ABSTRACT:Despite concerns about the toxicity of allogeneic hematopoietic cell transplantation (alloHCT) in older patients, prospective data characterizing prevalence or risk stratification for geriatric morbidity such as disability or frailty are limited. We prospectively assessed the prognostic impact of the novel composite health assessment risk model (CHARM), a score established to predict 1-year nonrelapse mortality (NRM), among 1105 patients aged ≥60 years enrolled on the Bone Marrow Transplant Clinical Trials Network Study 1704. Secondary end points were assessed post-alloHCT at day 100 (D100), D180, and D365 in multivariable models adjusted with predetermined clinical variables. Among alloHCT survivors, the prevalence of disability by instrumental activities of daily living (IADL), frailty by the Physical Frailty Phenotype, and physical function impairment by Patient Reported Measurement Information System (PROMIS) was highest at D100 and lower on D180 and D365. Higher CHARM scores were independently associated with greater disability (coefficient, -0.64; 95% confidence interval [CI], -0.85 to -0.43; P< .001), increased frailty (coefficient, 0.19; CI, 0.081-0.31; P< .001), worse PROMIS physical function, greater PROMIS depression, increased serious organ toxicity by D100, more cognitive decline at D100, and higher mortality after acute graft-versus-host disease (GVHD) but not significantly associated with PROMIS anxiety or acute GVHD. Higher CHARM scores predicted worse disability-free survival (odds ratio [OR], 2.03; CI, 1.66-2.48; P< .001) and lower frailty-free survival (OR, 2.00; CI, 1.61-2.49). In summary, CHARM is an independent prognostic scoring system not only for NRM but also for geriatric morbidity and functional limitation-free survival through 1 year after alloHCT. Pre-alloHCT CHARM is a novel tool to aid shared decision-making for older patients. This trial was registered at www.clinicaltrials.gov as #NCT03992352.

ABSTRACT:Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models' performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P < .0001) and worse OS (HR, 2.09; P < .0001). Bootstrap bias-corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.

The combination of 3 days of anthracycline and 7 days of infusional cytarabine (3+7) has been the most-commonly aministered induction chemotherapy regimen for newly diagnosed patients eligible for intensive therapy over five decades. However, CR rates and long-term outcomes in non-favorable risk AML induced with 3+7 have been unsatisfactory. We previously demonstrated that initial remission induction therapy with the combination of three days of idarubicin with five days of fludarabine and intermediate dose cytarabine (FLAG-Ida) results in improved outcomes without added toxicity compared to 3+7 in non-favorable risk AML (Solh et al Leukemia Research 2020). The addition of venetoclax to FLAG-Ida (FLAG-Ida-Ven) was recently shown to be tolerable and efficacious (DiNardo et al Am J Hematol 2022) but has not been directly compared to FLAG-Ida. Starting in mid-2022 our center changed its preferred initial intensive induction regimen for AML from FLAG-Ida to FLAG-Ida-Ven. Venetoclax was administered without ramp-up for 14 consecutive days starting on d1 of the regimen. Here we compare patients induced with FLAG-Ida-Ven to those induced with FLAG-Ida over a five -year period at our center. All consecutive patients receiving initial induction for AML with either regimen from January 2019 to March 2024 (n=200) were included in the analysis (FLAG-Ida =154, FLAG-Ida-Ven=46). Diagnostic procedures, supportive care measures and response assessments were identical between patients treated with the two regimens. FLT-3 inhibitor therapy was added to all patients with a FLT-3 activating mutation and gemtuzumab ozogamicin (GO)was added to all patients with core-binding factor (CBF) AML during induction therapy. Patient characteristics, response and hematopoietic cell transplantation (HCT) data was extracted from our institutional database where they had been prospectively entered. Patient characteristics for patients treated with FLAG-Ida-Ven and FLAG-Ida respectively were well matched and not statistically different : Median age 55 vs 57; male 54% vs 54%; race -white 67% vs 71%, black 26% vs 20%; WBC at diagnosis 11.5 vs 19 x 10e9/L, median BM blasts 51% vs 60%, cytogenetic risk groups - favorable 15% vs 14%, intermediate 76% vs 71%, adverse 9% vs 15%; NCCN overall risk group - favorable 28% vs 32%, intermediate 20% vs 17%, adverse 52% vs 51%. Complete remission (CR) and Composite CR (CRc) rates following a single cycle of FLAG-Ida-Ven vs FLAG-Ida were 93% vs 83% (p=0.07) and 98% vs 88% (p=0.05) respectively. In NCCN poor/intermediate risk AML, CR rates were 91% vs 75% (p=0.06) and CRc rates were 97% vs 83% (p=0.047) respectively. Hospital length of stay for induction therapy was slightly shorter for FLAG-Ida-Ven than FLAG-Ida: median 23 vs 26 d (p=0.042) IQR 21-29 d vs 23-30. Deaths within 60 days of start of induction were 9% vs 4% (p=NS) and positive blood cultures during induction were seen in 30% vs 26% (p=NS). For patients with NCCN intermediate/poor risk AML 55% vs 59% (p=NS) of patients induced with FLAG-Ida-Ven and FLAG-Ida proceeded to HCT within 6 months of induction with no significant difference in type of donor or regimen used. Estimated K-M probabilities of one year leukemia-free survival (LFS) for FLAG-Ida-Ven vs FLAG-Ida were 75% vs 77% (p=NS). For patients undergoing HCT, one-year LFS post-transplant was 76% vs 80% (p=NS). This direct comparison of patients consecutively treated over 5 years at a single center suggests that addition of venetoclax to the FLAG-Ida regimen results in significantly higher composite CR rates in non-favorable risk AML without additional toxicity or prolongation of inpatient stay. A similar proportion of non-favorable risk AML treated with either regimen proceeded to HCT within 6 months. Analysis of LFS and post-transplant outcomes was limited by relatively short follow-up among the FLAG-Ida-Ven cohort and will benefit from later reassessment. FLAG-Ida-Ven should be considered a standard remission induction regimen for fit newly diagnosed AML patients especially for patients with non-favorable risk disease.

Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3 to 4 acute GVHD (versus 0-1) was associated with inferior 3-year overall survival (OS 47% versus 64%, P = .041), due to higher NRM (25% versus 10%, P = .013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% versus 58%, P = .027) and a trend towards lower relapse (24% versus 36%, P = .08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% versus 4%, P = .010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3 to 4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, P < .001 and HR3.35, P < .001, respectively). In addition, grade 3 to 4 acute GVHD predicted worse OS (HR 1.80, P = .007) and DFS (HR 1.55, P = .041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. In summary, both grade 3 to 4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.

In the context of haploidentical donor transplantation (HIDT) utilizing post-transplant cyclophosphamide (PTCY), our group has previously demonstrated that mismatch at HLA-DPB1 predicts a higher incidence of chronic GVHD, regardless of permissiveness by the TCE algorithm or directionality of the mismatch. HLA Evolutionary Divergence (HED) can predict the quantify of divergence between two alleles of the same HLA locus. The divergent allele advantage hypothesis proposes that diversity between HLA alleles of the same locus will increase the capacity of peptide antigen presentation, resulting in increased protection against pathogens and malignancy. As higher divergence may also increase the presentation of self-peptides resulting in autoreactive T cells, we hypothesized that higher divergence in recipient HLA-DPB1 alleles may better inform the association of HLA-DP mismatch with chronic GVHD. To that end, we studied 322 consecutive recipient/donor pairs who received HIDT with PTCY at our center between 2005-2020 with a median follow up of 57.2 months. In addition to HLA-DPB1 matching and vector, we calculated HED using the GRAHAM distance score within the recipient HLA-DPB1 loci. HLA-DPB1 mismatch vector was bidirectional (n=167), graft vs host (GVH only, n=49), host vs graft (HVG only, n=39) and matched (n=67). The median HED score in the HLA-DPB1 recipient was 4.06 (range 0-10.68). Recipients were grouped into 4 different cohort based on the direction of HLA-DPB1 mismatch and the HED score (high >4.06 vs low): matched (n=67), HLA-DPB1 mismatched GVH/bidirectional low divergence (n=104), HLA-DPB1 mismatched GVH/bidirectional high divergence (n=112) and HLA-DPB1 mismatch HVG (n=39). Patient's characteristics were median age 49.5 (19,80) years, male sex 58%, disease ( AML 38%, ALL 21%, MDS 12%, NHL 10%, other 19%); Cell source (PBSC 80%); regimen intensity ( myeloablative 49%); HCT-CI comorbidity index ≥3 in 50%; disease risk ( high/very high 35%); donor male sex 61% and female donor to male recipient (21%). Donor was a child, sibling/half sibling or parent in 47%, 38% and 14% respectively. In univariate analysis, high HED score in recipient HLA-DPB1 had no impact on OS, DFS, Relapse or NRM but was significant for all grade ( HR 2.10, p=0.005) and moderate-severe (HR 1.86, p=0.04) cGVHD compared to patients with low HED score. A subgroup analysis comparing cGVHD cumulative incidences based on vector and divergence score showed that HLA-DPB1 MM in GVH/bidirectional with high HED had higher all grade and moderate-severe cGHVD compared to matched recipients (P=0.01 and 0.004). Additionally, patients with HLA-DPB1 MM in GVH/bidirectional high HED score had higher all grade and moderate-severe cGVHD compared to MM in GVH/bidirectional with low HED score (p=0.005 and 0.013) A multivariable analysis using cox model was performed on moderate-severe cGVHD and showed that in addition to black race and being transplanted in earlier years ( 2005-2013 vs later), patients with HLA-DPB1 mismatched in GVH/bidirectional with high divergence score had higher risk of mod-severe cGVHD ( HR 2.20, CI 1.09-4.43, p=0.028) than matched HLA-DPB1. Similarly, patients with HLA-DPB1 MM in the HVG direction had higher risk of mod-severe cGVHD compared to matched (HR 2.57, CI 1.15-5.74, p=0.002). In conclusion, our analysis shows that in the context of PTCY-based HIDT, recipient with more divergent HLA-DPB1 alleles are at significantly higher risk of moderate-to-severe chronic GVHD when a HLA-DPB1 mismatch is present in the GVH/bidirectional direction, a result predicted by the divergent allele advantage hypothesis. Furthermore, the presence of an HLA-DPB1 mismatch in the HVG-only direction also resulted in more chronic GVHD, a finding requiring further mechanistic study. In recipients with more divergent HLA-DPB1 alleles by HED scoring, care will need to be taken in donor selection to balance the detrimental effects of HLA-DPB1 mismatch on chronic GVHD with the known beneficial effects of a TCE non-permissive HLA-DPB1 mismatch in terms of relapse reduction.

The alloimmune response giving rise to the potent graft-versus-malignancy effect of allogeneic transplant can also be associated with morbidity and mortality from GVHD. The relative risk/benefit of having acute and/or chronic GVHD in the context of haploidentical donor transplantation (HIDT) has not been definitively studied. To this end, we studied the effects of acute and chronic GVHD following HIDT and post-transplant cyclophosphamide (PTCy), utilizing both landmark analysis (LA) and time-dependent multivariable analysis (MVA), in 335 consecutive HIDT recipients transplanted between 2005 and 2021. Recipient characteristics included a median age of 50 (19.80) years, 57% male, HCT-CI≥50%, diagnoses of acute leukemia[201], MDS/CML[62], lymphoma/CLL[72]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23, 207) months. Landmarks were defined as Day +40 for acute GVHD and one-year for chronic GVHD. In this analysis, development of grade III-IV acute GVHD was associated with significantly inferior 3-yr transplant outcomes compared to recipients with grade 0-1 acute GVHD (OS and DFS 38% and 36% vs. 63% and 55%, p=0.008 and p=0.010, respectively), whereas development of grade II acute GVHD was associated with improved OS and DFS (80% and 75% respectively). Compared to patients with grade III-IV acute GVHD, those with grade II acute GVHD had significantly lower NRM (5% vs. 23%, p=0.020) and relapse (20% vs. 42%, p=0.033). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM risk (15% vs. 4%, p=0.010), but had no impact on relapse, DFS or OS. The impact of grade III-IV acute GVHD and moderate-to-severe chronic GVHD was further evaluated in Cox MVA, whereby GVHD events were treated as time-dependent covariates. After controlling for other significant variables (e.g. patient and donor age, disease risk index, year of transplant), both grade III-IV acute and moderate-to-severe chronic GVHD were associated with significantly higher NRM (HR 3.38, 95% CI 1.73-6.64, p<0.001 and HR3.35, 95% CI 1.72-6.53, p<0.001 respectively). By contrast, only grade III-IV acute GVHD predicted worse OS (HR 1.80, 95% CI 1.17-2.75, p=0.007) and DFS (HR 1.55, 95% CI 1.02-2.32, p=0.041). Contrary to the positive effect of grade II acute GVHD on survival in landmark analysis, no such association was found in MVA for any transplant outcome. In summary, both grade III-IV acute GVHD and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT in both landmark analysis and time-dependent MVA. In addition, grade III-IV acute GVHD predicted inferior survival. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.

The human leukocyte antigen (HLA) divergence allele advantage hypothesis states that an HLA genotype with two alleles that are more divergent results in more diverse presentation of immunopeptidomes. Higher divergence in the recipient after transplantation from a matched donor, will allow more tumor associated antigen s (TAA) and potentially lower risk of relapse. On the contrary, low HLA evolutionary divergence (HED) in HLA class I and HLA-DR were found to be strong predictors for worse overall survival after matched related donor transplantation. In the haploidentical transplantation (HIDT) setting with post-transplant cyclophosphamide (PTCY) , the level divergence in the donor can have an impact on the ability of donor cells to recognize recipient TAAs and potentially affect transplant outcomes. Additionally, Antigen presenting cells from donor have an impact on graft versus tumor effect post allogeneic transplantation (Jiang Ming Li, 2004). To study the effect of HED in donor HLA-B and its impact on transplant outcomes, we studied 322 consecutive recipient/donor pairs who received their transplant at our center with a median follow up of 69.2 months (range 30-208). HED was calculated as pairwise differences using Grantham distance metric by perl script (https:// sourceforge.net/projects/granthamdist/). We hypothesized that a higher HED score in donor HLA-B will improve survival post HIDT. Data were collected from our database where it was prospectively entered. Patient diagnosis included AML (n=122), ALL (n=68), MDS (n=41), NHL (n=50), other (n=41). Baseline recipient characteristics included a median age of 50 years (19,80), 53% white, HCT-CI≥3 in 50%, Disease risk (intermediate 53%, high/very high 33%), PBSC graft 80% and myeloablative conditioning 49%. Donor characteristics were median age 37 years (13,73), CMV positive 61%, male 61% and female donor to male recipient 21%. Pairwise divergence of donor HLA -B showed the median HED score of 7.93 (0-14.33). On univariate analysis using median cutoffs, a high HED (>7.93) in donor HLA-B was associated with better OS ( HR 0.71, p=0.05), DFS ( HR 0.71, P=0.05), non-relapse mortality NRM (HR 0.51, p=0.03) and similar relapse ( HR 0.84, p=0.4) compared to lower HED scores. A multivariable analysis adjusting for factors such as disease risk, sex, comorbidity score and race, a high HED in donor HLA-B was significant for lower risk of non-relapse mortality (HR 0.509, p=0.04) compared to lower HED. In conclusion, our data show that among HIDT recipients, a high HED in donor HLA-B has significant impact on transplant outcomes and survival by improving NRM. The benefit of higher HED in HLA-B among donors can be used to select the best donor to lower transplant mortality

Despite significant advances in its management, chronic GVHD remains a major cause of morbidity and mortality among patients receiving allogeneic hematopoietic cell transplantation (Allo). Frontline therapy with systemic corticosteroids alone or in combination with sirolimus or a calcineurin inhibitor is often inadequate as 70% of patients require subsequent therapy due to lack of efficacy or intolerance to side effects (Carpenter el al, Hematologic 2018). In the last few years, several new drugs were approved for cGVHD including Ibrutinib, Ruxolitinib and Belumosudil with response rates reaching >70%. These drugs, however, carry significant adverse events, compliance requirements and financial burden. Extracorporeal photopheresis has been a widely adopted modality of therapy for chronic GVHD failing or intolerant to steroids. ECP has a very well tolerated safety profile and can be combined with other chronic GVHD therapies without adding significant toxicity. The role of ECP in the recent era of new chronic GVHD drugs has not been well reported. Here, we report on our experience of 289 consecutive chronic GVHD patients who were treated at our center using ECP (n=87) or no ECP ( n=202) and received their transplant between 2015 and 2022. Frontline therapy at our center is steroids plus sirolimus or calcineurin inhibitor +/- rituximab. Subsequent therapies are based on organs involved, side effects, patient compliance, and physician preference. ECP was used as second line in 16 and third line and beyond in 71 patients. All patients received standardized antimicrobial prophylaxis, routine response assessment monthly and a detailed symptom score assessment every 3 months. Patients were assessed by a single GVHD nurse provider to document severity and response based on 2014 NIH consensus GVHD criteria. We compared both groups in terms of overall response rate, changes in NIH symptom score and survival endpoints. Patients characteristics were as follows: median age 54(18-76), male 57%, most common diagnosis ( AML 34%, ALL 18%, MDS 23%, other 25%), donor ( haplo 35%, MRD 32%, MUD 32%), cell source ( PBSC 90%), disease risk DF DRI (low/intermediate 77%, high/very high 23%) and HCT-CI 0-2 (40%). Both groups (ECP and no ECP) had similar baseline characteristics with median onset to chronic GVHD of 261 vs 246 days (p=0.95). Severity of chronic GVHD was similar between both groups mild (37% vs 50%), moderate (45% vs 38%) and severe (17% vs 12%), p=0.10. patients who received ECP had a higher number of organs involved at onset of GVHD (2.2 organs vs 1.8, p=0.02) compared to no ECP. Most common organs involved were skin (42%), mouth (67%), eyes (36%), liver (21%), GI (16%), musculoskeletal (9%) and lung (5%). The distribution of organ involvement was significant for more skin (50% vs 38%) in ECP vs no ECP. Patients received different medications for chronic GVHD including tacrolimus (n=199), sirolimus (n=143), rituximab 9 n=212), Steroids (n=289), Ruxolitinib (n=83), Belumosudil (n=43), ibrutinib (n=39), Imatinib ( n=24), budesonide (n=47) and infliximab (n=21). The overall response and complete response rates at 6 months were 76% and 36% for ECP vs 68% and 46% for no ECP. There was no difference in ECP response if it was used before (n=49), concomitant (n=12) or after (n=36) Ruxolitinib and/or Belumosudil. The NIH symptom score reduction at 6 months was higher in ECP (1.95) compared to no ECP (1.42). There was no difference in 3 year OS (81.5 vs 83.4%), DFS ( 73% vs 78%), Relapse ( 16% vs 13%) and NRM (13% vs 10%), p=NS for ECP and no ECP groups. In conclusion, our data shows that ECP alone or in combination with other treatments is highly effective treatment for chronic GVHD with comparable responses and higher reduction in GVHD total symptom score compared to non-ECP modalities.

Approximately 10-25% of newly diagnosed B-lineage acute lymphoblastic leukemias have a Philadelphia-like (Ph-like) phenotype. These leukemias lack a BCR-ABL fusion but show similar gene-expression profiling to Ph+ALL. Molecular abnormalities associated with Ph-like include overexpression/rearrangement of CRLF2 with or without JAK-STAT pathway mutations, or fusions involving tyrosine kinases (eg ABL1&2, CSF1R, PDGFRB, JAK2 or EPOR). Patients with Ph-like ALL are typically younger and more likely to be of Hispanic origin than other adult patients with B-lineage ALL and have been associated with a worse overall prognosis (5-year event-free and overall survival < 30%, Jain et al Blood 2017). Since 2017 our program has aimed to identify such patients early using molecular and flow-cytometry profiling and to treat identified Ph-like ALL with age-stratified chemotherapy including pediatric-inspired regimens for patients aged <40. Furthermore, we have aimed to take all eligible patients to allogeneic hematopoietic cell transplantation (AHCT)in a MRD negative state as soon as feasible with routine use of HLA-haploidentical donors when matched donors were unavailable. MRD status was evaluated using the Clonoseq assay and/or fusion specific Q-PCR. We hypothesized that using this approach within an integrated program where the same physicians administer leukemia chemotherapy and AHCT and patients are evaluated for AHCT at the time of diagnosis, that outcomes would improve compared to those observed historically. Of 177 consecutive adult patients with newly diagnosed ALL treated at our center between June 2017 and July 2023 152 (86%) were of B-lineage. Twenty-three patients were identified as Ph-like, comprising 13% of all ALL and 15% of B-lineage ALL patients. Characteristics of Ph-like ALL were: median age 39 (19-72); male (70%); Hispanic ethnicity (61%); race (white 83%, Asian 9%,undeclared 8%), WBC at diagnosis- median 58 x 10e9/L (2-345), cytogenetics (abnormal 48%), molecular abnormality - CRLF2 rearrangement/overexpression (73%), rearrangements of JAK2 (9%), EPOR (5%), ABL1 (5%) PDGFRB (5%); Induction regimen type- Pediatric inspired (50%), HyperCVAD based (36%), Reduced-intensity (14%). Median time from diagnosis to start of induction chemotherapy (excluding pre-phase) was 7d (2-18). Median follow-up of survivors 39 m (12-80m). There were 2 induction deaths (8%). Ninety-one percent of all patients and 100% of evaluable patients achieved a CR in a median of 32 d and 1 cycle (range 1-4). Fifteen patients (65%) proceeded to AHCT in a median of 125 d (23-321 d) from achievement of CR1. Reasons for failure to receive AHCT were: relapse/death pre-AHCT (2), age/KPS/comorbidity (1), lack of caregivers/psychosocial support (2), IEC (2), patient refusal (1). Characteristics of patients receiving AHCT (n=15) were: age - median 35 years (19-68); male (73%), Hispanic ethnicity (73%), donor - haploidentical (53%) matched related (33%) matched unrelated (14%); disease status at AHCT CR1 (93%), CR2 (7%); MRD status at AHCT - negative( 64%) positive (22%), not evaluable (14%); regimen intensity -myeloablative (79%), RIC (7%), non-myeloablative (14%); MRD status pre-AHCT- negative (68%), positive 20%, not evaluable (12%). Median follow-up for surviving transplanted patients is 45 m (17-77m). Kaplan-Meier estimates of overall survival(OS), disease-free survival (DFS) and cumulative incidence of non-relapse mortality (NRM) for all patients following induction are 73%, 41%, 18% at 2 years post induction and 61%, 35% and 25% at 3 years post induction. For patients receiving AHCT, estimated OS, DFS, relapse and non-relapse mortality post-transplant were 80%, 53%, 33% and 13% at 2 years respectively and 64%, 44%, 33% and 22% respectively at 3 years, with no relapses seen after 2 years. These data suggest that the approach described when used in adult patients with Ph-like ALL produces more promising outcomes than historically described. Blinatumomab was not used during consolidation therapy in the reported patients. Its incorporation in the routine therapy of newly diagnosed patients may increase the proportion of patients receiving AHCT in a MRD negative state and further improve outcomes in this historically poor risk patient population.

IntroductionHaploidentical allografts (Haplo) were originally performed using non-myeloablative conditioning (NMA) and marrow grafts. Data on mucositis when using Halpo with intensified and myeloablative regimens and PBSC grafts and post-transplant high-dose cyclophosphamide (ptCY) are not reported.Methods & ObjectivesWe assessed 66 consecutive patients undergoing dose intensified Haplo at our center between 2018 and 2022. Patients received one of two dose-intensified regimens- 1) MAC - fludarabine 30mg/m2/d x 3d and TBI 1200cGy in 8 fractions over 4 days (n=52) 2) RIC – fludarabine 30mg/m2/d x 5 d and melphalan 140mg/m2 × 1d (n=14). All patients received a PBSC graft capped at 5 × 10e6 CD34 cells/kg followed by GVHD prophylaxis with standard ptCy (50mg/kg/d x 2 d), tacrolimus and MMF. Patients were managed as inpatients through d+5 for anticipated CRS and then discharged for outpatient management if well.ResultsPatient characteristics: median age 47 (20-64); male 61%; diagnosis -AML/MPS 65%, ALL30%, NHL 5%; DRI-low/intermediate 77%, high/very high 23%; HCT-CI (0-2) 45% >2) 55%; CMV pos 74%, donor: median age 31(15-70), relationship -sibling 39%, child 39%, parent 18%, other 3%; CMV pos 50%, Female to male 23%. Median follow-up was 33m (7-56). Thirty-three (50%) of patients developed mucositis requiring inpatient management (20% gd3) with median onset on d 7 (3-13). Median days on parenteral opiates and parenteral nutrition were 5 (0-11) and 3 (0-11) respectively. Median number of inpatient days during d0-30 was significantly greater for patients with mucositis vs no mucositis (16 d vs 11 d, p<0.001). However, the number of patients developing gram positive (27% vs 24%), gram negative (6% vs 6%), viral (30% vs 36%) and fungal infections (3% vs 6%) in d3-30 was not significantly different. Estimated 3-year survival, DFS, NRM, relapse and chronic GVHD and d 180 CI of acute GVHD gd 2-4 were not significantly different between patients with mucositis vs no mucositis. When comparing MAC to RIC, incidence (48% vs 57%) and severity (gd3- 19% vs 21%) of mucositis were not different. For MAC patients, gd 2-4 acute GVHD at d 180 was 72 vs 48% in patients developing mucositis vs no mucositis (p=0.09). Other outcome parameters were not significantly different for patients developing mucositis.ConclusionsHalf of patients receiving conditioning with either of the two intensified regimens combined with ptCy for Haplo develop clinically significant mucositis requiring inpatient management. While number of inpatient days were significantly longer for patients who develop mucositis, other outcomes were not worse.

Total Body Irradiation (TBI) is often included in conditioning regimens prior to haploidentical donor transplantation (HIDT) in order to improve engraftment and reduce graft failure, however the technique is resource intensive, expensive, and not universally available globally. Therefore, chemotherapy-only preparative regimens that can provide sufficient immune- and myelo-ablation to eliminate the need for TBI are clearly desirable. Starting in 2015, we introduced an intensive conditioning regimen of fludarabine 150mg/m2 and Mel 140mg/m2 (FM), which allowed sustained engraftment for haploidentical transplant recipients without the need of TBI (Solh et al., Adv Hematol 2021). In this analysis, we compared contemporaneous recipients of FM (n=25) with those receiving fludarabine and TBI 1200 cGy (FTBI, n=124) from 2015-2023. Eligible patients were 18-64 years with acute leukemia or MDS/CML receiving a first HIDT. Compared with FTBI, FM recipients were older (median 55 vs. 43 yrs) with more comorbidity (HCT-CI ≥3 80% vs. 47%). DRI was low, intermediate and high/v.high in 8%, 67% and 25% and comparable between groups. Compared with FTBI, FM recipients had similar ANC recovery (16 vs. 16 days), slower PLT recovery (33 vs. 27 days) and more graft failure (12% vs. 0%). Grade ≥1 cytokine release syndrome (CRS) was similar in FM vs FTBI recipients (93.6% vs. 92.0%), whereas grade ≥2 CRS was significantly higher in FM patients (16% vs. 0.8%, p=0.003). HLA-DR matching in the GVH direction was associated with significantly less CRS (73% vs. 98%, p<0.001), however the percentage of HLA-DRB1 GVH matching was similar in FM vs. FTBI recipients (16% vs. 21%). FM recipients required longer inpatient hospitalization in the first 30 days (median 17 vs. 13.5 days, p=0.014). Acute GVHD grade 2-4 was significantly less in FM recipients (28% vs. 56%, p=0.005, whereas grade 3-4 acute GVHD and chronic GVHD were statistically similar. In FM recipients, there was a trend for inferior 3-yr OS (63% vs. 75%, p=0.09) and DFS (50% vs. 68%, p=0.09) in univariate analysis, but this did not reach statistical significance in multivariable analysis when controlled for HCT-CI and DRI (OS HR 1.70, p=0.14; DFS HR 1.61, p=0.16). The 3-yr cumulative incidence of relapse (34% vs. 23%) and non-relapse mortality (16% vs. 9%)) were not statistically different in FM vs. FTBI recipients, respectively. In summary, within the statistical limitations of this analysis, TBI-free conditioning with FM provided transplant outcomes not statistically different from FTBI in younger HIDT recipients needing intensive conditioning, at the expense of more frequent high-grade CRS, graft failure and requirement for inpatient hospitalization. Acute GVHD was less frequent in FM patients. Thus, FM is a reasonable alternative to FTBI for patients requiring intensive conditioning, where TBI is unavailable or impractical.

Introduction: The BMT CTN 1704 study developed and validated the CHARM that stratified risk for non-relapse mortality and overall mortality among older adults, performing better than the HCT-CI alone (Artz A et al, Blood. 2023;142:109) and equally to two machine learning models. CHARM assigns a total score for 7 health variables: increasing age, higher HCT-CI scores, lower albumin, higher C-reactive protein, higher percent of weight loss over the preceding year, lower patient-reported performance status scores, and lower cognitive score per Montreal cognitive assessment (MoCA). A CHARM calculator is available at:https://cibmtr.org/CIBMTR/OffNav/DevSandbox/CHARM-Risk-NRM-Calculator No multi-institutional prospective data exist on functional trajectories and morbidity after HCT in older patients. We now report on the association of CHARM to trajectories of secondary morbidity outcomes among allo-HCT survivors of this large, prospective study. Patients and Methods: Allo-HCT candidates, aged ≥60 years (yrs), were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. The primary analysis includes 1105 patients proceeding to allo-HCT on study and secondary endpoints were assessed at day (D) 100, 180 and 365 except MoCA and organ toxicity were restricted to D100 and frailty had inadequate data for D100. A sequential multiple imputation strategy was implemented to impute endpoints for survivors at each time point with missing data. Analyses on multiply imputed datasets were conducted and the results combined using Rubin's rule. Associations between CHARM scores and secondary outcomes were analyzed using a multivariable Cox, Fine-Gray, Generalized Estimating Equations, and logistic regression model for survival, competing risks, continuous, and binary outcomes, respectively, with latter two focused on surviving patients. Models were adjusted for other variables including conditioning intensity, graft-versus-host disease (GVHD) prophylaxis regimen, disease-risk index, donor-recipient gender match, ethnicity, baseline value of the dependent variable, and visit timepoints. Results: Higher CHARM scores were associated with development of serious organ toxicities by D100 (OR: 2.05, [1.52-2.78], p<0.0001) and ≥2 worsening score on the MoCA (odds ratio (OR) 1.55 [1.16-2.1], p=0.003). Among survivors at all timepoints, higher CHARM scores were associated with greater disability by instrumental activities of daily living (IADL) (Slope -0.640 [-0.433-0.846], p<0.001) and worsening Patient-Reported Outcomes Measurement Reporting System (PROMIS) physical function (Slope -0.981 [-0.057 - -1.904], p=0.037), depression (Slope 0.763 [0.042-1.484], p=0.038) and in a lesser magnitude anxiety (Slope 0.659, p=0.076). Among survivors at D180 and D365, higher CHARM scores were associated with worse frailty (Slope 0.193 [0.081-0.305], p<0.001). CHARM scores were not associated with development of acute GVHD grades 2-4 or 3-4 but were associated with post-GVHD increased mortality (HR: 1.61, [1.25-2.08], p=0.0002). Higher CHARM scores are associated with a lower incidence of chronic GVHD (HR: 0.83, p=0.026), likely due to the effect of CHARM on the competing risk of death leaving fewer patients at risk for chronic GVHD. Conclusions: The novel primary CHARM, originally developed to predict risks of NRM, also predicts worse frailty, disability, cognitive decline, and serious organ toxicities; outcomes that are critically important to older recipients of allo-HCT. CHARM therefore informs risks of transplant morbidity, separate from risks of developing acute GVHD. Results further support adopting CHARM in practice to counsel patients, expedite HCT referrals for lower risk CHARM, and design trials for high CHARM score patients.

The optimal duration of Graft-Versus-Host-Disease (GVHD) prevention following allogeneic stem cell transplantation (alloSCT) has not been well studied. Although practice varies among transplant centers, immunosuppression (IS) is typically tapered or stopped between 3 and 6 months post alloSCT. Moreover, disease risk, adverse IS reactions, and donor-recipient HLA disparity may influence the duration of GVHD prophylaxis. Therefore, we conducted a single center retrospective analysis to determine the effects of stopping IS prior to 180 days versus continuing for 180 days or more on overall survival (OS), relapse free survival (RFS), chronic GVHD free relapse free survival (CGFRFS) and non-relapse mortality (NRM). We evaluated patients that received an alloSCT between 1/1/13 and 12/31/23. We excluded patients that were receiving a second alloSCT, and those that had GVHD or died prior to day 100 after alloSCT. Three hundred and fifty two patients met these criteria. Median age was 55 (range 19-78) and 55% were male. The most common diagnoses were acute myelogenous leukemia (36%), myelodysplastic syndrome (21%), acute lymphocytic leukemia (18%) and non-Hodgkin's lymphoma (7%). IS was discontinued prior to 180 days in 185 patients (53%). Donor types were matched-related (42%), haploidentical (31%) or matched-unrelated (27%). Eighty-nine percent of the patients were given GVHD prevention with either a post-cyclophosphamide (P-Cy) based regimen (41%) or a tacrolimus/methotrexate regimen (48%). Patient demographics and disease-related characteristics were similar in each group except for the Dana Farber disease risk index (DF-DRI) and more patients on IS < 180 days received post-transplant cyclophosphamide based GVHD prevention. Acute GVHD occurred in 30% of the IS < 180 day group versus 19% in the > 180 day group. Chronic GVHD incidence was similar between the groups (35% vs. 41%). The 3-year survival estimates for IS < 180 vs. IS > 180 were OS=77% vs. 91% (p=0.009), RFS=76% vs. 90% (p=0.026), CGFRFS=72% vs. 80% (p=0.36), and NRM=12% vs. 3% (p=0.08). Using a 1-year landmark analysis, OS and RFS were significantly better in the group taking IS > 180 days. A multivariate Cox analysis revealed the significant variables for OS with a hazard ratio (HR) > 1 were stopping IS < 180 days (HR 8.6, p<0.001), patient age > 55 (HR 2.42, p<0.001), high/very high DF-DRI (HR 1.72, p<0.010), and non-myeloablative versus reduced intensity conditioning (HR 2.26, p=0.005). P-Cy containing GVHD prevention had the only significant positive survival benefit of HR< 1 (HR .60, p=0.033). Interestingly, the significant variables for RFS with a HR > 1 were patient age > 55, high/very high DF-DRI, and non-myeloablative versus reduced intensity conditioning. Stopping IS <180 days had no benefit on in reducing relapse risk (p=0.27). This analysis highlights how complicated the post-transplant period is with several variables effecting GVHD, disease-related, and survival outcomes. More systematic prospective studies are needed to determine the ideal duration of IS. Moreover, studies that incorporate newer GVHD prevention strategies like cyclophosphamide and abatacept are needed to evaluate their effects on IS duration, survival, GVHD, and other long-term effects.

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS D, 18.3% versus 12.7%; DFS D, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased

Haploidentical related donor transplantation with PTCY has expanded the donor availability and made it feasible for most patients with high risk hematologic malignancies to receive a curative transplantation. Haplo with PTCY carries similar disease control and lower incidences of GVHD compared to matched donors using calcineurin inhibitor based GVHD prophylaxis. Chronic GVHD among transplant patients who are one-year survivors after matched related or unrelated allogeneic transplantation was shown to be associated with higher non relapse mortality and worse overall survival 1 . The impact of clinically significant chronic GVHD requiring immunosuppression (IS) on haplo recipients with PTCY who have survived one-year post-transplant has not been studied and is being assessed in this analysis. A total of 322 consecutive adult patients who received haplo transplant with PTCY at our center were included in this study. Two hundred and forty-nine survived first year post-transplant and were included in the primary analysis for predictors of being immunosuppression (IS) free at one year. Two hundred and twenty-one patients were free of relapse at 1-year post haplo and were included in the analyzing the effect of IS free status on non-relapse mortality (NRM), progression free survival (PFS), Relapse and overall survival (OS). Median follow up for survivors was 63.9 months (18.3-165). Patient, disease, and transplant related characteristics were retrieved from our database where they have been prospectively entered. All patient received standard GVHD prophylaxis of PTCY, Mycophenolate (stop day +35) and Tacrolimus through day 180. A total of 163 patients (65%) were IS free at one-year post haplo. Patients' characteristics were as follows: median age 48 (19,80) years, male sex 56%, Race (white 61%, black 34%), most common diagnosis ( AML/MDS 55%), comorbidity index HCT-CI ≥3 52%, cell source (PBSC 81%), and myeloablative intensity (49%). Both groups IS free and still on IS had similar baseline characteristics except for higher female-male donor (28% vs 15 %, P=0.03) and female donors (48% vs 30%, p=0.008) for patients on IS at 1-year. Logistic regression to identify patients more likely to be on IS at 1-year post Haplo showed that female donor sex to be a significant risk (OR 2.11, CI 1.21-3.69, p=0.009). In a Cox analysis on the effects of IS on transplant outcomes, being on IS at 1-year had no impact on OS (HR 1.44, CI 0.90-2.31, p=0.13) or relapse (HR 0.77, CI 0.37-1.61, p=0.49) but a significantly higher NRM ( HR 4.18, CI 1.80-6.72, p<0.001) and a trend towards worse PFS (HR 1.59, CI .95-2.66, p=0.08). These results indicate that female donors are significant risk factor for requiring IS at one-year post haplo with PTCY. Additionally, clinically significant chronic GVHD requiring IS at one-year post haplo with PTCY has no significant effect on relapse but is associated with higher NRM and a trend towards worse PFS. These results can be used to inform appropriate donor selection to avoid late complications among haplo recipients.

Graft versus tumor relies on tumor-associated antigens (TAAs) that are presented to donor T cells via human leukocyte antigens (HLAs). The HLA evolutionary divergence (HED) between alleles of a single individual can dictate the ability to present TAAs. The impact of HED in haploidentical donor transplantation (HIDT) has not been studied. We studied the effect of HED on transplant outcomes following HIDT. We analyzed 322 consecutive recipient/donor pairs with a median follow-up of 57.2 months. Pairwise divergence of HLA class I and II showed that HLA-B, -DRB1, and -DQB1 contributing most to mean HED. The mean HED was class I 6.85 (HLA-A 7.08, -B 8.24, and -C 5.07), class II 8.58 (HLA-DRB1 10.97, -DQB1 10.06 and -DPB1 4.06). A high HED in class I mismatched recipient/donor haplotype (RD MM) was significant for worse DFS (HR 1.11, p = 0.020), and relapse (HR 1.11, p = 0.02). Also, a high HED in RD MM HLA-B haplotype had worse OS (HR 1.07, p = 0.02), DFS (HR 1.09, p = 0.002), higher relapse (HR 1.10, p = 0.003), and similar NRM to low HED. The multivariate analysis showed that high HED in RD MM HLA-B (>= 7.8 vs <7.8) had worse DFS (HR 1.53, p = 0.01), higher relapse (HR 1.61, p = 0.024), and similar NRM and OS.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has shown remarkable efficacy in treating certain hematologic malignancies, particularly in relapsed or refractory non-Hodgkin Lymphomas (r/r NHL). Currently, there are five FDA-approved CAR-T therapies for r/r NHL. These therapies have produced durable responses and sometimes put r/r NHLs into complete remission. However, CAR-T therapies are frequently associated with severe adverse effects, including Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), often leading to lengthy hospitalizations and significant morbidity and mortality. Prophylactic regimens have been developed to reduce the risk of CRS and ICANs. We have performed a retrospective cohort study comparing outpatient administration of axicabtagene ciloleucel combined with our steroid-based prophylactic regimen (n=40) to Lisocabtagene maraleucel (n=47) and Tisagenleleucel (n=28) therapies in patients with r/r NHL receiving outpatient CAR-T therapy between January 2018 and March 2024. Patients were admitted on the day of cell therapy infusion and discharged the same day. Admissions were reserved for complications requiring inpatient care. Dexamethasone 10mg was started on day 0 through day 2 for patients receiving axicabtagene. Our population consisted of self-identified White, Black/African American, Asian, Native American/Alaskan, or declined (78%, 14.6%, 4.8%, 1.6%, 1.0%). All patients were risk-stratified before CAR-T infusion. Every patient was assessed for CRS and ICANS for the duration of their treatment. Patients who developed CRS or ICANS were graded using the American Society for Transplantation and Cellular Therapy (ASTCT) and Immune Effector Cell-Associated Hematotoxicity (ICAHT) standardized grading systems, respectively. Primary outcome measures were max grade CRS, max grade ICANS, number of days with absolute neutrophil count ≤ 500 cells/µL, number of days platelet ≤20K/µL, number of admissions to the hospital, hospital length of stay (days), day 100 disease status, and overall survival. All statistical analyses used alpha levels of 0.05 and 95% confidence intervals. Of the 115 CAR-T infusions, 71 patients (61.7%) developed CRS, and 40 patients (34.7%) developed ICANS during treatment. The incidence of CRS by grade in the investigational and control group was: grade 1 (n=16, 40%; n=25, 32.8%), grade 2 (n=16, 40%; n=9, 11.8%), grade 3 (n=0, 0%; n=2, 2.6%), grade 4 (n=2, 5%; n=1, 1.4%), respectively (P=0.232). The incidence of ICANS by grade in the investigational and control group was: grade 1 (n=6, 15%; n=10, 13.15%), grade 2 (n=1, 2.5%; n=6, 7.8%), grade 3 (n=11, 27.5%; n=4, 5.26%), grade 4 (n=1, 2.5%; n=1, 2.5%), respectively (P=0.076). The mean number of days with ANC ≤ 500 cells/µL was 17.65 CI [11.56, 23.73] in the investigational group and 9.0 CI [6.52, 11.47] for the control (P=0.012). The mean number of days with platelet count ≤ 20K/µL was 22.65 CI [12.51, 32.78] in the investigational group and 6.89 CI [2.56, 11.21] in the control (P=0.007). The mean hospital length of stay (days) for the investigational group was 12.94 CI [7.96, 17.92] and 7.99 CI [5.79, 10.18] for the control (P=0.077). The mean number of hospitalizations for the investigational group was 1.9 CI [1.60, 2.19] and 2.05 CI [1.70, 2.35] for the control (P=0.497). The investigational and control groups had a day 100 disease status of complete remission (42.5%; 30.0%), partial remission (10.0%; 8.0%), stable (2.5%; 4.0%), progression (15.0%; 13.0%), relapsed (10.0%; 5.0%), deceased (7.50%; 28.0%), and no status (12.5%; 12.0%). The overall survival of the investigational and control groups was 60% (n=24) and 50.6% (n=38), respectively (P=0.343). Our data shows no statistical difference between the experimental and control groups in the max grade CRS, max grade ICANS, number of hospitalizations, and hospital length of stay. This indicates that the prophylactic regimen used with outpatient axicabtagene ciloleucel achieved similar toxicity profiles and hospitalization statistics compared to the standard treatments.