Background Allogeneic hematopoietic cell transplantation (allo-HCT) remains central to curative therapy for adults with acute lymphoblastic leukemia (ALL). Despite advances in conditioning and supportive care, relapse, non-relapse mortality (NRM), and graft-versus-host disease (GVHD) remain major limitations. Reduced-intensity conditioning (RIC) has broadened transplant eligibility for older and comorbid patients, but comparative outcomes remain uncertain. We report a 17-year institutional experience evaluating survival, NRM, and GVHD across conditioning strategies and clinical subgroups. Methods We retrospectively analyzed all adults with ALL who underwent allo-HCT at Yale New Haven Hospital between 2008 and 2025. Conditioning regimens included fludarabine- or pentostatin-based RIC with low-dose total body irradiation (TBI) and myeloablative (MA) regimens using busulfan- or TBI-based platforms. GVHD prophylaxis consisted of calcineurin inhibitor–based therapy, with post-transplant cyclophosphamide (PTCy) in a subset. The primary endpoint was overall survival (OS); secondary endpoints included NRM at day 100, engraftment, and grade II–IV acute and chronic GVHD at 1 year. OS was estimated by Kaplan–Meier and compared by log-rank testing. Results A total of 120 patients were included. Median age was 43 years (range 18–75); 58% were male. Subtypes included Ph+ B-ALL (n=42), Ph– B-ALL (n=61), and T-ALL (n=17). Most patients (70%) underwent transplant in CR1. Donors were matched related (n=36), matched unrelated (n=17), mismatched related (n=6), and mismatched unrelated (n=61). Conditioning was MA (n=70) or RIC/NMA (n=50). Median follow-up was 73 months (95% CI, 61–96). All patients engrafted. Day 100 NRM was 7.5%; 1-year grade II–IV acute GVHD and chronic GVHD were 8.3% and 39%, respectively.Median OS was 10.4 years (95% CI, 3.4–NR); 1-, 5-, and 10-year OS were 78.3%, 53.6%, and 50%. MA conditioning improved OS versus RIC/NMA (126 vs 19 mo, p=0.0013). Survival also differed by age group: AYA (18–39 NR), adults (40–59 years, 126 months), and older adults (60–75 years, 14.5 mo, p<0.001). CR1 and low CIBMTR risk were associated with superior OS (169 vs 25 months, p=0.005; 169 vs 25 months, p=0.004). Outcomes were similar by lineage, donor match, race, and sex. Among RIC recipients, Pento/TBI showed survival comparable to other RIC regimens. Conclusions In this 17-year single-center experience, allo-HCT provided durable long-term survival in adults with ALL, with low early NRM and manageable GVHD. Myeloablative conditioning was associated with superior outcomes, while older age, higher CIBMTR risk, and transplantation beyond CR1 predicted worse survival. These data reflect consistent, long-term results within our institutional program and reinforce the value of myeloablative approaches when clinically feasible.

Background/Objectives: Obesity and inflammatory conditions, including steatotic liver disease, are known to impact the hematopoietic niche and immune surveillance. Therefore, assessing the impact of steatotic liver disease on recipients of allogeneic stem cell transplantation (allo-HSCT) with bone marrow origin neoplasms is clinically relevant and an underexplored area of investigation. Methods: We followed the clinical course of allo-HSCT recipient patients with steatotic liver. Results: From 2014 to 2020 at our center, we identified 18 patients (5.8% of 306 patients screened) with steatotic liver disease detected on non-contrast CT imaging pre-transplant. With a minimum of 5 years follow-up for all, eight patients experienced post-transplant relapses (44%). Relapses (78%) followed by infections (55%) were the major contributors of mortality in this cohort. Pre-transplant transaminases were normal (AST median 28, ALT median 37) in all, while most patients (89%; 16/18) developed abnormal transaminases in the first-year post-transplantation without evidence of permanent liver injury. None experienced veno-occlusive disease of the liver. The cumulative incidence of acute graft-versus-host disease (aGVHD) was 33% (6/18), with 55% (10/18) experiencing chronic graft-versus-host disease (cGVHD). Conclusions: Our descriptive study highlights that radiologically detected steatotic liver disease is not a contraindication to proceeding with allogeneic stem cell transplant, and its association with transaminitis, relapse, immune complications, and post-transplant metabolic health requires future mechanistic studies.

Background Older adults with acute lymphoblastic leukemia (ALL) have inferior outcomes with induction therapy and remain underrepresented in transplant studies. Population data show that only 5–9% of patients aged ≥60 years undergo allogeneic transplantation. Conditioning for this group must balance efficacy and tolerability. Total-body irradiation (TBI) remains biologically important in ALL for its ability to control CNS disease and provide broad anti-leukemic cytoreduction. Pentostatin, a purine analog with favorable immunosuppressive and toxicity profiles, may offer a safer reduced-intensity platform when combined with low-dose TBI. We evaluated outcomes of older adults with ALL treated with pentostatin/TBI (Pento/TBI) conditioning. Methods We retrospectively reviewed adults aged ≥60 years with ALL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) at Yale between 2009 and 2025 using Pento/TBI, consisting of continuous-infusion pentostatin (8 mg/m² over 48 hours) and TBI (600 cGy in three fractions). Donor type, disease status, and post-transplant cyclophosphamide (PTCy) use were recorded. Outcomes included overall survival (OS), non-relapse mortality (NRM), and acute and chronic GVHD, analyzed by Kaplan–Meier and cumulative incidence methods. Results Twenty-four adults aged 60–75 years (median 67) with Ph+ B-ALL (n=11), Ph− B-ALL (n=10), and T-ALL (n=3) received Pento/TBI. Donors were matched related (21%), matched unrelated (29%), mismatched related (46%), and mismatched unrelated (4%). Sixteen patients were in first complete remission (CR1) and eight in ≥CR2. Five (21%) received PTCy. All engrafted. At a median follow-up of 66 months (range 9–NR), median OS was 14.5 months (95% CI, 6.3–18); 1-, 3-, and 5-year OS were 60%, 20%, and 13%, respectively. The 100-day NRM was 8.3%. Grade II–IV acute GVHD occurred in 17% and chronic GVHD in 25%. OS did not differ by age, remission status, or lineage. Conclusions Pentostatin combined with low-dose TBI achieved consistent engraftment, low early mortality, and manageable GVHD rates in older adults with ALL. This regimen provided effective disease control with acceptable toxicity, supporting its use as a feasible reduced-intensity platform for patients not eligible for myeloablative conditioning. Although long-term survival remains limited in this high-risk population, these results highlight the potential role of pentostatin/TBI as a well-tolerated conditioning strategy that preserves the biologic advantages of TBI in ALL.

Background: NCT05002816 is an ongoing phase Ib/II trial evaluating the safety, tolerability and preliminary efficacy of the unique combination of Elotuzumab and Belantamab mafodotin in patients with relapsed/refractory myeloma (RRMM). Combining monoclonal antibodies simultaneously targeting SLAMF7 and BCMA could prevent antigen loss and development of resistance. Here we present interim biologic correlatives on the first 20 patients from this trial exploring patient's bone marrow (BM) myeloma -intrinsic and -extrinsic factors impacting clinical response. Methods: This single-arm phase Ib/II study has enrolled thus far 20 patients with triple-class refractory RRMM as of Aug 1, 2025. Patients with progression after prior BCMA-targeted therapy are eligible. Elotuzumab is administered via intravenous (IV) infusion at an established dose of 10 mg/kg on days 1, 8, 15, 22 every 28 days for cycles 1 and 2; followed by 20mg/kg on day 1 of each 28-day cycle. Belantamab mafodotin is administered via IV infusion with the starting dose of 1.9 mg/kg IV at every 4-week interval, with subsequent dose-reduction based on toxicity. Immune profiling of tumor biological samples is performed via flow cytometry. We define the expression levels of multiple immunotherapeutic targets such as SLAMF7 and BCMA on patient's BM CD138+ myeloma cells collected at multiple time points (at screening, after 3 cycles and at the end of treatment) as well as cellular changes within the BM CD138-negative cell populations by flow-cytometry. Results: Median age of patients is 66.5 years (range 59-79). The patient population is heavily pretreated with 5 prior median lines of therapy (range 2-8). Phase I part of the study was completed after 10 patients concluded safety follow-up. The safety and preliminary efficacy of the phase I part of this study were previously reported and were notable for an encouraging preliminary with partial responses (PR) in 4/10 (40%) and stable disease (SD) in additional 3/10 (30%) of patients.1 Notably, 40% (4/10) of patients were refractory to prior BCMA-targeted therapy (2 post-BCMA bispecific antibody, 2 post-BCMA chimeric antigen receptor T-cell therapy [CART]). We find that SLAMF7 expression levels decrease in 8/10 (80%) of patients who progressed over time with this treatment, while no significant change in BCMA expression is noted. Quantitative profiling of SLAMF7 density shows a statistically significant decrease upon treatment (average number of SLAMF7 molecules per cell before treatment is 2,675 compared to 1,382 at the end of treatment) based on n=16 patients analyzed thus far. The association with clinical responses will be performed at the time of completion of the trial accrual. Further, we observe a significant increase in CD19+ B-cells after starting treatment and decreased PD1+ T cells upon continued treatment. No significant differences were observed in myeloid cell populations. Conclusion: In summary, combination therapy with belantamab mafodotin and elotuzumab has shown an encouraging safety profile and a promising preliminary efficacy including among those with prior failure of BCMA-targeted therapy, as previously reported.1 Our preliminary data suggest that decreased SLAMF7 density may predicts inferior clinical response among poor responders, likely representing one mechanism of escape while the impact on B-cell and T-cell compartments may contribute to disease response in patients with heavily pretreated RRMM. Funding and Product for this study was provided by GSK . GSK was provided the opportunity to provide a courtesy review of the preliminary version of this publication for accuracy only, but the authors are solely responsible for final content and interpretation. Please ensure the legal entity name is as per the contract with GSK. Ref:Sabrina Browning, Terri Parker, Natalia Neparidze, et al. Poster Presentation. Open-label, single-arm phase Ib/II study of immune combination therapy with elotuzumab and belantamab mafodotin in patients with relapsed refractory multiple myeloma. ASCO June 2024, Chicago, IL

ABSTRACT:The ETAL-1 trial demonstrated that upfront allogeneic hematopoietic stem cell transplant (HSCT) improved disease-free survival, but not overall survival, when compared with consolidation chemotherapy followed by "delayed" HSCT on relapse in patients with intermediate-risk acute myeloid leukemia (AML). However, the health-economic implications of upfront HSCT compared with delayed HSCT are unknown. We developed a partitioned survival analysis model using derived survival data, probabilities of salvage treatments, utilities, and costs from the ETAL-1 trial and published literature. The primary outcome was the incremental net monetary benefit (INMB) from the perspective of the United States and United Kingdom health care systems, at all accepted willingness-to-pay (WTP) thresholds: $50 000 to $150 000 per quality-adjusted life year (QALY), and £20 000 to £30 000 per QALY, respectively. The respective INMBs favored upfront HSCT, and were $497 100 (95% confidence interval [CI], $259 800-$719 600) and £235 600 (95% CI, £166 800-£298 500) at WTP thresholds of $150 000 per QALY and £30 000 per QALY. Across deterministic sensitivity analyses, no model input changed the conclusion that upfront HSCT is the cost-effective strategy in either jurisdiction. Probabilistic sensitivity analysis showed that upfront HSCT was cost-effective in 100% of iterations, and was less costly and more effective (ie, "dominant") in >90% of iterations in both health care systems. In conclusion, we conducted a partitioned survival analysis based on the ETAL-1 trial, and showed that proceeding to HSCT in first remission is the cost-effective strategy in the care of patients with intermediate-risk AML in both the United States and the United Kingdom, as compared with delayed HSCT.

During the COVID-19 pandemic, hematopoietic stem cell transplant (HSCT) recipients had elevated mortality rates from SARS-CoV-2 infection, ranging between 10-40%. SARS-CoV-2 mRNA vaccines are important tools in preventing severe disease, yet their efficacy post-transplant remains unclear, especially in patients subjected to myeloablative chemotherapy and immunosuppression. We evaluated humoral and adaptive immune responses to the SARS-CoV-2 mRNA vaccination series in 42 HSCT recipients and 5 healthy controls. Post-vaccination responses were assessed by anti-spike IgG and nucleocapsid levels, and antigen specific T cell activity. Immune profiling was performed using clinical flow and mass cytometry. Patients were selected based on humoral and cellular responses for single-cell RNA with TCR and BCR sequencing. Our studies revealed defects in memory T cells that correlated with an absence of cellular response despite nearly universal humoral response. Several patients with a robust antibody response developed COVID-19 infection, but none developed severe disease or died from the infection.

Introduction Mature T-cell lymphomas, including aggressive nodal PTCL, advanced stage CTCL, and extranodal cytotoxic lymphomas, are associated with poor outcomes. While karyotype (KT) abnormalities are frequently detected in these diseases, limited data exist on their prognostic significance. We evaluated the impact of KT abnormalities, including complex KT and specific chromosomal lesions, along with clinical and demographic factors, on overall survival (OS) in a single-center cohort. Methods We retrospectively reviewed 189 patients (pts) diagnosed with T-cell lymphoma who had successful metaphase KT at diagnosis from peripheral blood (PB), bone marrow (BM), or tumor tissue. T-cell lymphomas were classified according to WHO 2022 into nodal, extranodal/cytotoxic, and cutaneous subtypes. CTCLs were stratified into indolent (Early-stage CTCL, IA–IB) and aggressive (Sézary syndrome, transformed mycosis fungoides). KTs classified as normal, abnormal, and complex (≥3 abnormalities), and recurrent abnormalities were recorded. Baseline clinical and lab data were collected. OS was estimated using the Kaplan-Meier (KM) method with 95% confidence intervals (CI). Univariate Cox proportional hazards (CPH) model identified factors associated with OS, and significant variables were entered into multivariate CPH models. Results The median age was 66 years (IQR 55-74); 65% were male and 35% were female. Overall, 58% of pts were alive at analysis. Nodal PTCL was the most common subtype (113 pts, 60%), followed by early CTCL (30, 16%), aggressive CTCL (24, 13%), and extranodal lymphomas (22, 12%). KT was obtained from 166 BM (86%), 26 PB (13%), and 2 tissue (1%) specimens. Among abnormal KTs, 63% were from BM, 35% from PB, and 2% from tissue. Specific abnormalities included gain of chr1 (5%), gain of chr3 (5%), gain of chr7 (5%), gain of chr8 (5%), monosomy 5 or del(5q) (4%), monosomy 9 or del(9q13q22) (4%), Monosomy 10 (4%), loss of chrY (5%), and presence of marker chromosomes (5%).Of the 189 pts, 48 (25%) had an abnormal KT, while 141 (75%) had a normal KT. Complex KT was observed in 31 (16%) pts. Abnormal non-complex and complex KTs were seen respectively in: aggressive CTCL (8%, 42%), nodal PTCL (4%, 13%), extranodal (9%, 14%), and early CTCL (27%, 10%). KM survival analysis showed a median OS for the entire cohort of 95 months (95% CI: 65-245). Pts with a normal KT had a median OS of 143 months (95% CI: 81-inf) compared with 34 months (95% CI: 18-83) for those with an abnormal KT. Pts without a complex KT had a median OS of 144 months (95% CI: 85-inf), whereas those with a complex KT had 14 months (95% CI: 4-25). For specific abnormalities, pts with gain of chr7 had OS of 3 months, gain of chr8 had 19 months, monosomy 5 or del(5q) had 4 months, loss of chrY had 30 months, gain of chr1 had 4.5 months, gain of chr3 had 7.5 months, monosomy 9 or del(9q13q22) had 2 months, monosomy 10 had 17 months, and marker chromosome presence had 5.5 months. Univariate CPH identified complex KT (HR = 3.9, p < 0.001), gain of chr1 (HR = 5.7, p < 0.001), gain of chr3 (HR = 4.6, p < 0.001), monosomy 5 or del(5q) (HR = 4.6, p < 0.001), gain of chr7 (HR = 4.2, p < 0.001), gain of chr8 (HR = 3.3, p < 0.001), monosomy 9 or del(9q13q22) (HR = 4.9, p < 0.001), monosomy 10 (HR = 2.8, p = 0.008), and marker chromosomes (HR = 4.6, p < 0.001) as adverse factors. Higher platelet count was protective (HR = 0.9, p < 0.001), while greater number of abnormalities increased hazard (HR = 1.1, p < 0.001). In multivariate CPH model, complex KT (HR = 3.1, 95% CI: 1.2-8.2, p = 0.019), monosomy 9 or del(9q13q22) (HR = 4.4, 95% CI: 1.2-15.4, p = 0.022), gain of chr1 (HR = 3.5, 95% CI: 1.1-11.8, p = 0.042), and low platelet count (HR = 0.98, 95% CI: 0.97-0.99, p = 0.006) remained independent predictors of poor OS. Conclusion: We demonstrate that cytogenetic abnormalities detected in PB or BM, most notably complex KTs, confer a markedly poor prognosis in aggressive T-cell lymphomas. The integration of KT data with clinical parameters, such as platelet count, offers a powerful approach to refine risk stratification, identify biologically high-risk subgroups, and potentially guide personalized therapeutic strategies in this challenging disease spectrum. To our knowledge, this is one of the largest single-center studies assessing the prognostic significance of KT in mature T-cell lymphomas, providing novel insights into the role of specific chromosomal lesions in patient outcomes.

T-cell lymphomas are a heterogeneous group of lymphoid malignancies with poor outcomes. Acceptable frontline treatment regimens include various combinations of prednisone, vincristine, cyclophosphamide, etoposide and doxorubicin with brentuximab included for CD30- positive disease especially anaplastic large cell lymphoma. We report that EPOCH is well tolerated with high response rates in aggressive T-cell lymphomas and can serve as a backbone for combination studies across subtypes. Background: T-cell lymphomas are a heterogeneous group of lymphoid malignancies with poor outcomes. Frontline multiagent chemotherapy options include CHOP (prednisone, vincristine, cyclophosphamide, and doxorubicin), brentuximab-CHP, CHOEP, and EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). Patients and Methods: We report our single institution data for safety and efficacy of EPOCH in 38 patients with aggressive T-cell lymphoma including both peripheral T cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). Results: Eighteen patients received EPOCH as first-line and 21 in the relapsed/refractory (R/R) setting. In 36 evaluable patients, the overall response rate (ORR) was 77% (95% CI, 61%-89%) with 19 (53%) patients achieving complete response (CR) (95% CI, 36%-69%). The ORR in first line and R/R settings were 80% (95% CI, 46%-94%) and 75% (95% CI, 52%-90%), respectively. Response rate was similar in Afr ican Amer ican versus Caucasian patients but was higher in CD30 negative versus positive patients. Most common grade 3/4 adverse events included cytopenias. Conclusions: Overall, EPOCH was well tolerated with high response rates in first line and R/R setting.

Acute myeloid leukemia (AML) with t(8;21) is a subset of core binding factor AML and is considered to be favorable risk disease in patients receiving intensive cytarabine based chemotherapy. However, relapse remains a significant clinical challenge. Mutations in KIT, which frequently co-occur in t(8;21) AML, have been associated with worse relapse free and overall survival. Avapritinib is a novel tyrosine kinase inhibitor targeting KIT mutations that is approved for systemic mastocytosis but doesn't currently have an established role in the treatment of AML. We present a case of a patient with extensively treated KIT D816H-mutated t(8;21) AML who experienced relapse after an allogeneic hematopoietic stem cell transplant and achieved a deep remission rapidly with avapritinib monotherapy. This case highlights the potential role of avapritinib as a targeted therapy for relapsed t(8;21) AML with KIT mutations, warranting further clinical investigation.

Background: Aggressive T-cell lymphomas are rare, biologically heterogeneous malignancies with a poor prognosis in the relapsed or refractory setting. Allogeneic stem cell transplantation (allo-SCT) offers curative potential through cytoreduction and a graft-versus-lymphoma (GVL) effect. While most reduced-intensity conditioning regimens rely on fludarabine, pentostatin is a purine analog with a distinct mechanism of action and a favorable immunosuppressive profile that supports donor engraftment with reduced toxicity. When combined with low-dose total body irradiation (TBI), this platform offers both lymphodepletion and potential disease control. We previously reported 3-year outcomes in 40 patients treated with pentostatin/TBI for T-cell lymphomas. This updated 75-patient analysis includes broader histologic representation, 5-year survival estimates, and evaluation of prognostic factors including remission status at transplant, age, histology, and donor type. Methods: This retrospective study included 75 patients with the following histologies: angioimmunoblastic T-cell lymphoma (AITL)=12, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) =12, T-cell prolymphocytic leukemia (T-PLL)=11, mycosis fungoides (MF)/Sézary syndrome (SS)=14, anaplastic large cell lymphoma (ALCL; ALK-positive and ALK-negative)=4, hepatosplenic T-cell lymphoma (HSTCL)=2, and rare subtypes (subcutaneous panniculitis-like T-cell lymphoma [SPTCL], extranodal NK/T-cell lymphoma [ENKTL], primary cutaneous gamma delta T-cell lymphoma [PCGD-TCL], adult T-cell leukemia/lymphoma [ATLL], primary cutaneous CD4+ and CD8+ lymphomas [PCSM-TCL and PC8-AECTCL], aggressive NK-cell leukemia [ANKL]) = 20. Patients received a conditioning regimen of continuous infusion pentostatin (8 mg/m² over 48 hours) and TBI (600 cGy in 3 fractions). Outcomes included engraftment, acute and chronic GVHD, and overall survival (OS). Kaplan-Meier and cumulative incidence methods were used. Results: The median age was 53 years (range, 20-77). Of the 75 patients, 68% were in complete remission (CR) at the time of transplant, and 35%, 45%, and 20% had matched related, matched unrelated, and mismatched donors, respectively. All patients received calcineurin inhibitor–based GVHD prophylaxis, and 12% also received post-transplant cyclophosphamide. Fourteen patients (19%) had undergone prior autologous transplant. The median follow-up was 75.2 months (range, 1-194; 95% CI: 67,119). The median overall survival (OS) for the cohort was 60 months (95% CI: 18.7, NR). The 1-year, 3-year, and 5-year OS rates were 71.5%, 58.5%, and 49%, respectively. At 5 years, OS was 54% for patients in CR and 39% for those not in CR (NCR) at the time of transplant. OS significantly differed by age, with patients >65 having inferior outcomes compared to younger patients (10.4 vs 112 months, p = 0.0174). OS did not significantly differ by remission status at transplant (CR: 109.6 months [95% CI: 13, NR] vs NCR 38.3 months [95% CI: 7.6, NR], p = 0.40), or by donor type (matched: 110 months [95% CI: 19, NR] vs mismatched: 18.7 months [95% CI: 3.4, NR] p= 0.29). There was no significant difference by histology; however, there was a trend of inferior survival in rare subtypes. The median OS was not reached for PTCL and MF/SS, with 5-year OS of 65% and 68%, respectively. The median OS for rare subtypes was 13 months, with a 5-year OS 37%. All patients engrafted. The 100-day non-relapse mortality was 9.3%. The cumulative incidence of grade II–IV acute GVHD was 34.7% and that of extensive chronic GVHD was 43%. The most common causes of death were relapse or progression (20%) and infection (5%). Conclusion: This 20-year institutional experience demonstrates that pentostatin and TBI is a well-tolerated and effective reduced-intensity conditioning platform for allogeneic transplant in T-cell lymphomas. The regimen was associated with full engraftment, low early mortality, and a 5-year OS of 49%—a result that compares favorably to published outcomes in this historically high-risk population. Notably, over 32% of patients underwent transplant not in remission and still experienced meaningful long-term survival, suggesting this regimen offers GVL efficacy even in chemoresistant disease. These results support the continued use and further prospective evaluation of pentostatin/TBI in T-cell lymphomas, particularly among older adults and those with rare subtypes.

Abstract Background: Morphologically atypical, non-clonal T-cell infiltrates have been demonstrated in a subset of Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and are associated with younger age and increased risk of relapse, but a corresponding non-invasive peripheral blood (PB) signature has not been defined. Phenotypically abnormal T-cells in PB or tissue biopsy specimens can mimic T-cell non-Hodgkin lymphoma and create diagnostic uncertainty. We describe a cohort of young patients with aggressive B-cell lymphomas who presented with a prominent, phenotypically aberrant yet non-clonal T-cell population in PB. Methods: We retrospectively identified six patients with B-cell lymphomas who, during initial diagnostic workup, exhibited a discrete abnormal T-cell population by multiparametric PB flow cytometry. We abstracted clinicopathologic variables (age, sex, stage, cytopenias, LDH), histopathology, and PB flow cytometry results, including T-cell clonality by T-cell receptor (TCR) Vβ repertoire analysis. Results: The cohort was young (median age 32.6 years; range 27.7–34.0; 4 male/2 female). Four of six patients had NLPHL (Pattern A, n=1; Pattern E, n=3), one patient had T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), and one had classic Hodgkin lymphoma (cHL). All presented with advanced disease (stage IIIB, n=1; stage IV, n=5) and cytopenias (pancytopenia, n=2; anemia with thrombocytopenia, n=1; isolated anemia, n=1; isolated thrombocytopenia, n=1; neutropenia, n=1), and LDH was elevated in most (n=5). PB flow identified a discrete aberrant T-cell population in all cases. A unifying feature in 5/6 was a sizable CD4+ T-cell subset with loss of CD26 (CD4+CD26−), comprising ~15–40% of total PB cellularity. Variable additional aberrancies included partial CD7 loss and CD10 expression. T-cell clonality was tested by TCR Vβ repertoire analysis in 5/6 patients and was negative in all, supporting a reactive, non-neoplastic process. Tissue specimens for these cases consistently showed T-cell-rich backgrounds, including NLPHL pattern E, a variant associated with more aggressive behavior. In the THRLBCL case, the same aberrant non-clonal T-cell population was demonstrated across PB, bone marrow aspirate, and diagnostic lymph node, indicating a systemic reactive infiltrate. Conclusion: Our findings highlight the clinical significance of a non-clonal, immunophenotypically aberrant CD4+CD26− T-cell population in young patients with T-cell-rich B-cell lymphomas—predominantly NLPHL and THRLBCL. This systemic reactive population poses a meaningful diagnostic pitfall because its phenotype can mimic T-cell lymphoma, particularly when initial tissue samples are scant or discordant. Beyond avoiding misclassification, the consistent association of this PB signature with T-cell-rich histologies and advanced presentation raises the hypothesis that it may serve as a non-invasive surrogate biomarker of the higher-risk NLPHL variant previously described in tissue studies. Given the enrichment of PD-L1/PD-L2 genetic alterations and sensitivity to PD-1 blockade reported in T-cell-rich microenvironments (e.g., cHL and THRLBCL), correlations between this PB phenotype, 9p24.1 alterations, and response to PD-1-based therapy merit prospective study. Recognition of this reactive immunophenotype should prompt careful clinicopathologic integration and heightened suspicion for an underlying T-cell-rich B-cell lymphoma when early biopsies are inconclusive. Although our series focuses on NLPHL/THRLBCL, we have also observed a similar T-cell population in a non-GCB DLBCL with a T-cell-rich microenvironment, suggesting this phenomenon may extend to other B-cell malignancies. Larger, prospective cohorts are needed to validate the prevalence of this immunophenotype, define its prognostic significance, and test its utility for risk stratification and response monitoring.

Background: Despite the efficacy of modern chemoimmunotherapy, a significant subset of patients with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) experience primary refractory or relapsed disease. Current risk stratification relies heavily on clinicopathologic scores and ‘double/triple-hit’ (DH/TH) genetic status. However, aggressive outcomes occur in non-DH/TH patients, and while TP53 mutations are established markers of poor prognosis, their predictive value is heterogeneous. Broader genomic signatures distinguishing patients who achieve durable remission from those who fail first-line therapy and require intensive salvage, including chimeric antigen receptor (CAR) T-cell therapy, remain incompletely defined. Identifying high-risk molecular signatures at diagnosis is crucial for guiding novel therapeutic strategies. Methods: We conducted a retrospective pilot analysis of 10 patients with DLBCL/HGBL treated with first-line anthracycline-based chemoimmunotherapy at Yale Cancer Center. Pre-treatment diagnostic tumor samples underwent comprehensive genomic profiling (CGP) with the FoundationOne® Heme assay. Patients were stratified based on response to first-line therapy: a durable complete response (CR) group (n=5) and a relapsed/refractory (R/R) group (n=5). Clinicopathologic variables were collected, including age, sex, stage, IPI score, ECOG performance status (PS), LDH, cell of origin (COO), and rearrangement status of MYC, BCL2, and BCL6. Genomic alterations were correlated with clinical trajectories. Statistical comparison of clinicopathologic variables was performed using the Mann-Whitney U test. Results: The CR (n=5) and R/R (n=5) groups were similar regarding baseline clinicopathologic variables (CR vs. R/R): Age at diagnosis (median 59.9 vs. 68.8 years, p=0.5), Sex (4M/1F in each group), Stage (median 2.0 vs. 3.0, p=0.9), IPI score (median 2.0 vs. 2.0, p=1.0), ECOG PS (median 1.0 vs. 0, p=0.5), LDH (median 474 vs. 344 U/L, p=0.8), and COO (3 GCB/2 non-GCB in each group). Within the R/R group, two patients (40%) demonstrated treatment resistance requiring CAR-T therapy. One patient required an allogeneic stem cell transplant after three lines of therapy, while the remaining responded to standard second-line salvage. Genomic profiling revealed a distinct molecular signature in the two patients requiring CAR-T, characterized by the co-occurrence of pathogenic, loss-of-function (LOF) TP53 mutations (R282W, R248Q) and concurrent inactivating mutations in key epigenetic modifier genes (KMT2D, CREBBP, EZH2). This dual signature was absent in the other three R/R patients and all durable CR patients (0/8). In contrast, 4/5 patients (80%) in the CR group were TP53 wild-type. The fifth CR patient harbored a TP53 variant (G245D) not classified as a canonical LOF mutation, alongside a KMT2D mutation. While alterations such as CDKN2A/B loss were identified in both cohorts, the dual signature of TP53 LOF and epigenetic pathway disruption appeared highly specific for chemotherapy resistance. Conclusion: In this hypothesis-generating pilot cohort, the combination of pathogenic, loss-of-function TP53 mutations and inactivation of critical epigenetic regulatory genes defines a high-risk molecular profile strongly associated with failure of standard chemoimmunotherapy and the necessity for cellular therapy. Our findings highlight that the functional consequence of TP53 mutations (LOF vs. non-LOF), particularly in the context of epigenetic dysregulation, may be a more critical predictor of outcome than TP53 mutation status in isolation. While validation in larger cohorts is essential, upfront identification of this dual pathway inactivation may identify patients unlikely to benefit from standard salvage approaches, warranting early stratification toward CAR-T therapy or clinical trials of novel agents.

Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection which is endemic in Japan, the Caribbean, Central Africa, and parts of South America. North American ATLL has distinct clinical and biologic characteristics than Asian ATLL, including differential response to treatment. This study was designed to evaluate the unique characteristics , treatment response, survival outcome and role of allogeneic stem cell transplant (alloSCT) in ATLL in an urban North American cohort. Methods: We used the Yale Joint Data Analytics Team (JDAT) to identify patients(pts) with ATLL diagnosed between 2002 and 2023. Key data including clinicopathologic characteristics, treatment and survival were collected from the electronic health records. Survival data was analyzed using the Kaplan-Meier Method with log-rank test and Cox proportional hazards regressions for univariate and multivariable analyses. A P value of <0.05 was considered significant. Statistical analysis was performed using STATA 14.2 software. Results: Twenty-three patients were included in analysis. Median age of diagnosis was 56 years (25-88) with 15 females (65%) and 8 males (35%). Majority of patients (87%) were of Caribbean origin with 78% identifying as Black or African American and 13% as Hispanic. Thirteen (57%) presented with acute subtype, 6 (26%) with smoldering disease, and 4 (17%) with lymphomatous subtype. At diagnosis, the median white blood cell (WBC) count was 9.4 ( range 3-112.2) and LDH was 417.5 (175-3663). Most patients (96%) presented with lymphadenopathy, 22% had splenomegaly, 4% had hepatomegaly, 17% had pulmonary disease, 13% had cutaneous manifestations, and 13% had other extranodal disease. At diagnosis, 9% had latent TB , one had human immunodeficiency virus (HIV), and one had candidiasis. Bone marrow was positive in 53% and 21 of 22 had circulating leukemia cells. FISH and karyotype were available in 10 pts and showed multiple chromosomal abnormalities in 9 and p53 mutation in 1. Of these 10 pts, only 2 are alive. First line treatments included EPOCH 39% (9), CHOEP (4), AZT/interferon (IFN) (3), CHOEP/EPOCH (2), AZT/IFN /EPOCH (1), HyperCVAD (1), high-dose methotrexate (HD-MTX) (1), and CHOP (1). Ten (45%) patients received CNS prophylaxis including intrathecal (IT)-MTX 50%, HD-MTX 30%, and IT-cytarabine 20%. The intent was to transplant all eligible patients with a complete response (CR) or a good partial response (PR). Response to first line therapy included CR in 6, PR in 10 and progressive disease (PD) in 7. Patients attaining CR or PR who were eligible for alloSCT based on donor availability and comorbidity score, received bridging therapy with several cycles of brentuximab (if CD30+) or nelarabine. The 8 pts who were able to undergo alloSCT had a median age of 45 years (25-65). Six pts had haploidentical matched donors, 1 had matched related donor and 1 had a matched unrelated donor. At a median follow-up of 58 months (mo), the median progression free survival (PFS) to first line treatment for the cohort of 23 pts was 8.6 mo (95%CI-4.6-13) and median overall survival (OS) was 23.4 mo (95%CI-8-33). For the alloSCT cohort, the median OS was 33 mo (95%CI 15 to NR) vs 13 mo (95%CI 2-26) for non-SCT group [HR0.39; P=0.08]. Five patients relapsed after alloSCT; the median time to relapse was 6.3 mo (95%CI-13 to 7). Of 5 pts who died after alloSCT, the median survival after transplant was 11.4 mo (95%CI 3 to 16) and most common cause of death was PD. In multivariable analysis for OS using three covariates of age at diagnosis, WBC count at diagnosis and alloSCT , age (HR 1.09; p= 0.008 ; 95% CI 1.02 to 1.16) and WBC at diagnosis (HR 1.03; p= 0.010 ; 95% CI 1.01 to 1.06) were associated with a worse OS. Conclusions: In this single institution cohort of ATLL patients, we report that despite aggressive front line multi-agent chemotherapy, only a third of patients were able to undergo potentially curative alloSCT. The novel use of agents such as brentuximab and nelarabine improved disease status at the time of transplant, however, outcomes remain poor with most progressing in the front line. Within the limitations of a single institution cohort, we report that age and WBC count at diagnosis are associated with a worse OS. Accurate diagnosis and early referral to centers with transplant and clinical trial availability is key to management of ATLL patients.