Center For International Blood And Marrow Transplant Research Research Articles

CURRENT USE AND OUTCOMES OF HEMATOPOIETIC STEM CELL TRANSPLANTATION: BRAZILIAN SUMMARY SLIDES – 2024

The development of the Brazilian Registry of Hematopoietic Cell Transplantation in collaboration with the Center for International Blood and Marrow Transplant Research (CIBMTR) allowed for an assessment of the activity and general outcomes of transplants in Brazil. Here, we report an updated activity. Brazilian transplant centers report their data to the CIBMTR, using the FormsNet3 platform. Information returns to Brazilian Cellular Therapy and Bone Marrow Transplant Society (SBTMO) through the Data Back to Centers (DBtC) tool. Data from patients who received an HCT from 2012 to 2023 from Brazilian centers were extracted from CIBMTR. Descriptive analysis was carried out by patient-, disease- and transplant-specific variables and overall survival analysis using Kaplan Meyer. A total of 12,230 patients were eligible for this study (5,573 autologous and 6,657 allogeneic transplants). The number of reporting centers increased from 40 to 44 during the period. The most common HCT indication in Brazil is AML for allogeneic HCT with 152 transplants year and multiple myeloma for autologous HCT with 245 transplants per year. Among allogeneic HCT, in the last 4 years, mismatched related donor was the main source of donors. Regarding the graft source for allogeneic transplants, BM was the most frequent among pediatric transplants, while PBSC was the most used in adults. Infections were the leading cause of death in the first 100 days after all types of transplants. Patients with acute leukemia who underwent HCT with advanced stage disease had lower survival rates compared to those at other stages. Despite the differences in the number of cases and follow-up time, the results in this study were similar to those presented in the United States (US) Summary Slides.

Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT.

Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.

An Optimal Multi-Locus HLA-Typing in Potential Donors of Allogeneic Hematopoietic Stem Cells

Background. HLA-typing and matched donor selection as well as the detection of donor-specific anti-HLA antibodies are essential for allogeneic hematopoietic cell transplantation (allo-HSCT). In accordance with the guidelines of the Center for International Blood and Marrow Transplant Research (CIBMTR) optimal HLA-typing is performed on 11 HLA genes (-A, ‐B, ‐C, ‐DRB1, ‐DRB3/4/5, ‐DQA1, ‐DQB1, ‐DPA1, and ‐DPB1) with an adequate coverage aiming to obtain the values at the two-field level.
 Aim. To assess the results of multi-locus HLA-typing in bone marrow/hematopoietic cell donors from the database at the National Research Center for Hematology in terms of their conformance with the CIBMTR guidelines for allo-HSCT and to analyze the frequency and distribution of HLA alleles and multi-locus HLA haplotypes.
 Materials & Methods. The study enrolled 3485 donors who were HLA-typed by next-generation sequencing.
 Results. In all donors, the alleles of HLA class I genes were identified at the fourth-field level (nucleotide sequence). When the results were reduced to the second-field level (amino acid sequence), 61 HLA-A, 92 HLA-B, and 49 HLA-C alleles were detected. The alleles of class II genes were discovered either at the two-field or high-resolution levels. Among the HLA-DRB locus genes, 57 DRB1, 11 DRB3, 6 DRB4, and 5 DRB5 alleles were identified. Also, 23 HLA-DQA1, 30 HLA-DQB1, 14 HLA-DPA1, and 33 HLA-DPB1 alleles were detected. There were reported 3289 different HLA haplotypes of A-B-C-DRB1-DQA1-DQB1-DPA1-DPB1 genes.
 Conclusion. The database created at the National Research Center for Hematology includes potential bone marrow/hematopoietic stem cell donors typed for 11 classical polymorphic genes HLA-A, ‐B, ‐C, ‐DRB1, ‐DRB3/4/5, ‐DQA1, ‐DQB1, ‐DPA1, and -DPB1, which is in line with the guidelines of CIBMTR. The frequency and distribution of HLA alleles and multi-locus HLA haplotypes in our donors correspond to those in populations of European origin. HLA-typing and donor selection with regard to 11 HLA genes will contribute to improving the outcomes of both unrelated and haploidentical HSCTs.

Incorporating patient-reported outcome data into a predictive calculator for allogeneic hematopoietic cell transplantation recipients.

The Center for International Blood and Marrow Transplant Research (CIBMTR) provides a 1-year overall survival calculator to estimate outcomes for individual patients before they undergo allogeneic hematopoietic cell transplantation (HCT) to inform risk. The calculator considers pre-HCT clinical and demographic characteristics, but not patient-reported outcomes (PROs). Because pre-HCT PRO scores have been associated with post-HCT outcomes, the authors hypothesized that adding PRO scores to the calculator would enhance its predictive power. Clinical data were obtained from the CIBMTR and the Blood and Marrow Transplant Clinical Trials Network. The PRO measures used were the 36-Item Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation. One thousand thirty-three adult patients were included. When adjusted for clinical characteristics, the SF-36 physical component score was significantly predictive of 1-year survival (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81-0.95; p=.0015), whereas the mental component score was not (HR, 1.02; 95% CI, 0.95-1.10; p=0.6396). The baseline single general health question on the SF-36 was also significantly associated with mortality (HR, 1.91 for those reporting fair/poor health vs. good, very good, or excellent health; 95% CI, 1.33-2.76; p=.0005). The addition of PRO scores to the calculator did not result in a significant change in the model's predictive ability. Self-reported pre-HCT scores were strongly predictive of self-reported health status (odds ratio, 3.35; 95% CI, 1.66-6.75; p=.0007) and quality of life (odds ratio, 3.24; 95% CI, 1.93-5.41; p<.0001) after HCT. The authors confirmed the significant, independent association of pre-HCT PRO scores with overall survival, although adding PRO scores to the survival calculator did not improve its performance. They also demonstrated that a single general health question was as accurate as the full measure for predicting survival, an important finding that may reduce respondent burden and promote its inclusion in routine clinical practice. Validation of these findings should be performed.

Donor Hematopoietic Cell Telomere Length and Magnitude of Post-HCT Shortening Predict Survival in Early Stage Leukemia and Myelodysplastic Syndrome

Introduction. Telomere length (TL) reflects cell replicative history and residual replicative potential. Telomeres in donated hematopoietic cells (HCs) shorten considerably after hematopoietic cell transplant (HCT) because of the extensive proliferation required to reconstitute the recipient hematopoietic system. Longer telomeres in donor HCs are associated with better survival post-HCT in patients with severe aplastic anemia (Gadalla et al., JAMA 2015; Blood 2018). However, it is unclear whether donor HC TL affects survival of patients receiving HCT for hematological malignancies. Methods. We identified 384 patients with leukemia or myelodysplastic neoplasms who received HCT between 2013 and 2016 at 1 st complete remission/early disease stage, and had post-HCT blood samples at day 90 (standard deviation: SD=14 days) in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 1202 repository. Pre-HCT matched donor samples were available at the Center for International Blood and Marrow Transplant Research (CIBMTR) biorepository. TL was measured by Southern blotting of the terminal restriction fragments. We used Cox proportional hazard models to evaluate the associations between HCT outcomes and (i) long donor HC telomeres (defined as ≥6.7 kb), and (ii) low post-HCT telomere shortening of donor HC TL (defined as &amp;lt;230 bp and calculated as the difference between pre-HCT donor HC TL and that in the recipient post-HCT). The telomere thresholds were determined by exploratory analyses relating HC TL parameters with recipients' outcomes. Study outcomes are 2-year overall survival (OS), relapse risk, and non-relapse mortality (NRM). We also calculated the adjusted cumulative risks of all-cause and cause-specific mortality associated with the two HC TL parameters using cause-specific competing risk methods. Follow-up started at day 100 post-HCT. Results. Patients' mean age was 49.6 years (SD=18) and that of the donors was 37.9 years (SD=15). About half (54.7%) of the patients received HCT from unrelated donors, and 9% from haplo-identical related donors. The 2- year OS probabilities were higher in patients receiving HCT from donors with HC TL ≥6.7 kb compared to those receiving HCT from donors with HC TL below this threshold (76% and 63%, respectively; p log-rank = 0.009). Similarly, recipients with telomere shortening of donated HCs ≥230 bp post-HCT compared with those below this threshold experienced better 2-year OS(78% and 62%, respectively; p=0.003). These associations remained significant after adjusting for donor age and predictive clinical factors (HR= 0.60, p = 0.03 for donor HC TL ≥ vs. &amp;lt; 6.7 kb; and HR = 1.95, p = 0.003 for donated HC telomere shortening post-HCT below vs. ≥ 230 bp). The leading cause of excess mortality differed by HC TL parameters. Donor HC TL of ≥6.7 kb was associated with lower risk of NRM (HR= 0.45, 95% CI = 0.22 - 0.93, p = 0.03; 2-year NRM risk of 9.0% vs. 15%). However, post-HCT telomere shortening of &amp;lt;230 bp was associated with higher risk of relapse (HR=1.82, 95% CI = 1.11 - 1.82, p=0.02; 2-year relapse-mortality risk of 28% vs. 12%) (Figure 1A). When considering the combined effect of donor HC TL and magnitude of TL shortening in recipient, the adjusted cumulative risk of all-cause mortality dropped in half (from 41% in patients with donor HC TL &amp;lt;6.7 kb and telomere shortening &amp;lt;230 bp to 21% in those with donor HC TL ≥6.7 kb and telomere shortening ≥230 bp (Figure 1B) Conclusions. Short telomeres in donated HCs and their limited telomere shortening after HCT are associated with poor survival in patients receiving HCT for hematological malignancies at 1st complete remission/early disease stage. The study suggests that TL in donors prior to HCT may be a useful marker for improved donor selection independent of age. Less HC telomere shortening in the recipients during the first 90 days might identify patients at higher risk for relapse of hematological malignancies.

Multicenter, Real-World Study in Patients with R/R Large B-Cell Lymphoma (LBCL) Who Received Lisocabtagene Maraleucel (liso-cel) in the United States (US)

Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells that has demonstrated efficacy and favorable safety based on clinical studies. Liso-cel is approved in the US for the treatment of adults with R/R LBCL after 1 or more lines of systemic therapy, but data describing outcomes in patients treated with liso-cel in the real-world setting are limited. We report real-world clinical effectiveness and safety of commercial liso-cel in patients with R/R LBCL based on a postmarketing study using data collected at the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods: This is a noninterventional, observational, multicenter study of US patients who were followed in the CIBMTR Cellular Therapy Registry between February 2021 and November 2022 after infusion with commercial liso-cel (conforming product only) for the treatment of R/R LBCL. Patients who received nonconforming product are being followed in a separate postmarketing study. The primary objective was to evaluate the real-world clinical effectiveness and safety outcomes of patients with R/R LBCL receiving liso-cel, including ORR, CR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results were analyzed and reported descriptively. Results: At data cutoff (May 4, 2023), 323 patients who received commercial liso-cel across &amp;gt; 50 treatment sites were included in the analysis. The median vein-to-vein time (from leukapheresis to liso-cel infusion) was 36 days (IQR, 34‒42), which is consistent with clinical studies of liso-cel. The median age was 70 years (range, 24‒91). Patients included those with high-risk disease (Table). Most patients had DLBCL not otherwise specified (NOS; 81%), 27% had disease transformed from indolent lymphoma, 12% had high-grade B-cell lymphoma (HGBCL), 37% had International Prognostic Index (IPI) ≥ 3, 6% had active CNS involvement, and 15% had prior transplant. The median number of prior lines of systemic therapy was 3 (range, 0‒11), with 25% of patients having received ≥ 4 lines. The median time from diagnosis to liso-cel infusion was 1.4 years (range, 0.2‒29.7). At a median follow-up of 7.4 months, ORR was 79%, with a 65% CR rate. Median time to response was 1.2 months (IQR, 1.0‒3.1). The median DOR has not been reached; DOR rate at 6 months was 73% (95% CI, 66%‒79%). The median PFS and median OS had not been reached at the time of data cutoff. Estimated 6-month PFS and OS rates were 64% and 82%, respectively. Most events of CRS and ICANS were of low grade, with no CRS and ICANS reported in 48% and 70% of patients, respectively. Overall, 52% of patients had CRS and 3% had grade ≥ 3 events. There was a high concordance on CRS grading per Lee 2014 and American Society for Transplantation and Cellular Therapy criteria. The most common treatments for CRS were tocilizumab (20%) and corticosteroids/tocilizumab (12%). ICANS was seen in 30% of patients, with grade ≥ 3 events in 11%. ICANS was mostly treated with corticosteroids (12%) and corticosteroids/antiepileptics (5%). Based on the attributed cause of death, grade 5 CRS or ICANS were observed in 3 and 3 patients, respectively, and all but 2 patients had concomitant causes of death, including disease progression (n = 3) and hemophagocytic lymphohistiocytosis (n = 2). Prolonged cytopenia (grade 4 thrombocytopenia and/or neutropenia persistent at 30 days postinfusion) occurred in 10% of patients. Conclusions: This is the first large, multicenter, real-world study of patients with R/R LBCL who received commercial liso-cel in the US. Baseline characteristics of patients treated in the real-world setting were consistent with or worse than the liso-cel registrational study experience, including the percentage of patients who had received ≥ 4 lines of prior systemic therapy (25% vs 26% in TRANSCEND). One-time infusion of liso-cel demonstrated deep and durable responses in patients with R/R LBCL across a broad age range, including those with high-risk features characteristic of poor prognosis. The incidence of severe (grade ≥ 3) CRS and ICANS was low. These results further support liso-cel as a therapeutic option with a favorable benefit/risk profile for a broad, real-world population of patients with R/R LBCL.

Age-Related Differences in Utilization of Allogeneic HCT for Acute Myeloid Leukemia in California: Results of a Population-Based, Novel Linked Dataset

Background: Acute myeloid leukemia (AML) predominantly affects older adults (median age at diagnosis is 67yrs), and often requires allogeneic hematopoietic cell transplantation (alloHCT) for cure. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), beginning in 2001, the largest growth in alloHCT for malignant diseases occurred in patients ≥65yrs. However, whether this is due to expanded utilization of alloHCT for newly diagnosed AML is unclear. Using a novel linked dataset, we examined patients with newly diagnosed AML in California to assess population-based alloHCT utilization over time and factors associated with receipt of alloHCT across age groups. Methods: Data obtained from a linkage between the CIBMTR database, California Cancer Registry (CCR) and Patient Discharge Data (PDD) included adolescents and young adults (AYA, 15-39y), adults (40-64y) and older adults (65-79y) with AML diagnosed between 2001-2016. Patients who received no induction chemotherapy, those who received autologous HCT, or had unspecified HCT type were excluded. Multivariable Fine-Gray regression analyses accounting for the competing risk of death were modeled separately across age cohorts. Results: 7,925 patients with newly diagnosed AML were included. AYAs comprised 15% of the cohort compared with adults (41%), and older adults (43%). Within the adult and older adult cohorts, the majority were non-Hispanic White, while 41% of the AYAs were Hispanic. Most AYA and adult patients had private health insurance; most older adults received Medicare. More AYAs (25%) had the lowest neighborhood SES relative to adults (15%) and older adults (14%). Approximately 30-40% of adults and older adults had 3+ comorbidities (using Elixhauser Comorbidity Index). Within each age cohort, approximately 25% of patients lived &amp;gt;50 miles from a transplant center. Examination of alloHCT utilization over time demonstrated that the use of alloHCT has increased within each age cohort (Figure 1). Although utilization among older adult patients increased from 2% to 13% at 2 years post AML diagnosis, the absolute magnitude of change was lowest in this age group and remains far lower than AYA and adult patients. Multivariable models (Figure 2) demonstrate that patient-level variables associated with alloHCT utilization also vary by age group. For AYAs, alloHCT utilization was lower for low and middle neighborhood SES (vs. high), uninsured and those covered by County/Public Health Service (vs. private insurance); and utilization was higher for males and more recent year of diagnosis. For adults, alloHCT utilization was lower for patients with increased age, male sex, non-Hispanic Black or Asian race/ethnicity (vs. non-Hispanic White), unmarried status (vs. married), low and middle SES, uninsured, Medicaid, Medicare, and County/Public Health Service, and 1-2 or ≥3 comorbidities (vs none); utilization was higher for more recent diagnosis year and patients living &amp;lt;50 miles distance from a transplant center (vs. 100+ miles). For older adults, utilization decreased with increasing age and was lower among Asian and unmarried patients, whereas more recent diagnosis year was associated with higher utilization. Conclusions:Using a novel population-based linked database encompassing &amp;gt;99% of newly diagnosed AML patients in California, we found that alloHCT utilization increased in all age cohorts over time; however, fewer than 14% of older adults who received leukemia induction ultimately received alloHCT even in the most recent era studied. As potential patient-level barriers to alloHCT differ across age groups, studies should explore further modifiable age-related factors and develop age-specific interventions to mitigate barriers to alloHCT utilization.

Predictors of Cytokine Release Syndrome and Neurotoxicity in Patients with Large B-Cell Lymphoma and Their Impact on Survival

Background: Autologous CAR-T therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). However, morbidity and mortality related to CAR-T toxicity remain significant concerns. This study aims to evaluate the patterns, risk factors, and implications of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19-CAR-T therapy in LBCL. Methods: This retrospective analysis includes 1916 LBCL patients treated with CD19-CAR-T cell therapy (axicabtagene-ciloleucel [axi-cel] 75% and tisagenlecleucel 25%) between 2018 and 2020 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patient demographics, baseline characteristics, treatment-related variables, and clinical outcomes were collected. The incidence, severity and timing of onset of CRS and ICANS (according to median time to onset) were analyzed, factors associated with these outcomes and their impact on overall survival as time dependent covariates were done using Cox Regression multivariate analyses. Results: The median age of the patients was 64 years, with a majority having a Karnofsky performance status (KPS) below 90% (61%) and not receiving bridging therapy (67%). CRS was observed in 75.1% of patients, with 9% experiencing severe CRS (grades ≥ 3). Similarly, 43% of patients experienced ICANS, with 20% having severe ICANS (grade ≥ 3). The median time to toxicity was shorter for CRS (4 days) compared to ICANS (7 days). Nearly all the patients who developed ICANS also experienced CRS (98%; ), and the correlation between these two events and respective severities are shown in the Figure 1a. In the multivariate analyses, factors associated with development of CRS were gender (women, Odds ratio [OR] 1.39, 95% confidence interval [CI] 1.10- 1.76, p=0.006), high LDH at time of infusion (OR 1.56; 95% CI 1.22 - 2.00, p=0.002) and product (axi-cel OR 4.60, 95% CI 3.56 -5.81, p&amp;lt;0.001). Factors associated with the development of ICANS included age (&amp;gt; 65 years, OR 1.83; 1.50-2.24, p&amp;lt;0.001), KPS (&amp;lt;80%, OR 2.48; 1.88-3.27, p&amp;lt;0.001), disease status at infusion (treatment resistant disease, OR 1.98; 1.09-3.58, p=0.024; and untreated relapse OR 2.62, 1.35-5.10, p=0.004) and product (axi-cel, OR 5.85; 4.47-7.64, p&amp;lt;0.0001). Factors associated with severe and early onset CRS and ICANS are listed in the table below. The median follow-up of 14.2 months, the estimated 12-month overall survival, progression-free survival (PFS), and treatment-related mortality were 61.6% (95% CI: 59.4-63.9), 42.2% (39.9-44.5), and 4.3% (3.4-5.3), respectively. Overall CRS, early onset CRS and overall ICANS were not associated with higher mortality, however grade &amp;gt;3 CRS (HR 1.79; 1.41-2.28, p&amp;lt;0.001), grade &amp;gt;3 ICANS (hazard ratio [HR] 1.34; 95% CI 1.13-1.59, p=0.002) and early onset ICANS (&amp;lt;7 days, HR 1.23; 1.05-1.44, p=0.01) were associated with higher mortality. The impact of severe CRS on survival are shown in the landmark analysis at 30 days from infusion in the figure 1B. Conclusion: In the largest analysis of CD19-CAR-T cell therapy toxicities to date, we observed a high burden of CRS and ICANS among LBCL patients. The CAR T cell product type was consistently associated with higher incidence, shorter onset and higher severity of both toxicities. High LDH, older age and low performance score also influence the severity and onset of these outcomes. Additionally, patients who developed higher grades of CRS/ICANS and earlier onset ICANS had a higher mortality, stressing the need to develop novel strategies to mitigate the incidence and optimize management of these patients to improve their outcomes.

MMF Is Associated with Worse OS in CMV Seropositive AML Patients Undergoing MUD HCT with Calcineurin-Inhibitor-Based Gvhd Prophylaxis

Background: Calcineurin-inhibitor (CNI) with mycophenolate mofetil (MMF) or methotrexate (MTX) is commonly used as graft-versus-host disease (GVHD) prophylaxis for HLA-matched hematopoietic cell transplantation (HCT) but MMF, which targets both T- and B-lymphocytes, is associated with higher risk for cytomegalovirus (CMV) reactivation [ Blood Adv.2023;7(8):1394-1403]. We investigated whether overall survival (OS) differed with MMF- vs MTX-based GVHD prophylaxis according to recipient CMV serostatus and underling HCT disease indication. Methods: We evaluated 3105 patients with acute myeloid leukemia (AML, n=1572), acute lymphoblastic leukemia (ALL, n=453) or myelodysplastic neoplasms (MDS, n=1080) who underwent HLA-matched unrelated donor (MUD) peripheral blood (PB) HCT from 2008-17 using a publicly available Center for International Blood and Marrow Transplant Research (CIBMTR) dataset. Four groups were compared: MTX/ CMV+ (n=1527), MTX/ CMV- (n=916), MMF/ CMV+ (n=395), and MMF/ CMV- (n=267). All patients also received tacrolimus; none received post-transplant cyclophosphamide (PTCy). Primary outcome was OS. Results: The median (interquartile range) age was 57 (45-64), 56 (45-64), 62 (54-68), and 61 (50-67) years in the respective 4 groups. Within each group, most patients had AML or MDS. Disease status was mostly early or intermediate (51-63%). About half had HCT-CI &amp;gt; 2. In vivo T cell depletion was used in 41%, 65%, 48% and 52%, respectively. More patients in the MTX groups received myeloablative conditioning (58% and 55%, respectively), while reduced intensity/non-myeloablative conditioning was more common in the MMF groups (73% and 65%, respectively). In multivariate models stratified by disease, we noted significantly worse OS in CMV+ patients who received MMF, but this effect was restricted to AML. Among AML patients, OS was only 31% (95% confidence interval [CI] 25-37) among the MMF/CMV+ group, but was higher and not significantly different for the MMF/CMV- (54%, 95% CI 45-63) and MTX/CMV+ (51%, 95% CI 48-55) groups compared to the MTX/CMV- group (58%, 95% CI 53-63) [ Figure 1, Table 1] In ALL, GVHD prophylaxis type/CMV serostatus had no significant association with OS. In MDS, CMV+ patients had worse OS (HR 1.2, 95% CI 1.01-1.4, p=0.03) than CMV- patients irrespective of GVHD prophylaxis (MMF/CMV+ vs MTX/CMV+: HR=1.1, 95% CI 0.8-1.4, p=0.5). Donor CMV serostatus had no impact on these associations. Data on CMV reactivation and causes of death were not available; however, our data suggest that the inferior OS in AML was driven mostly by higher non-relapse mortality and some increase in relapse (data not shown). To evaluate how the use of PTCy prophylaxis might impact the interaction between MMF and recipient CMV+ serostatus, we next analyzed a separate CIBMTR MUD PB-HCT cohort that received PTCy/CNI/MMF prophylaxis (N=242; AML, n=136, ALL, n=42; MDS, n=64) and assessed the effect of CMV serostatus on OS. A majority (95%) received HCT from 2015-18. Our results showed that CMV+ recipients had a significantly worse OS than CMV- recipients, but only in AML (HR 2.7, 95% CI 1.1-6.4, p=0.03) and not in ALL (HR 0.4, 95% CI 0.1-1.5, p=0.2), or MDS (HR 0.7, 95% CI 0.3-1.5, p=0.3). As all patients in this cohort received PTCy/CNI/MMF, we were unable to assess the independent impact of MMF and CMV serostatus in this setting. Nevertheless, these data suggest similar trends as seen in the CNI cohort (without PTCy), where the inferior OS in the MMF/CMV+ group was noted only in AML patients. Conclusion: Our data suggest that the use of MMF with CNI-based prophylaxis (without PTCy) should be avoided in AML CMV+ patients. Why this adverse effect of CMV seropositivity and MMF prophylaxis is restricted to AML patients, and not seen in ALL, and whether the same applies to PTCy-prophylaxis with/without MMF, needs further investigation but could be due to CMV-induced expansion of NK cells [ Béziat. Blood. 2013; Foley. Blood. 2012] which mediates alloreactivity against AML but not ALL [ Ruggeri Blood 1999] and is suppressed by MMF more than MTX [ Ohata. BBMT. 2011].

Comparison of Vital Status, Cause of Death, and Follow-Up after Hematopoietic Cell Transplantation in Linked Center for International Blood and Marrow Transplant Research and California Cancer Registry Data, 1991 to 2018

Assessing outcomes following hematopoietic cell transplantation (HCT) poses challenges due to the necessity for systematic and often prolonged patient follow-up. Linking the HCT database of the Center for International Blood and Marrow Transplant Research (CIBMTR) with cancer registry data may improve long-term outcome ascertainment, but the reliability of mortality data in death certificates from cancer registries among HCT recipients remains unknown. We compared the classification of vital status and primary cause of death (COD), as well as the length of follow-up between the CIBMTR and California Cancer Registry (CCR) to assess the possibility of supplementing the CIBMTR with cancer registry data. This retrospective study leveraged a linked CIBMTR-CCR dataset. We included patients who were California residents at the time of HCT and received a first allogeneic (allo) or autologous (auto) HCT for a hematologic malignancy diagnosed during 1991-2016. Follow-up was through 2018. We analyzed 18,450 patients (alloHCT, n = 8232; autoHCT, n = 10,218). The Vital status agreement was 97.7% for alloHCT and 97.2% for autoHCT. Unknown COD was higher in CIBMTR (12.9%) than in CCR (1.6%). After excluding patients with unknown COD information, the overall agreement of primary COD (cancer versus noncancer) was 53.7% for alloHCT and 83.2% for autoHCT. This agreement was lower within the first 100 days post-HCT (alloHCT, 31.0%; autoHCT, 54.6%). Compared with CIBMTR, deaths due to cancer were higher in CCR (alloHCT, 90.0%; autoHCT, 90.1% versus alloHCT, 47.3%; autoHCT, 82.5% in CIBMTR). CIBMTR reports more frequently noncancer-related deaths, including graft-versus-host disease and infections. The cumulative incidence of cancer-specific mortality at 20 years differed, particularly for alloHCT (CCR, 53.7%; CIBMTR, 27.6%). The median follow-up among alive patients was longer in CCR (alloHCT, 6.0 years; autoHCT, 4.7 years) than in CIBMTR (alloHCT, 5.0 years; autoHCT, 3.8 years). Our findings highlight the completeness of vital status data in CIBMTR but reveal substantial disagreement in primary COD. Consequently, caution is required when interpreting HCT studies that use only death certificates to estimate cause-specific mortality outcomes. Improving the accuracy of COD registration and follow-up completeness by developing communication pathways between cancer registries and hospital-based cohorts may enhance our understanding of late effects and long-term outcomes among HCT survivors.

Allogeneic hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a CIBMTR analysis

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Real World Utilization of Cranial or Craniospinal Radiation in Adult Acute Lymphoid Leukemia Patients: Data from the Center for International Blood and Marrow Transplant Research

Though CNS involvement at diagnosis in adult acute lymphoid leukemia (ALL) is relatively rare (3-7%), >50 % of patients will develop CNS relapse without CNS-directed therapy. Radiation therapy is commonly used as part of stem cell transplant (SCT) conditioning. Historically, a cranial boost was given to reduce risk of CNS relapse. While a CNS boost is not a universal part of prophylaxis, CNS directed RT is used in patients at highest risk for CNS relapse following transplantation, typically those with CNS disease at diagnosis or after induction. There is little data on real world utilization of CNS directed radiation as part of SCT for adult ALL patients. The Center for International Blood and Marrow Transplant Research (CIBMTR) database was queried for adult ALL patients undergoing SCT between 2013 - 2019 who received TBI as part of their regimen where data was available on CNS directed RT. Patient demographics, pre-transplant response to induction, CNS status pre/post-transplant, and overall survival information were collected. Results were stratified by cranial irradiation (CNS-RT), craniospinal irradiation (CSI), or no cranial RT (nCRT). Radiation dose is not collected by the CIBMTR. The data presented here are preliminary and were obtained from the Statistical Center of the Center for International Blood and Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory or Scientific Committees of the CIBMTR. A total of 1240 patients were identified, of which 59 (5%) received CNS-RT, 2 (0.2%) received CSI, 989 (80%) received nCRT, and 190 (15%) had unknown CNS RT status. Median age was younger in patients receiving CNS-RT (26y, range 19-66y) or CSI (34y, 22-46y) compared to patients receiving nCRT (42y, 18-79y). Patients receiving CNS radiation had more advanced disease at time of transplant (17% requiring 3+ lines of induction before CR vs 50% vs 5%, respectively). 24% of CNS-RT patients and 50% of CSI patients had CNS disease at diagnosis compared to 7% of nCRT patients. 37% of CNS-RT patients and 100% of CSI patients had CNS disease prior to transplant compared to 11% of nCRT patients. Overall survival at 1-5 years was numerically higher with CNS-RT compared to no RT, though 95% confidence intervals overlapped at each follow up point. Data from the CIBMTR on real world utilization of CNS-RT or CSI in adult ALL patients suggest inconsistent practice patterns with 11% of patients without any cranial RT having CNS disease prior to transplant and 57% of CNS-RT patients having no CNS disease prior to transplant. These data offer an interesting analysis of current CNS radiation practice patterns in the past 10 years for adult ALL patients, though interpretation is limited by the retrospective nature of the study and by significant limitations of available data.

Improved outcomes of UM171–expanded cord blood transplantation compared with other graft sources: real-world evidence

AbstractCord blood (CB) transplantation is hampered by low cell dose and high nonrelapse mortality (NRM). A phase 1-2 trial of UM171-expanded CB transplants demonstrated safety and favorable preliminary efficacy. The aim of the current analysis was to retrospectively compare results of the phase 1-2 trial with those after unmanipulated CB and matched-unrelated donor (MUD) transplants. Data from recipients of CB and MUD transplants were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Patients were directly matched for the number of previous allogeneic hematopoietic stem cell transplants (alloHCT), disease and refined Disease Risk Index. Patients were further matched by propensity score for age, comorbidity index, and performance status. Primary end points included NRM, progression-free survival (PFS), overall survival (OS), and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) at 1 and 2 years after alloHCT. Overall, 137 patients from CIBMTR (67 CB, 70 MUD) and 22 with UM171-expanded CB were included. NRM at 1 and 2 years was lower, PFS and GRFS at 2 years and OS at 1 year were improved for UM171-expanded CBs compared with CB controls. Compared with MUD controls, UM171 recipients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades 3-4 acute GVHD and chronic GVHD compared with MUD graft recipients. Compared with real-world evidence with CB and MUD alloHCT, this study suggests that UM171-expanded CB recipients may benefit from lower NRM and higher GRFS. This trial was registered at www.clinicaltrials.gov as #NCT02668315.

Application of the CIBMTR One Year Survival Outcomes Calculator as a tool for retrospective analysis.

The Web-based One Year Survival Outcomes Calculator developed by the Center for International Blood and Marrow Transplant Research (CIBMTR) applies large-scale registry data to generate individualized estimates of overall survival (OS) probability 1 year after first allogeneic hematopoietic cell transplant (HCT) and can therefore provide a data-driven foundation for personalized patient counseling. We assessed the calibration of the CIBMTR One Year Survival Outcomes Calculator when applied to retrospective data among adult recipients of first allogeneic HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) with peripheral blood stem cell transplant (PBSCT) from a 7/8- or 8/8-matched donor from 2000 through 2015 at a single center. Predicted 1 year OS was estimated for each patient using the CIBMTR Calculator. Corresponding observed 1 year OS was estimated for each group by the Kaplan-Meier method. A weighted Kaplan-Meier estimator was used to visually display the average of observed 1 year survival estimates over the continuous range of predicted OS. In the first analysis of its kind, we demonstrated that the CIBMTR One Year Survival Outcomes Calculator could be applied to larger patient cohorts and predicted 1 year prognosis with general agreement between predicted and observed survival.

Impact of Donor Age on Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults with Acute Myeloid Leukemia

Allogeneic hematopoietic cell transplantation (alloHCT) provides cure for older patients with acute myeloid leukemia (AML); however, disease relapse remains a major concern. Based on recent data suggesting that younger donor age confers the greatest benefit for alloHCT with matched unrelated donors (MUDs), we attempted to answer a practical question: which donor type provides the best outcomes when an older patient with AML has a matched sibling donor (MSD, also older) versus the best MUD? This retrospective cohort registry study accessed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) in patients with AML age ≥ 50 years undergoing alloHCT from older MSDs (age ≥ 50 years) or younger MUDs (age ≤ 35 years) between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis. The primary outcome was relapse risk. Secondary outcomes included nonrelapse mortality (NRM), GVHD, disease-free survival (DFS), and overall survival. Among 4684 eligible patients, 1736 underwent alloHCT with an older MSD (median donor age, 60 years), and 2948 underwent alloHCT from a younger MUD (median donor age, 25 years). In multivariable analysis, compared to older MSDs, the use of younger MUDs conferred a decreased relapse risk (hazard ratio [HR], .86; P=.005) and a significantly lower adjusted 5-year cumulative incidence of relapse (35% versus 41%; P=.003), but was associated with an increased risk for chronic GVHD (HR, 1.18; 95% confidence interval [CI], 1.08 to 1.29; P=.0002) and greater NRM only in the earlier period of 2011 to 2015 (HR, 1.24; P=.016). The corresponding NRM rates were significantly lower in the more recent period of 2016 to 2018 (HR, .78; P=.017). The adjusted 5-year DFS probability was 44% (95% CI, 42% to 46%) with an alloHCT from younger MUDs compared to 41% (95% CI, 38% to 43%) with older MSDs (P=.04). In summary, for older patients with AML undergoing alloHCT, the use of younger MUDs is associated with decreased relapse risk and improved DFS compared with the use of older MSDs.

Rates of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) from Center for International Blood and Marrow Transplant Research (CIBMTR) data on US subjects (SUBJ) with lymphoma following chimeric antigen receptor T cell therapy (CAR-T).

7528 Background: The engineered T-cell products axicabtagene ciloleucel (axi-cel) and brexucabtagene autoleucel (brexu-cel) are FDA approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), respectively. This study investigated real-world rates of CRS and ICANS following CAR-T. Methods: This study analyzed CIBMTR data of US SUBJ receiving axi-cel or brexu-cel for any indication from Oct 2020–Dec 2021 with ≥1 follow-up visit. CRS and ICANS were graded per American Society for Transplantation and Cellular Therapy consensus guidelines. Results: 927 SUBJ (median age, 63 y; men, 65%) from 87 centers were analyzed. Most received axi-cel (76%), 83% of whom had DLBCL or transformed follicular lymphoma (tFL); 24% received brexu-cel (MCL). Most SUBJ had Ann Arbor stage III/IV (63%), no active central nervous system disease (84%), and refractory disease at CAR-T infusion (66%). Among all 589 SUBJ with DLBCL/tFL who received axi-cel, 54% achieved complete response, 17% partial response, and 6% stable disease. 89/715 SUBJ with available data received treatment for CRS prevention, mostly tocilizumab alone (80% [71/89]) or in combination (3% [3/89]). Overall, 766 SUBJ (83%) developed CRS (grade ≥3, 64 [8%]; Table). Of the 89 SUBJ who received CRS prevention treatment, 78% developed CRS, with 3% (3/89) having grade ≥3. 77% of SUBJ with CRS received CRS treatment, 97% of whom received tocilizumab (alone or in combination [eg, with corticosteroids]). Most (64%) SUBJ with grade 1 CRS received treatment, 63% of whom received tocilizumab alone. ICANS occurred in 424/876 SUBJ with ICANS data (48%; Table), of whom 205 (48%) had grade ≥3. ICANS treatment was reported and administered to 86% of SUBJ with ICANS, 92% of whom received corticosteroids. Conclusions: CRS and ICANS incidence rates were consistent with previously published literature and highlight potential burdens of CAR-T. In addition, the treatment landscape for CRS is changing; SUBJ with grade 1 CRS often received treatment. These data will inform the design of future studies aimed at preventing and treating CAR-T toxicities. [Table: see text]

Biologic indicators of donor socioeconomic disadvantage and recipient mortality following allogeneic hematopoietic cell transplantation.

6500 Background: Allogeneic hematopoietic cell transplantation (HCT) carries significant risks, with low socioeconomic status (SES) being predictive of increased mortality. Our team recently discovered that socioeconomic disadvantage among unrelated HCT donors results in decreased recipient overall survival (OS) and increased treatment-related mortality (TRM) within a cohort from the Center for International Blood and Marrow Transplant Research (CIBMTR). We also demonstrated that upregulation of the stress- and SES-related gene expression profile termed the ‘conserved transcriptional response to adversity’ (CTRA) is associated with low SES and worse outcomes among HCT recipients. Here, we hypothesize that donor immunologic characteristics associated with neighborhood socioeconomic disadvantage (CTRA) will confer prognostic risk to HCT recipients as indicated by inferior long-term recipient outcomes. Methods: Among a subset of the above cohort for which donor whole blood samples were available from the CIBMTR repository, we evaluated whether donor cell CTRA gene regulation was associated with inferior HCT outcomes at 3 years in recipients being treated for hematologic malignancy. Multivariable models adjusted for donor and recipient characteristics evaluated associations between donor CTRA and recipient OS, TRM, disease free survival (DFS), relapse, and acute and chronic graft versus host disease. Results were considered significant if P&lt;0.05. Results: We identified 263 donor-recipient pairs for study inclusion. Median recipient age at hematologic malignancy diagnosis was 53 years (range 19-77), 46% were female, and 54% had acute myeloid leukemia. Donors were 35% female and median age at donation was 31 years (range 18-60). In RNA sequencing data from HCT donors, greater CTRA expression was associated with reduced OS (covariate-adjusted HR=1.94/CTRA SD, 95% CI [1.01, 3.71], p=.046) which was driven predominately by increased TRM (adjusted HR=5.04, [2.20, 11.50], p=.0001). These clinical outcomes are consistent with those observed to be associated with donor SES in our prior work. Donor cell effects on transplant outcomes derived predominately from the pro-inflammatory component of the CTRA (OS: adjusted HR=1.67, [1.20, 2.33], p = .0026; TRM: adjusted HR=2.21, [1.21, 4.06], p=.010) and emerged above and beyond the effects of the recipients’ own SES, as well as multiple other recipient disease, treatment, and demographic factors. Donor CTRA was not associated with relapse, DFS, or other transplant outcomes. Conclusions: For the first time, we show that transcriptome patterning among HCT donors, consistent with neighborhood SES disadvantage, results in adverse recipient HCT outcomes. These findings suggest that SES has a biologic impact at either the stem or immune cell level that persists even when transplanted into a new host.

Primary Cancer Matters in Therapy-related Myeloid Neoplasm Patients Receiving Allogeneic Hematopoietic Cell Transplantation: A Study From the Chronic Malignancies Working Party of the EBMT

Primary Cancer Matters in Therapy-related Myeloid Neoplasm Patients Receiving Allogeneic Hematopoietic Cell Transplantation: A Study From the Chronic Malignancies Working Party of the EBMT

Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research

The use of HLA-mismatched donors could enable more patients with ethnically diverse backgrounds to receive allogeneic hematopoietic cell transplantation (HCT) in the United States. However, real-world trends and outcomes following mismatched donor HCT for diverse patients remain largely undefined. We conducted this study to determine whether the use of mismatched donor platforms have increased the access to allogeneic HCT for ethnically diverse patients, particularly through the application of novel graft-versus-host disease (GVHD) prophylaxis regimens, and whether outcomes for diverse patients are comparable to those of non-Hispanic White patients. This observational cross-sectional study used real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. All patients receiving their first allogeneic HCT in the United States between 2009 and 2020 were included, with a focus on transplantations performed in 2020. Data from patients undergoing allogeneic HCT using bone marrow, peripheral blood, or cord blood from HLA-matched or mismatched related and unrelated donors were analyzed. Specifically, relative proportion of allogeneic HCT was generated as percentage of total for donor type and for patient age, disease indication, GVHD prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival. Compared to matched related donor and matched unrelated donor HCT, more ethnically diverse patients received mismatched unrelated donor, haploidentical donor, and cord blood HCT. Although matched unrelated donor remains the most common donor type, the use of haploidentical donors has increased significantly over the last 5 years. Paralleling this increase in haploidentical HCT is the increased use of post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis. Relative to previous transplantation eras, the most contemporary era is associated with the highest survival rates following allogeneic HCT irrespective of patient race and ethnicity. Nonetheless, disease relapse remains the primary cause of death for both adult and pediatric allogeneic HCT recipients by donor type and across all patient racial/ethnic groups. Ethnically diverse patients are undergoing allogeneic HCT at higher rates, largely through the use of alternative donor platforms incorporating PTCy. Maintaining access to potential life-saving allogeneic HCT using alternative donors and novel GVHD prophylaxis strategies and improving HCT outcomes, particularly disease relapse, remain urgent clinical needs.

492 - Association between Patient-Reported Social Determinant of Health Outcomes and a Social Genomics Profile in Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

492 - Association between Patient-Reported Social Determinant of Health Outcomes and a Social Genomics Profile in Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis