Marrow Transplant Clinical Trials Network Research Articles

Defining and Grading Infections in Clinical Trials Involving Hematopoietic Cell Transplantation: A Report From the BMT CTN Infectious Disease Technical Committee

The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) was established in 2001 to conduct large multi-institutional clinical trials addressing important issues towards improving the outcomes of HCT and other cellular therapies. Trials conducted by the network investigating new advances in HCT and cellular therapy not only assess efficacy but require careful capturing and severity assessment of adverse events and toxicities. Adverse infectious events in cancer clinical trials are typically graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). However, there are limitations to this framework as it relates to HCT given the associated immunodeficiency and delayed immune reconstitution. The BMT-CTN Infection Grading System is a monitoring tool developed by the BMT CTN to capture and monitor infectious complications and differs from the CTCAE by its classification of infections based on their potential impact on morbidity and mortality for HCT recipients. Here we offer a report from the BMT CTN Infectious Disease Technical Committee regarding the rationale, development, and revising of BMT-CTN Infection Grading System and future directions as it applies to future clinical trials involving HCT and cellular therapy recipients.

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.

Out-of-Pocket Costs and Financial Hardship Among Participants of the BMT CTN 1102 Study

Introduction The Blood and Marrow Transplant Clinical Trials Network 1102 study (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial, where patients aged 50-75 with intermediate-2 or high risk de novo myelodysplastic syndrome (MDS) were assigned to reduced-intensity allogeneic hematopoietic cell transplantation (alloHCT) or best supportive care (non-alloHCT) based on donor availability. A parallel economic evaluation was performed alongside BMT CTN 1102. Here, we report on the financial impact of the treatment protocol on patients using a prospective cost diary study conducted within the trial. Methods BMT CTN 1102 enrollees were offered the option to participate in the parallel cost diary study at the same time of primary study enrollment. The cost diary survey instrument, comprised of 19 questions, covered the domains of out-of-pocket (OOP) costs of healthcare and financial hardship indicators. Surveys were distributed at 1- (1M), 7- (7M), and 19-months (19M) after enrollment. Study participants were grouped by actual treatment received, rather than group assignment. Responses were analyzed using univariate Fisher's exact and Wilcoxon rank sum tests for association. Results Out of 216 enrollee invitations, 138 patients (64%) returned at least one survey. Total completed surveys at the 1M, 7M, and 19M timepoints were 103 (39%), 93 (35%), and 71 (27%), respectively. 50 (36%) completed only one survey, while 41 (39%) completed surveys at all three timepoints. Of all respondents, median age was 67.7 years (IQR: 64.8-70.3), 88 (64%) were male, 128 (93%) white, and 126 (91%) were non-Hispanic. Among respondents of the 1M, 7M and 19M surveys, 82 (80%), 78 (84%), 65 (92%) received alloHCT, respectively. Mean OOP costs by category are presented in Table 1. While alloHCT patients experienced higher OOP costs compared to non-alloHCT patients across all categories (outpatient services, prescription medications, and accommodations for healthcare), none of the comparisons were statistically significant. However, total OOP costs were significantly higher among alloHCT patients at 1 and 7 months (mean over past 30 days, 1M: $889 vs. $217, p=0.046; 7M: $678 vs. $349, p=0.03; 19M: $328 vs. $103, p=0.15). Financial hardship indicators are presented in Table 2. While alloHCT patients experienced greater financial hardship compared to non-alloHCT patients across all categories (mobilized reserve funds, borrowed money to pay for care, developed debt due to care), none of the comparisons were statistically significant. However, alloHCT patients were significantly more likely to experience at least one of these factors of financial hardship at 7 months (1M: 38% vs. 19%, p=0.13; 7M: 42% vs. 13%; p=0.04; 19M: 37% vs. 0%, p=0.08). Discussion Patients with MDS who received alloHCT incurred substantially more OOP costs overall compared to patients who did not receive alloHCT, most notably for accommodations related to alloHCT. Similarly, alloHCT patients were more likely to develop financial hardship, including mobilizing reserve funds, borrowing money, and developing debt. These findings demonstrate that treatment-related OOP expenditures associated with alloHCT are substantial and may pose significant burdens for some populations receiving alloHCT. Financial navigation and assistance, which have been shown to help patients address cost burden in solid tumor settings, should be considered for MDS patients prior to alloHCT. Small final sample sizes limited our analyses significantly; further research into OOP costs and financial hardship among larger cohorts of alloHCT patients are necessary to confirm these findings. Acknowledgement Support for this study was provided by grants #U10HL069294 and #U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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.

The Composite Health Risk Assessment Model (CHARM) to Predict 1-Year Non-Relapse Mortality (NRM) Among Older Recipients of Allogeneic Transplantation: A Prospective BMT-CTN Study 1704

Introduction: Allogeneic hematopoietic cell transplantation (HCT) remains the only therapy for long-term disease control for many high-risk hematologic malignancies (HM). HCT use in older HM patients (pts) continues to increase. However, concerns of excessive transplant-related morbidity and non-relapse mortality (NRM) limit referrals and broader application of curative intent HCT. The HCT-comorbidity index (HCT-CI) was initially developed to improve risk-stratification of NRM. More recently, geriatric assessment (GA) and biomarkers have emerged as promising additional tools that may refine estimates of these risks. We hypothesized that a combination of health assessments by GA and biomarkers would constitute a robust and valid model, CHARM, for accurate personalized estimation of one-year (1-yr) NRM. Here, we report the results of the largest, first of its kind, prospective study of older recipients of HCT through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1704 study (NCT03992352). Patients and Methods: Adults aged ≥60 years (yrs) with HM institutionally eligible for HCT were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. Within 21 days of conditioning, 13 prospectively identified older pt.-specific health variables, informed from prior studies, were collected: age, HCT-CI, % of weight loss over the past yr, pt reported Karnofsky performance status, PROMIS physical function scale, instrumental activities of daily living (IADL), number of falls, PROMIS depression scale, number of prescribed medications, 4-meter walk speed, cognition by the Montreal Cognitive Assessment (MoCA), C-reactive protein (CRP) and albumin. The CHARM score to predict NRM within 1 yr was built using a multivariable (MVA) Fine-Gray model, with multiple imputation to handle modest missingness in covariates and grouped penalized variable selection using SCAD to identify variables to retain in the model. Final variables were used as continuous. The model further considered adjustment for conditioning intensity, CMV serostatus, and donor type. Area under the ROC curve (AUC) was calculated to validate the CHARM and compare to HCT-CI alone, with bootstrap sampling to correct for optimism in the within-sample AUC. MVA of overall survival (OS) within 1 yr used the CHARM score and adjusted for other significant variables derived from stepwise regression. Results: The primary analysis included 1105 pts who were confirmed eligible and proceeded to transplant. Median age was 67 (range 60-82) and 32% were ≥ 70 yrs. AML (45%) and MDS (30%) were the most common indications and matched donors the most frequent donor type at 72%. Reduced intensity conditioning with fludarabine (flu)-melphalan (38%) and flu-busulfan (20%) were the most common regimens. Baseline geriatric vulnerabilities among evaluable pts were frequent including slow walk speed (&amp;lt;0.8 meter/second) in 22%, any IADL limitation in 37%, and cognitive impairment (MoCA &amp;lt; 23) in 12%. 1-yr NRM was lower than expected at 14.4% with 1-yr OS of 72%. In the MVA model, albumin, CRP, HCT-CI, and weight loss were independently associated with NRM (Table) and comprised the CHARM. Of note, increasing age did not significantly affect NRM. The CHARM had within sample and bootstrap corrected AUC of 0.641 and 0.607 whereas the HCT-CI alone achieved corresponding AUC values of 0.601 and 0.598. NRM by tertiles is shown in Figure. Each point increase in the CHARM (median -2.2504, range -3.6327 to 0.1381), was associated with a hazard ratio (HR) of 2.83 (95% CI 2.12 - 3.78, p &amp;lt; 0.0001) for NRM. The CHARM also predicted overall mortality within 1-yr with a HR of 2.04 (1.65- 2.53, p &amp;lt;0.0001) per one point increase, independent of the disease risk index, which had a HR of 1.5 (95% CI 1.12 - 1.99, p =0.0059) for high/very high vs low/intermediate categories. Conclusions: We report on the first prospectively established tool, CHARM, to risk-stratify older adult HCT comprised of simple and readily available parameters in transplant and oncology clinics. Adopting CHARM in practice may promote HCT referrals and access for older pts, given low risks of NRM among CHARM lower 2/3 rd tertiles. Identifying high-risk CHARM pts pre-HCT will promote developing novel strategies to reduce NRM. Further analysis of the impacts of the 13 health assessment variables on geriatric morbidity such as disability trajectories is in-process.

Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507

Background: Allogeneic hematopoietic stem-cell transplantation has curative potential for sickle cell disease (SCD). Event-free survival (EFS) in children with SCD is &amp;gt;90% after a bone marrow transplant (BMT) from a myeloablative matched sibling donor (MSD). Unfortunately, &amp;lt;15% of patients with SCD have MSD, and myeloablative conditioning can be prohibitively toxic in adults with SCD. Reduced intensity HLA-haploidentical BMT with post-transplant cyclophosphamide (PTCy) has been shown in small studies to expand the donor pool with encouraging results. Still, concerns about graft failure and graft-versus-host disease (GVHD) persist. We present the results of a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507, multi-center single-arm, phase-II, prospective clinical trial (clinicaltrials.gov #NCT03263559) of haploidentical-BMT with PTCy to estimate EFS at 2-years in adults with severe SCD. Pediatric stratum data is not included in the data presentation and will be available in 2-years. Study Design and Methods: Eligibility: SCD patients aged 15.00-45.99 years with prior stroke, recurrent ACS or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec were eligible. Participants were required to have an HLA-haploidentical first-degree relative donor, willing and able to donate bone marrow. The primary objective was EFS (survival without primary or secondary graft failure or second infusion of stem cells) at 2 years after haploidentical-BMT. Secondary objectives included determining the impact on clinical and laboratory manifestations of SCD and other transplant outcomes at 2 years post haploidentical-BMT. The protocol was opened for enrollment on 10/5/2017, completed accrual on 01/6/2021, and data are current as of 8/2023. Preconditioning with hydroxyurea (HU) 30mg/kg/day (Day-70 to Day-10); Conditioning regimen included Thymoglobulin (rATG), Thiotepa, Fludarabine, Cyclophosphamide, and Total Body Irradiation (TBI). GVHD prophylaxis included PTCy, sirolimus, and mycophenolate mofetil, figure. Results: A total of 54 eligible participants enrolled from 19 sites; 42 (78%) proceeded to transplant. Amongst enrolled participants, 59.3% are male, 92.6% are Black, and 3.7% are Hispanic. 10 participants started HU but did not proceed to BMT, and 2 did not start HU or proceed to BMT. Reasons included donor issues (n=4), withdrawal of consent (n=2), insurance coverage (n=2), death (n=1), and other (n=3). 38/42 (90%) participants completed the study as planned; 2 participants withdrew consent, and 2 were lost to follow-up. The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had Hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8. Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant. Only 13 (31%) participants achieved the intended 30 mg/kg/day dosing of HU preconditioning. Estimated 2-year EFS is 88% (95% CI: 73.5%, 94.8%); all except one qualifying event occurred within 12 months. The 2-year overall survival (OS) post-HU was 93.0% (95% CI: 79.8%, 97.7%), and the 2-year OS post-transplant was 95.0% (95% CI: 81.5%, 98.7%); 2 (4.8%) participants had primary graft failure, and 1 (2.4%) had secondary graft failure before day +100. The cumulative incidence of grades II-IV acute GVHD at day 100 was 26.2% (95% CI: 14.0%, 40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI: 0.9%, 14.4%). There were two deaths in the first year post-BMT (1 -organ failure; 1-ARDS), none in the second year; 33 (78.6%) participants reported at least one re-admission post-BMT, mainly due to either bacterial infection (n=41) or viral reactivation (n=36), table. Conclusion: This multi-center phase-II trial of a reduced intensity haploidentical-BMT in adults with SCD shows durable donor engraftment at 2-years with low mortality. The 2-year EFS and OS are comparable to that reported after MSD myeloablative BMT. These results support haploidentical BMT with PTCy as a suitable and tolerable curative therapy for adults with SCD and severe end-organ toxicity such as stroke and pulmonary hypertension, a population typically excluded from participating in myeloablative gene therapy and gene editing trials.

Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups: Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study.

Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study. We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity). The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). Among those with a TP53 mutation, OS was similar between TP53single versus TP53multihit (22% ± 8% v 20% ± 6% at 3 years; P = .31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P = .001). HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.

Results From the Blood and Marrow Transplant Clinical Trials Network: How Should We Prevent Graft-versus-host Disease in 2023?

Results From the Blood and Marrow Transplant Clinical Trials Network: How Should We Prevent Graft-versus-host Disease in 2023?

Pilot Study of Donor-Engrafted Clonal Hematopoiesis Evolution and Clinical Outcomes in Allogeneic Hematopoietic Cell Transplantation Recipients Using a National Registry

Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n=27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH+ donors. All of the donor CH mutations (n=7/7; 100%) were detected in recipients at day 56 or day 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change, .005; range, -.008 to .024). Doubling time analysis of recipient day 56 and day 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in HCT recipients with CH+ donors (37.5% versus 25.1%); however, the risk for aGVHD by donor CH status did not reach statistical significance (hazard ratio, 1.35; 95% confidence interval, .61 to 3.01; P=.47). There were no statistically significant differences in the cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, the incidence of cGVHD was lower in recipients of grafts from DNMT3A CH+ donors versus donors without DNMT3A CH (34.4% versus 57%; P=.035). Donor cell leukemia was not reported in any donor-recipient pairs. CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, RICr, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT.

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n= 25) and other IEIs (n= 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32μg/mL (P= .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32μg/mL (P= .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P= .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.

Health-Related Quality of Life in Double Umbilical Cord Blood versus Haploidentical Marrow Transplantation: A Quality of Life Analysis Report of BMT CTN 1101

The Blood and Marrow Transplant Clinical Trials Network study 1101 (BMT CTN 1101; ClinicaTrials.gov identifier NCT01597778) was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QoL) of patients with hematologic malignancies undergoing double umbilical cord blood transplantation (dUCBT) or HLA-haploidentical bone marrow transplantation (haplo-BMT) after reduced-intensity conditioning. At a 5-year follow-up, there were no significant differences in progression- free survival (PFS) or overall survival (OS) between the 2 cohorts. The impact of alternative donor source on QoL is unknown, however. English- and Spanish-speaking patients completed the Functional Assessment of Cancer Therapy-General (FACT-G), Short Form 36 (SF-36), EuroQoL-5 Dimensions EQ-5D, and Global QoL patient-reported outcome (PRO) assessments pretransplantation and at 12 and 24 months post-transplantation. We compared longitudinal QoL measures between the dUCBT and haplo-BMT cohorts and investigated the association of QoL and clinical outcomes using an inverse probability weighted-independent estimating equations method, accounting for missingness and baseline variables. We found no significant differences between the 2 cohorts in any of the QoL scores pretransplantation and at 12 and 24 months post-transplantation. Pretransplantation scores were the only significant predictors of post-transplantation QoL scores. Relapse and grade III-IV acute graft-versus-host disease (GVHD) were associated with significant declines in mean FACT-BMT and SF-36 Physical Component scores, and chronic GVHD was associated with a decline in mean EQ-5D utility scores. There were no significant associations between pretransplantation QoL scores and OS or PFS. Donor type did not impact post-transplantation QoL. Pretransplantation QoL scores and clinical events of GVHD and relapse were the only predictors of post-transplantation QoL. QoL was not associated with survival in either treatment arm. PROs may be valuable tools in pretransplantation risk assessment strategies to improve QoL outcomes.

Transplant-Associated Thrombotic Microangiopathy in the Context of Allogenic Hematopoietic Stem Cell Transplantation: Where We Stand.

Transplant-associated thrombotic microangiopathy (TA-TMA) constitutes a significant contributor to the increased morbidity and mortality after allogenic hematopoietic stem cell transplantation (allo-HSCT). TA-TMA is a heterogenous disease, characterized by the triad of endothelial cell activation, complement dysregulation and microvascular hemolytic anemia, which may affect all organs. The lack of consensus diagnostic criteria, along with the common clinical features mimicking other diseases that complicate allo-HSCT, make the diagnosis of TA-TMA particularly challenging. Significant effort has been made to recognize specific risk factors predisposing to the development of TA-TMA and to identify serum biomarkers predicting the development of the disease. With regard to treatment, therapeutic plasma exchange (TPE) has been traditionally used, although with doubtful efficacy. On the other hand, the pivotal role of complement activation in the pathophysiology of TA-TMA has led to the exploration of the therapeutic potential of complement inhibitors in this setting. Eculizumab has been proposed as a first-line therapeutic agent in TA-TMA, owing to the very promising results in both pediatric and adult clinical trials. Pharmacokinetic and pharmacodynamic studies and CH50 levels are of paramount importance in the allo-HSCT setting, as a different dosing schedule (more intensive-in dose and frequency-at the beginning) seems to be required for successful outcomes. Furthermore, Narsoplimab, a MASP-2 inhibitor, recently received a Breakthrough Therapy Designation from the FDA for the treatment of TA-TMA after allo-HSCT. Finally, the decision to withdraw the CNIs, although initially advised by the Bone and Marrow Transplant Clinical Trials Network Committee, remains debatable owing to the controversial results of recent clinical trials. This review summarizes the current updates on pathophysiology, diagnosis and therapeutic approaches and emphasizes future goals and perspectives.

2097. Bacterial Infections in the Setting of Late Neutropenia Following CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Non-Hodgkin Lymphoma (NHL)

Abstract Background Cellular therapies such as CAR-T therapy have excellent clinical efficacy for treatment of relapsed and refractory hematologic malignancies. Late neutropenia, occurring more than 30 days after CAR-T cell infusion, is a frequent complication, though its impact on infection risk is not well understood. Methods We performed a retrospective study of 280 adults receiving CD19 CAR-T therapy for NHL between December 2017 and September 2021 (n=280). Levofloxacin prophylaxis was used after CAR-T infusion until initial count recovery (absolute neutrophil count (ANC) ≥ 1000). Patients were evaluated for late neutropenia with ANC &amp;lt; 1000 during three time periods following cell infusion: day 30 – 100; day 100 – 365; and after day 365. Infections were recorded if there was a microbiologic diagnosis with correlating symptoms and treatment. Infection severity was determined using Blood and Marrow Transplant Clinical Trials Network criteria. Patients were censored on the first day of any additional antineoplastic therapy after relapse, death or last follow up until 1/25/2022. Results Of 280 patients with NHL who received CAR-T therapy, 116 (41%) had late neutropenia. Baseline characteristics and early CAR-T toxicities are shown in Table 1. Amongst patients with late neutropenia, 11 (9%) developed a bacterial infection during late neutropenia and 3 (3%) developed Clostridioides difficile infection. The most frequent infection site was the bloodstream (n=5), followed by the urinary tract (UTI; n=4). Most infections were moderate in severity (n = 9, 64%), though several were serious (Severe=4; Life-threatening=1). Median time from CAR-T therapy to bacterial infection was 70 days (range 30 - 584); 10 occurred among 99 at risk during day 30-100 (10%), 3 among 39 at risk during day 101-365 (8%), and 1 among 12 at risk after day 365 (8%). All but one of the severe or life-threatening infections occurred prior to Day 100. Characteristics and timing of individual infections are outlined in Table 3. Table 3.Characteristics and Timing of Individual Bacterial Infections Conclusion Bacterial infections were relatively uncommon in patients with late neutropenia after CD19 CAR-T therapy for NHL in the absence of antibacterial prophylaxis and most severe infections in this population occurred between day 30 and 100. Further studies are needed to inform optimal prevention strategies. Disclosures Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Scynexis: Grant/Research Support Caron Jacobson, MD, MMSc, Abintus Bio: Advisor/Consultant|Bluebird Bio: Advisor/Consultant|BMS/Celgene: Advisor/Consultant|Daiichi-Sankyo: Advisor/Consultant|Epizyme: Advisor/Consultant|ImmPACT Bio: Advisor/Consultant|Instill Bio: Advisor/Consultant|Ipsen: Advisor/Consultant|Kite/Gilead: Advisor/Consultant|Kite/Gilead: Grant/Research Support|Lonza: Advisor/Consultant|Novartis: Advisor/Consultant|Pfizer: Grant/Research Support.

Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703

Introduction: Controlling both GVHD and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success. For three decades, the standard GVHD prophylaxis strategy has been a calcineurin inhibitor such as tacrolimus (Tac) plus methotrexate (MTX). Although several approaches have been tried in recent years to improve upon Tac/MTX, intensifying immunosuppression frequently comes with an increased risk of serious infections or relapse and usually no effect on chronic GVHD even if acute GVHD is reduced. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) previously completed a phase II study comparing three novel GVHD prophylaxis regimens to contemporaneous controls receiving Tac/MTX (BMT CTN 1203) in order to determine the most promising novel GVHD prophylaxis approach with reduced intensity conditioning (RIC). The most promising GVHD prophylaxis regimen in BMT CTN 1203 was a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF). Here, we report the results of the randomized phase III study comparing outcomes of alloHCT in those randomized to receive PTCy/Tac/MMF versus standard Tac/MTX. Patients and Methods: Eligible adults (age 18+) with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (N=128), 8/8 matched unrelated (N=288), or 7/8 single mismatch (N=15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status were randomized 1:1 to receive PTCy/Tac/MMF (N=214) or Tac/MTX (N=217), stratified by transplant center and Disease Risk Index (DRI). The primary endpoint of the study was GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause. The primary hypothesis was that PTCy/Tac/MMF has a ≥15% higher GRFS at 1 year than Tac/MTX in the intent-to-treat population. Secondary endpoints included the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival. Results: The 2 study arms were well balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy (Figure panel A). In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GRFS than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted 1-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm, Figure panel B). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GVHD. The Day 100 grade III-IV acute GVHD was 6.3% vs 14.7% (p=0.001), and chronic GVHD rate at 1 year was 21.9% vs 35.1% (p=0.005) for PTCy vs Tac/MTX, respectively. There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%, p=0.9), or OS rate at 1 year post transplant (76.8% vs 72.6% , p=0.3), in PTCy vs Tac/MTX. The cumulative incidence of engraftment was lower for PTCy for neutrophils ≥ 500/mm3 by day +28 (90.3% vs 93.4%, p=0.03), platelets ≥ 50,000/mm3 by day +100 (79.5% vs 83.7%, p<0.001), and lymphocytes ≥ 1000/mm3 by 1 year (47.1% vs 63.2%, p<0.001). Grade 3 infection rates were similar between the arms (12.2% for PTCy vs 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% vs 23.5%, p=0.002). There was no difference in CMV reactivation between the treatment arms (7.3% for PTCy vs 7.1%, p=0.8). There was no significant difference in proportion of chimerism at day +100 (>95% donor in 68.6% for PTCy vs 67.8%, p=0.2) or secondary graft failure between the arms (2.9% for PTCy vs 0.9%, p=0.2). Conclusions: BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Biomarkers for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Myeloablative Allogeneic Hematopoietic Cell Transplantation: Results from the Blood and Marrow Transplant Clinical Trials Network 1202 Study

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). This study aimed to determine a blood biomarker signature early post-HCT that identifies patients at high risk for VOD/SOS. A set of 23 plasma biomarkers, selected from the VOD/SOS literature, was measured on days 0, 7, and 14 after myeloablative HCT using blood samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1202. Eligible cases were diagnosed with VOD/SOS in BMT CTN 1202 using the Baltimore criteria. Controls (without VOD/SOS) were matched to cases for conditioning regimen and age. Significant biomarkers were identified using the Bonferroni-adjusted Wilcoxon rank-sum test (P ≤ .002). Thirty-three patients with mild or severe VOD/SOS were identified (cases) and matched to 107 controls. Two, 8, and 5 biomarkers measured from the plasma of these patients were significantly associated with the development of VOD/SOS at days 0, 7, and 14, respectively, with the strongest associations on days 7 and 14. Biomarker associations were stronger for severe VOD/SOS risk and were stronger prognostic markers for VOD/SOS cases occurring within 28 days of HCT. Hyaluronan was most strongly associated with VOD/SOS risk, with an area under the receiver operating characteristic curve (AUC) of .81 on day 7 and .79 on day 14. Multivariate models of up to 5 biomarkers generated AUCs ranging from .82 to .85. All associations with VOD/SOS risk were independent of clinical risk factors. This study confirms previously identified biomarkers of VOD/SOS risk and identified novel prognostic biomarker signatures that identify patients at risk for VOD/SOS shortly after HCT. Multivariate analysis suggests that a combination of up to 5 of these protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.

Alternative Bone Marrow Transplantation with Post-Transplant Cyclophosphamide (PTCy) As Initial Therapy for Acquired Severe Aplastic Anemia (SAA)

Immunosuppressive therapy (IST) is standard front-line treatment for SAA, except for patients aged <20 years with a suitable HLA-matched sibling donor (MSD) for BMT. The hematopoietic response after IST, even with the addition of eltrombopag, is ~ 70%-80% and 5-year survival is 60% to 85%. Failure-free survival (alive and in remission without clonal disease) beyond 10 years after IST is ~50%. In contrast, long-term survival after BMT is ~90% in patients aged < 20 years, and 75% in older patients. Currently, BMT with an unrelated or HLA-haploidentical (haplo) donor is reserved for failure of IST because of morbidity and mortality concerns. PTCy improves the safety and efficacy of haplo BMT by facilitating engraftment and decreasing graft-vs-host disease (GVHD), with survival comparable to MSD BMT. Here we review the outcomes of alternative donor BMT and PTCy in treatment-naïve (TN) SAA patients. Eligible patients met criteria for SAA and were TN. Fanconi anemia and telomere biology disorder patients were excluded. Non-myeloablative (NM) conditioning included rabbit antithymocyte globulin (0.5 mg/kg day-9 and 2 mg/kg on days -8,-7), fludarabine (30mg/m2/day on days -6 to -2), low dose CY (14.5 mg/kg on days -6, -5) and total body irradiation (TBI) (200cGy or 400 cGy day -1). After the marrow graft was infused on day 0, cyclophosphamide 50 mg/kg/day IV was administered on days 3 and 4 post-transplant. All received mycophenolate mofetil (MMF) from day 5-35 and tacrolimus from day 5 through 1 year. Neutrophil recovery was defined as occurring on the first of three consecutive days of an ANC >1.0 x109/L. Red cell recovery was defined as days from transplant to the last red blood cell transfusion. Platelet recovery was defined as the first day of a platelet count >50,000 without transfusion in the preceding 7 days. Thirty-two eligible patients were treated at Johns Hopkins between 9/2016 and 5/2022. Median follow-up for all patients is 40 months (range 2-78). Table 1 shows demographics. The median age was 25 years (range 3-63) with 24 patients age >20 years, and 56% were males. Median time to neutrophil recovery was 20 days (range 14-88). Median time to red cell recovery was 25 days with 90% transfusion independence by day 60. Median time to platelet recovery was 25 days with 90% transfusion independence by day 100. TBI dose was increased from 200 to 400 cGy to reduce graft failure after graft loss in 3 of the first 7 patients; 2 of these 3 died (from infection and graft failure) and one has been re-transplanted and is now 100% donor. Overall survival at 3 years post-transplant is 93%. (Figure 1) All 24 consecutive patients who received 400 cGy are alive and well with engraftment. CMV reactivated in 13 patients, and 6 required therapy. Rates of acute and chronic GVHD were both 7%, none developed grade 3-4 acute or extensive chronic GVHD, and all patients beyond day 365 are off treatment for GVHD. No secondary malignancies have been observed. NM BMT with PTCy, using mostly haplo donors, can cure SAA. Increasing TBI dose from 200 to 400 cGy improves engraftment. Rates of infection and mortality are not increased compared to standard upfront IST. Historical data show that >50% of patients in this age range require transplantation subsequent to IST. Upfront BMT, as described here, allows patients to come off immunosuppression by 6-12 months post-BMT, prevents the morbidity of prolonged IST, and may reduce healthcare costs. Most patients receiving 200 cGy TBI maintain fertility; we are monitoring fertility rates after 400cGy. This approach forms the basis for the upcoming Bone Marrow Transplant Clinical Trials Network multicenter study in TN acquired SAA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bringing Patient and Caregivers Voices to the Clinical Trial Chorus: A Report From the BMT CTN Patient and Caregiver Advocacy Task Force

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute for more than 2 decades, is focused on improving the outcomes of hematopoietic cell transplantation (HCT) and other cellular therapies. It answered critical questions about conditioning intensity, donor choice, graft-versus-host disease prevention and treatment, and relapse mitigation strategies in a manner made possible by an extensive network of centers that have enrolled more than 16,000 patients to more than 55 trials. Although the BMT CTN has engaged patients in a variety of ways since its establishment, there is a growing realization that increasing that engagement and including caregivers offers many additional benefits to patients and investigators alike. Bringing the voice of patients and caregivers to clinical trial design is likely to enhance trial participation and reduce barriers to recruitment/retention. Unless clinical trials are designed with unique considerations of patients who have socioeconomic and access challenges, these populations will remain under-represented in HCT trials with limited generalizability of results. The next main frontier in our field is patient and caregiver access to high-quality HCT facilities coupled with the opportunity to participate in relevant, meaningful clinical research. In 2021, the BMT CTN Executive Committee convened a Patient and Caregiver Advocacy Task Force with a diverse membership representing a variety of stakeholders. The charge to the Task Force was to provide achievable recommendations for incorporating patient input at all steps of clinical trial development from initial concept to dissemination of results. Four focus areas were identified: (1) patient and caregiver input in research portfolio; (2) patient engagement in informed consent, protocol development and trial conduct; (3) communication to patients about trial progress, primary outcomes and secondary analyses; and (4) increased awareness among patients who may be considering BMT or cell therapy about BMT CTN trials. Three specific initiatives were considered as high priority by the Task Force: Fostering patient and caregiver engagement in development of the research portfolio and protocols; Developing communication plans for ongoing studies; and Simplifying the process for informed consent to make it more patient friendly. The BMT CTN has established a patient and caregiver advocacy committee that is tasked with developing concrete steps to incorporate recommendations of the BMT CTN Task Force in its current and future work. The BMT CTN recognizes patient and caregivers are valuable partners whose voice will enhance the conduct of impactful trials in BMT and cell therapy.

Enrollment Lessons from a Biological Assignment Study of Marrow Transplantation versus Standard Care for Adolescents and Young Adults with Sickle Cell Disease: Considerations for Future Gene and Cellular Therapy Trials

We previously conducted a single-arm feasibility study (STRIDE1) of myeloablative bone marrow transplantation (BMT) in adolescents and young adults with sickle cell disease (SCD). The trial identified donors before entry, enrolled well, and found no unexpected regimen-related toxicity. Although many single-arm studies have been published, there are no controlled trials of either BMT or gene therapy in SCD. Therefore, we designed a comparative trial by biological assignment (available donor versus no donor). This multicenter National Institutes of Health-funded study (Blood and Marrow Transplant Clinical Trials Network 1503; STRIDE2) enrolled patients between 2016 and 2021 at 35 sites. Lagging recruitment led to study closure, and here we report the impediments to accrual. The BMT regimen and entry criteria were from STRIDE1, and 2-year survival was the primary endpoint. To minimize selection bias from prior HLA typing, STRIDE2 excluded individuals with previously identified donors. Accrual was stopped at 69% of target (138 enrolled; assigned 28 with donor, 96 with no donor). Barriers to enrollment included lower than expected frequency of HLA-matched related and unrelated donors; loss of enrollees owing to previously identified donors; conventional care arm dissuading some seeking BMT; challenging short-term endpoints in SCD, including incomplete documentation of sickle pain episodes; state Medicaid (primary insurers of SCD) denial of BMT coverage for adult SCD despite the study having secured Coverage with Evidence Development from the Center for Medicare & Medicaid Services; slowed accrual in 2019 to 2021 during the Coronavirus disease 2019 pandemic; and restriction of BMT resourcing for nonmalignant diseases by academic medical (cancer) centers. Social obstacles and access to BMT centers also limited entry, as did practitioner and participant concerns over suitability, cost, and toxicity. Planning for future controlled trials of curative therapy in SCD and other nonmalignant diseases likely will meet these enrollment challenges. Lessons from this trial may aid the development of future comparative studies.

Decoupling blood telomere length from age in recipients of allogeneic hematopoietic cell transplant in the BMT-CTN 1202.

The age of allogeneic hematopoietic cell transplant (HCT) donors and their hematopoietic cell telomere length (TL) might affect recipients’ outcomes. Our goals were to examine the possible effect of these donors’ factors on the recipients’ hematopoietic cell TL and quantify hematopoietic cell TL shortening in the critical first three-month post-HCT. We measured hematopoietic cell TL parameters in 75 recipient-donor pairs, from the Blood and Marrow Transplant Clinical Trials Network (protocol#1202), by Southern blotting (SB), the Telomeres Shortest Length Assay (TeSLA), and quantitative PCR (qPCR). Recipients’ hematopoietic cell TL parameters post-HCT correlated with donors’ age (p<0.001 for all methods), but not recipients’ own age, and with donors’ pre-HCT hematopoietic cell TL (p<0.0001 for all). Multivariate analyses showed that donors’ hematopoietic cell TL pre-HCT, independent of donors’ age, explained most of the variability in recipients’ hematopoietic cell TL post-HCT (81% for SB, 56% for TeSLA, and 65% for qPCR; p>0.0001 for all). SB and TeSLA detected hematopoietic cell TL shortening in all recipients post-HCT (mean=0.52kb and 0.47kb, respectively; >15-fold the annual TL shortening in adults; p<0.00001 for both), but qPCR detected shortening only in 57.5% of recipients. TeSLA detected a buildup of post-HCT of telomeres <3 kb in 96% of recipients (p<0.0001). In conclusion, HCT decouples hematopoietic cell TL in the recipients from their own age to reflect the donors’ age. The potential donors’ age effect on outcomes of HCT might be partially mediated by short hematopoietic cell TL in older donors. qPCR-based TL measurement is suboptimal for detecting telomere shortening post-HCT.

A Multicenter Phase II, Double-Blind, Placebo-Controlled Trial of Maintenance Ixazomib After Allogeneic Transplantation for High-Risk Multiple Myeloma: Results of the Blood and Marrow Transplant Clinical Trials Network 1302 Trial

The role of allogeneic hematopoietic cell transplantation (allo-HCT) followed by maintenance therapy in high-risk multiple myeloma (MM) remains controversial. We evaluated the efficacy of ixazomib maintenance therapy after reduced-intensity conditioning allo-HCT from HLA-matched donors in patients with high-risk MM. The primary study endpoint was progression-free survival (PFS) postrandomization, treated as a time to event. Secondary endpoints were grade II-IV and grade II-IV acute graft-versus-host-disease (GVHD), chronic GVHD, best response, disease progression, nonrelapse mortality (NRM), overall survival (OS), toxicity, infection, and health-related quality of life. In this phase 2, double-blinded, prospective multicenter trial, we randomized patients with high-risk MM (ie, those with poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous HCT) to ixazomib (3 mg on days 1, 8, and 15) or placebo after allo-HCT. The conditioning regimen included fludarabine/melphalan/bortezomib with tacrolimus plus methotrexate for GVHD. Fifty-seven patients were enrolled, of whom 52 (91.2%) underwent allo-HCT and 43 (82.7%) were randomized to ixazomib versus placebo. At 21 months postrandomization, the ixazomib and placebo groups had similar PFS (55.3% versus 59.1%; P=1.00) and OS (94.7% versus 86.4%; P=.17). The cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% versus 0%) and chronic GVHD at 12 months (68.6% versus 63.6%) also were similar in the 2 groups. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with a corresponding NRM of 11.7%. These results demonstrate the safety and durable disease control with allo-HCT in high-risk MM patients. We could not adequately assess the efficacy of ixazomib maintenance because the trial terminated early owing to enrollment delays, but there was no indication of any impact on outcomes.