cidara: Other: Personal Fees - serve on data monitoring committee for clinical trial; ReViral: Other: Personal Fees - serve on data monitoring committee for clinical trial.

BackgroundThe association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.MethodsThis study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014‐2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.ResultsThe median age was 55 years (range, 18‐83 years). The median PCS was –0.21 (range, –1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was –0.13 (range, –1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00‐1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00‐1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02‐1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.ConclusionsPatients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.

BackgroundMultiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard‐risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent.MethodsThis study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187).ResultsAfrican Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation–Comorbidity Index (HCT‐CI). Fewer African Americans with t(11;14) (21%) had a coexistent high‐risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression‐free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30‐0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT‐CI, and receipt of maintenance.ConclusionsRace may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.

BackgroundUpfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults.MethodsThe authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression‐free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori.ResultsAn increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m2 overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m2. On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1‐1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9‐1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1‐1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1‐1.4 [P = .02]) compared with the reference group (those aged 60‐69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m2 was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m2, including day 100 NRM (1% [95% CI, 1%‐2%] vs 0% [95% CI, 0%‐1%]; P = .003]), 2‐year PFS (64% [95% CI, 60%‐67%] vs 69% [95% CI, 66%‐73%]; P = .003), and 2‐year OS (85% [95% CI, 82%‐87%] vs 89% [95% CI, 86%‐91%]; P = .01]), likely representing frailty.ConclusionsThe results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.