Inferior Overall Survival Research Articles

Prognostic value of pretreatment lymphocyte-to-monocyte ratio in patients with glioma: a meta-analysis

BackgroundMany studies have explored the prognostic role of the lymphocyte-to-monocyte ratio (LMR) in patients with glioma, but the results have been inconsistent. We therefore conducted the current meta-analysis to identify the accurate prognostic effect of LMR in glioma.MethodsThe electronic databases of PubMed, Web of Science, Embase, and Cochrane Library were thoroughly searched from inception to July 25, 2023. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to estimate the prognostic role of LMR for glioma.ResultsA total of 16 studies comprising 3,407 patients were included in this meta-analysis. A low LMR was significantly associated with worse overall survival (OS) (HR = 1.35, 95% CI = 1.13–1.61, p = 0.001) in glioma. However, there was no significant correlation between LMR and progression-free survival (PFS) (HR = 1.20, 95% CI = 0.75–1.91, p = 0.442) in glioma patients. Subgroup analysis indicated that a low LMR was significantly associated with inferior OS and PFS in glioma when using a cutoff value of ≤ 3.7 or when patients received mixed treatment.ConclusionsThis meta-analysis demonstrated that a low LMR was significantly associated with poor OS in glioma. There was no significant correlation between LMR and PFS in glioma patients. The LMR could be a promising and cost-effective prognostic biomarker in patients with glioma in clinical practice.

Impact of Cytogenetic Abnormalities, Induction and Maintenance Regimens on Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: A Decade-Long Real-World Experience.

High-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) has become a standard of care for transplant eligible newly diagnosed multiple myeloma (NDMM) patients. While cytogenetic abnormalities have been shown to affect outcomes after HDT-ASCT in clinical trials, these trials often exclude or underrepresent elderly patients with comorbidities and those belonging to ethnic minorities. We describe our institutional experience highlighting the impact of high-risk cytogenetic abnormalities (HRCAs) on outcomes after HDT-ASCT for NDMM patients. A total of 449 patients with NDMM who underwent HDT-ASCT between February 2012 and August 2022 were included in this retrospective analysis. HRCAs included the presence of one or more of: deletion 17p, t(14;16), t(4;14), and amplification 1q. Survival analyses, including progression-free survival (PFS) and overall survival (OS), were performed using Kaplan-Meier estimator. With a median follow-up of 29 (1 - 128) months for the entire patient population, the best overall response rate for the patients with HRCAs was lower compared to those with standard risk cytogenetics (90% vs. 96%; P = 0.01). Patients with HRCAs had an inferior PFS compared to patients with standard-risk cytogenetics (29 vs. 58 months; P < 0.001) without a difference in OS (70 months vs. not reached; P = 0.13). In a multivariable analysis adjusting for factors including age, race, and comorbidities, HRCAs, non-lenalidomide-based maintenance, non-proteasome inhibitor-based maintenance, and age greater than 65 were associated with inferior PFS. Amongst these factors, only non-lenalidomide-based maintenance was associated with inferior OS.

Abstract C053: Multi-omics guided design of lymphoid organoids to study cooperative cell signaling in lymphomas

Abstract Our collaborative research (Cell1) used 1001 patients of diffuse large B-cell lymphoma (DLBCL) to show that genetic alterations interact with clinical factors to impact overall survival (OS) in DLBCL. B cell receptor (BCR) signaling-driven activated B cell-like (ABC) DLBCL subtypes is the most chemo-resistant subtype to the frontline therapy R-CHOP, with 40% of patients experiencing no response or relapse. We have systematically examined disparities in lymphoma outcomes and identified African-American (AA) patients as a poor-risk population in DLBCL, with a diagnosis age 10 years younger than other racial groups. We found that AA-DLBCL patients experienced inferior 5-year OS compared to non-Hispanic whites (38% vs 46%)2,3. We performed the first-ever characterization of genetic alterations among AA-DLBCL patients and demonstrated distinct mutation patterns across DLBCL arising in AA ancestry groups4. While some of the most frequent genetic mutations in AA-DLBCL are related to chromatin and epigenetics, few studies have investigated racial disparities in patients with aggressive ABC DLBCLs. The mechanisms that determine this racial inequality are unknown but may lie in the particular spectrum of mutations that act in concert with intricate survival signals imparted by the lymph node tumor microenvironment (Ly-TME). The pathogenesis of ABC DLBCLs has been linked to constitutive activation of and cooperation between the BCR and Toll-like receptor (TLR) pathways. These pathways are emerging as novel therapeutic targets, with a particular interest in MALT1 (mucosa-associated lymphoid tissue translocation protein 1). However, the genetic heterogeneity of ABC DLBCLs and the cooperative signaling mediated by the Ly-TME have led to discrepancies in drug responses. As a first step towards understanding Ly-TME in DLBCLs (Nature Materials5), we used DLBCL patient samples from multiple cohorts, covering &amp;gt;1100 samples and imaging analysis to determine immune and ECM cues in the lymphoid TME. These samples were not classified into racial categories. We designed a biomaterials-based modular lymphoma organoid that presents specific integrin ligands at controlled densities to DLBCLs. Human ABC-DLBCLs responded to MALT1 inhibition in an integrin-ligand-dependent manner. TLR activation with TLR agonists rescued cells from MALT1 inhibitors, possibly due to increased MALT1 expression. The inclusion of T-cell signals increased MALT1 expression and rescued cells from MALT1 inhibitor-mediated killing in cell lines and human PDX organoids. Changes in RNA-seq and phosphorylation in the TLR &amp; BCR pathways were used to inform effective combination therapy approaches with MALT1 inhibitors in vitro and in vivo5. Ongoing work is determining the racial disparities in AA lymphomas through complex interactions between Ly-TME and DLBCLs.

Co-Expression of C-MYC/BCL2 Is Associated with Inferior Survival Outcomes in Relapsed/Refractory Diffuse Large B-Cell Lymphoma after Autologous Stem Cell Transplantation - a Nationwide Retrospective Analysis in Singapore

Introduction Co-expression of C-MYC and BCL2 in diffuse large b-cell lymphomas (DLBCL), also termed double-expressor lymphomas (DEL), has been shown to be associated with poorer outcomes after standard R-CHOP induction therapy. Approximately 70% of DEL will relapse within 5 years. The subsequent traditional approach with potential for cure has been high dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). Whilst factors such as remission status after front-line treatment and early relapse have been associated with poorer outcomes after ASCT, data are limited regarding significance of DEL status on survival outcomes post-ASCT. We retrospectively studied the prognostic impact of DEL status on outcomes in patients with relapsed or refractory (R/R) DLBCL who underwent ASCT. Methods This was a retrospective, nationwide study of adults patients, &amp;gt;18 years old, with R/R DLBCL who underwent autologous hematopoietic stem cell transplantation (ASCT) between 2010 and 2022 at the only 2 transplant centers in Singapore - Singapore General Hospital and National University Cancer Institute. Patients with double/triple hit lymphoma, defined as concurrent rearrangements of MYC and BCL2 and/or BCL6 by fluorescence in situ hybridization (FISH) analysis, were not included in this study. Patients with transformed indolent B-cell NHL (non hodgkin lymphoma), primary mediastinal B-cell lymphoma, primary CNS (central nervous system) lymphoma, or Richter transformation of chronic lymphocytic leukemia were excluded. Only patients that had available MYC and BCL-2 immunohistochemistry (IHC) were included in this study. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to assess associations between covariates of interest and OS or PFS. Results A total of 72 patients were included, 44 (61.1%) non-double expressor DLBCL (non-DEL) and 28 (38.9%) double expressor DLBCL (DEL). Patient demographics and disease characteristics at relapse were similar in both groups aside from a higher incidence of CNS involvement in the non-DEL group as compared to DEL group, 34.1% vs 10.7% (Table 1). Both groups achieved a &amp;gt;90% response (CR and PR) after second-line salvage chemotherapy as well as a &amp;gt;90% response post-transplant (CR and PR). Patients with DEL however were more likely to relapse post-transplant, 69.7% vs 40.9% (p = 0.032) and were also associated with increased odds of all-cause mortality, 60.7% vs 36.4% (p=0.043). This significance was maintained on multivariable analysis, HR 4.22 95% CI 1.20 - 14.84 (p=0.025) and HR 4.32 95% CI 1.10 - 17.15 (p=0.038) respectively. The median follow up for survivors were 42 months (range, 26 to 64 months) in the DEL patients and 60 months (range, 46 to 88 months) in the non-DEL patients. The 5-year PFS in patients with DEL was inferior to non-DEL patients, 23.3% vs 49.6% respectively, p=0.022. DEL patients were also associated with inferior 5-year OS, 40.2% vs 65.7%, p=0.041. In multivariable model, DEL status remained significantly associated with inferior PFS and OS. We also observed that patients with CNS involvement at relapse had inferior PFS and OS. Male gender and a less than complete metabolic response (CR) status prior to transplant, assessed on PET-CT, was also associated with inferior OS. Conclusion Co-expression of C-MYC/BCL2 was associated with inferior outcomes after ASCT in patients with R/R DLBCL. While ASCT has been the standard curative approach in the R/R setting, considerations for novel targeting therapies to achieve a deeper response prior to transplant or the upfront use of chimeric antigen receptor T-cell therapy at first relapse may be further explored in this high-risk subset of patients.

Resistance Mechanisms Impacting Bispecific Antibody (BsAbs) and Chimeric Antigen Receptor (CAR) T-Cell Therapy Outcomes in Large B Cell Lymphoma (LBCL) Patients

Introduction: BsAbs and CAR T-cell therapy have revolutionized the treatment landscape of patients with relapsed/refractory (R/R) LBCL. Regrettably, less than 40% of patients will attain durable responses, and determinants of response remain unclear. Our aim was to identify tumoral characteristics that can predict resistance to CAR T-cell therapy and BsAbs in LBCL patients. Methods: We retrospectively collected clinical data and obtained pre-treatment formalin-fixed and paraffin-embedded specimens prior CAR T-cell and BsAb treatment from 56 LBCL patients from 4 centers. Targeted NGS was performed to identify variants and copy number variations (CNVs) across a custom gene panel of 200 genes. These include lymphoma related genes, and genes involved in tumor antigen presentation, B and T lymphocyte interaction, and cell death pathway. Variables assessing response where Overall Response Rate (ORR), Complete Response Rate (CRR), Progression-Free Survival (PFS), and Overall Survival (OS). To ascertain each gene's influence on these endpoints, a logistic model was used for ORR and CRR comparisons, while Kaplan-Meier and Cox methods were employed to analyze PFS and OS. Results: A total of 56 patients were included in the study, 36 patients treated with CAR T-cell and 36 with BsAbs (16 patients received both). Samples were obtained for 31 patients prior to CAR T-cell therapy (CAR T-cell cohort) and 34 cases prior to BsAbs (BsAbs cohort). Baseline characteristics of the patient population are shown in Table 1. In summary, median age was 62 years, 57% were male, 42% had a previous indolent lymphoma and median previous lines were 2 (range 1-4). Best response included CRR in 59%, with a median PFS and OS of 13.6 (CI95% 5.98 - Not reached [NR]) and 29.5 (CI95% 15.7 - NR) months, respectively. Median follow-up for the full cohort was 18.7 months (CI95% 15.1 - 24). As per the CAR T-cell cohort, ORR and CRR were 81% and 68%, respectively. Median PFS and OS for CAR-T-cell cohort was 29.4 months (CI95% 5.98 - NR) and NR, respectively. Regarding the BsAb cohort, ORR and CRR were 66% and 50%, respectively. Median PFS and OS was 10 (CI95% 5.16 - NR) and 22.5 (CI95% 14.4 - NR) months, respectively. For the full cohort, the most frequently altered genes, considering both mutations and CNVs, were KMT2D (66%), TP53 (60%), CREBBP (58%), IGLL5 (51%), REL (42%), EZH2 (38%), BCL2 (38%), TNFRSF14 (37%), SGK1 (32%) and KLHL6 (32%) (Figure 1). The most frequent CNVs were gains of 2p16.1 (34%), 3q28 (15%), 6p(14%), 11q (12%), 21q (12%), 3q (10%); and losses of 17p (32%), 6q (26%), 1p36.32 (25%), 13q14.2 (18%), 19p13.3 (18%), 4q35.1(16%), (10q23.31 (12%), 9p21.3 (10%). Focusing on the CAR T-cell cohort (n=31), mutations and/or deletions in EP300 (7%, n=2)( p=0.01) and KLHL6 (n=2, 7%) ( p=0.04) were associated with an inferior PFS. In addition, mutations and/or deletions in KLHL6 ( p=0.02) and EP300 (n=3, 10%) ( p=0.05), and amplifications in MYC (n=3,10%) ( p=0.031) were associated with shorter OS. No differences in PFS and OS were oberved in patients with mutations and/or deletions in TP53 (n=19, 63%). Regarding RHOA patients with mutations or deletions (n=2, 7%) did not present an inferior PFS ( p=0.88) or OS ( p=0.52). The analyzed alterations did not show an impact on response rate. In terms of patients who received BsAbs (n=34), we observed that mutations and/or deletions in TP53 (n=19, 58%) ( p=0.04) , RHOA (n=5, 15%) ( p=0.05) and GNAI2 (n=5,15%) ( p=0.02)were associated with aninferior PFS. Mutations and/or deletions in TP53 (p=0.04) , RHOA (p=0.009) , GNAI2 ( p=0.01) and CD274(PDL1)-PDCD1LG2(PDL2) (12%, n=3) ( p=0.01) were associated with an inferior OS. Regarding MYC, 8 cases were mutated (n=2, 6%), amplified (n=5, 15%) or both (n=1, 3%), but these alterations were not associated with an inferior PFS (p=0.46) or OS ( p=0.27). Again, no impact on response rate was observed for patients carrying alterations. Conclusions: In our study, a pattern of genetic alterations predicting worse OS was observed in patients treated with CAR T-cells ( KLHL6 EP300 and MYC) and BsAbs (TP53, RHOA, PDL1, PDL2, GNAI2). This important information will aid in the development of targeted strategies to overcome resistance and improve treatment outcomes.

Treatment Patterns and Outcomes for Patients with Classic Hodgkin Lymphoma (cHL) and Cardiomyopathy with Low Ejection Fraction (EF): Real-World Evidence (RWE) from 16 US Academic Centers

Introduction The cornerstone for management of newly diagnosed patients (pts) with cHL is an anthracycline (AC) based chemotherapy (chemo) regimen. There are a paucity of data available regarding treatment patterns and outcomes for cHL pts with low EF. Furthermore, cHL pts with low EF are typically excluded from clinical trials limiting our understanding on management of these pts. Methods This was a multicenter retrospective cohort study evaluating pts with newly diagnosed cHL with low EF from 16 US medical centers. Eligible pts included adults diagnosed after 1/1/2010 with pretreatment EF of &amp;lt;50% on echocardiogram. Pts who developed reduced EF during or after first-line treatment were excluded. Based on EF, pts were divided into 2 groups (gp): &amp;lt;45% (gp 1) and 45-49% (gp 2). First-line treatment was categorized into AC based and non-AC based therapies. Primary outcome was progression-free survival (PFS). Secondary outcomes included response rates to first-line therapy and overall survival (OS). Time to event endpoints were evaluated by Kaplan-Meier and Cox proportional hazard methods. Results The study included 69 pts with a median age of 55 yrs (21-88), 74% males, and performance status (PS) of ECOG 0-1 in 65%. There were 37 (54%) pts in gp 1 and 32 (46%) in gp 2. 39 pts received AC and 30 received non-AC based therapies. Pts in the AC group were significantly younger (median age, 46 vs 64 yrs), had higher proportion with EF of 45-49% (72% vs 13%) &amp; ECOG PS of 0-1 (82% vs 54%) compared to non-AC based therapies. Among the 30 pts who received non-AC based therapies, 26 were in gp 1 and 4 in gp 2. Non-AC based therapies included BV monotherapy (n=6), non-AC BV-based therapies (n=11), and other non-AC chemo (n=13). The most common BV based therapy was BV+dacarbazine (n=4) followed by BV+bendamustine (n=3), while the most common other non-AC chemo was MOPP (n=4) followed by ChlVPP (n=3). The overall response rate (ORR) and complete response rate (CRR) to AC based therapy was 77% (30/39) and 69% (27/39), respectively. Among the non-AC therapies, the ORR/CR rates for BV monotherapy, BV based therapies, and other non-AC chemo were 33%/17%, 55%/27%, and 61%/54%, respectively. The median PFS for the entire cohort was 2.7 yrs (95%CI= 0.80-5.01). The median PFS for gp 1 vs gp 2 was 1.55 yrs and 4.20 yrs, respectively (p=0.26). The median PFS was significantly longer in pts receiving AC based compared to non-AC therapies (5.01 yrs vs 0.55 yrs, &amp;lt;0.001, Figure 1) with 3- and 5-yr PFS estimates of 62% vs 27%, and 54% vs 16%, respectively. Among the recipients of non-AC therapies, the 3-year PFS estimates for BV monotherapy, BV based therapies, and other non-AC chemo was 20%, 34%, and 42%, respectively (p=0.25). The median OS for the entire cohort was 5.6 yrs (95% CI=3.47-NR). The median OS for gp 1 vs gp 2 was 5.41 yrs and 5.73 yrs, respectively (p=0.82). The median OS was significantly longer in pts receiving AC based compared to non-AC therapies (7.43 yrs vs 3.20 yrs, p=0.003) with 3- and 5-yr OS estimates of 80% vs 60% and 80% vs 30%, respectively. Among the recipients of non-AC therapies, the 3-year OS estimates for BV monotherapy, BV based therapies and other non-AC chemo were 44%, 78% and 51%, respectively. Univariable Cox models tested baseline pt and disease variables and found increasing age, ECOG PS ≥2, and the presence of geriatric syndrome to be prognostic of inferior PFS and OS but not EF gp. Only increasing age remained associated with significantly inferior PFS and OS in multivariable analysis ( Table 1). After adjusting for these variables together with the inclusion of first-line treatment (AC vs non-AC based therapies), we found first-line treatment with AC-based therapy was associated with superior PFS (aHR= 0.39, 95% CI=0.15-0.97, p=0.04) but not OS (aHR= 0.51 (95% CI=0.16-1.65, p=0.26, Table 1). With inclusion of treatment, only age remained associated with inferior OS in the multivariable adjustment (aHR=1.27, 95%CI=1.04-1.54). Conclusion This first RWE of cHL pts with low EF found that a majority of pts with EF of 45-49% were treated with AC-based therapies. Furthermore, PFS was improved for pts who received AC-based therapies. However, outcomes appeared modest for pts compared with expectant outcomes. Collectively, these data underscore the critical need for prospective interventional studies in this challenging pt population. Further data on AC dosing, safety, risk of AC-induced heart failure, etc. will be presented at the meeting.

The Comparison between BM and PBSC for the Patients with Pre-Transplant Pulmonary Dysfunction in HLA-Matched Allo-HCT: Subgroup Analysis Exploring the Impact Based on HCT Factors

Introduction Pre-transplant pulmonary dysfunction is known as an important risk factor for lung complications and subsequent non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT). However, it remains unknown which cell source would be optimal for the patients with pre-transplant pulmonary dysfunction and whether the impact of cell source would differ according to recipient age, donor relation, and conditioning regimens. Therefore, we evaluated the impact of stem cell sources in patients with pre-transplant pulmonary dysfunction and in the subgroups. Patients and methods We performed a retrospective analysis of clinical data on 3374 allo-HCT in Japan between 2016 and 2020 using Japanese registry database. All patients had standard-risk disease and underwent their first allo-HCT from an HLA-matched donor. Their clinical outcomes were compared between peripheral blood stem cells (PBSCs) and bone marrow (BM) grafts individually in two distinct cohorts, namely the Lung-scored (LS) cohort and the normal cohort, based on the presence of lung scores determined by the Hematopoietic Cell Transplantation-specific Comorbidity Index. In addition, we conducted subgroup analyses to explore potential differences in the impact of cell sources on these outcomes according to the recipient age (≥50 or &amp;lt; 50), donor relation (related or unrelated), and conditioning regimens (cyclophosphamide [CY] / total body irradiation [TBI]-based myeloablative conditioning [MAC], busulfan [BU]-based MAC, or reduced-intensity conditioning [RIC]). Results In the LS cohort, the 2-year overall survival (OS) tended to be higher in the BM group than that in the PBSCs group (71.9% vs 61.4%; P = 0.052). However, in the normal cohort, there was no significant difference between both the cell source types (71.6% vs 73.1%; P = 0.13). Multivariate analyses showed that PBSCs were significantly associated with inferior OS in the LS cohort (hazard ratio [HR], 1.60 [95% CI, 1.06-2.42], P = 0.026). On the other hand, cell source type did not significantly affect OS in the normal cohort (HR, 0.94 [95% CI, 0.78-1.14], P = 0.55). We also found that PBSCs were significantly associated with an increased risk of NRM in the LS cohort (HR, 1.90 [95% CI, 1.03-3.52], P = 0.041), while cell source types did not affect NRM in the normal cohort (HR, 0.85 [95% CI, 0.64-1.13], P = 0.26). PBSCs were not identified as a risk factor for relapse in both cohorts. When we focused on the LS cohort alone, the Figure 1 summarized the impact of the use of PBSCs in the subgroups according to age, donor relation, and conditioning regimens. Briefly, the use of PBSCs exhibited a significant adverse impact on OS (HR, 3.07 [95% CI, 1.16-8.11], P = 0.024) in patients younger than 50 years old. For recipients aged 50 years or older, PBSCs were not associated with inferior OS (HR, 1.49 [95% CI, 0.91-2.42], P=0.11), although it tended to be associated with an increased risk of NRM with a borderline significance (HR, 1.94 [95% CI, 0.99-3.78], P = 0.053, Figure 1). Focusing on the subgroup stratified according to their donor relation, the use of PBSCs were not associated with inferior OS or an increased risk of NRM in both allo-HCT groups from a related donor or unrelated donor. Furthermore, focusing on the subgroups stratified according to conditioning regimens, the use of PBSCs had a significantly negative impact on OS in the subgroup with CY/TBI-based MAC (HR, 7.48 [95% CI, 2.87-19.51], P &amp;lt; 0.001). On the other hand, the use of PBSCs had no significant impact on OS or NRM in the subgroups of BU-based MAC or RIC. Regarding relapse incidences, the impacts of the use of PBSCs were not different in any of the individual subgroups. Conclusion The use of PBSCs were associated with inferior survival in the LS cohort, but not in the normal cohort. When we focused on the subgroups of the LS cohort alone, the use of PBSCs were associated with inferior survival in the subgroup of younger recipients or those with CY/TBI-based MAC. These patients in the LS cohort might benefit from the use of BM. These results should be validated in another registry study, and further research would be warranted for the purpose of preventing adverse impact of PBSCs or the optimal cell source selection.

Patterns of Care and Prognostic Modeling Following Follicular Lymphoma Transformation to Aggressive B-Cell Lymphoma: An Analysis from the LEO Consortium

Introduction: Histologic transformation (HT) from follicular lymphoma (FL) to an aggressive lymphoma is infrequent but has unfavorable outcomes. Sarkozy et al. (J Clin Oncol, 2019) reported that approximately half of FL-related deaths within the first decade of diagnosis occurred following HT. Our recent analysis showed heterogeneous outcomes with median overall survival (OS) of 61 months (Day et al., ASH, 2022). Prognostic tools post HT would be clinically useful but development has been limited by small cohort sizes. Factors previously associated with outcomes following HT have included age, time to progression, prior therapy, anthracycline exposure, and early HT. Utilizing the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real World Evidence (CReWE), we describe patterns of care and evaluate other prognostic factors following HT. Methods: This multicenter observational cohort consists of prospectively enrolled patients in the LEO Cohort, and patients with HT retrospectively identified at LEO centers. Patients diagnosed with biopsy proven grade 1-3A FL at diagnosis, and a subsequent biopsy showing HT to an aggressive lymphoma (FL grade 3B, diffuse large B cell lymphoma [DLBCL], or high-grade B cell lymphoma [HGBCL]) between 2002-2022, were eligible for the study. Patients with a component of FL grade 3B, DLBCL, or HGBCL at diagnosis were excluded. HGBCL was defined as double or triple hit or another aggressive subtype. OS was defined as the time from HT until death from any cause and calculated via Kaplan-Meier. Associations between clinical factors at time of HT and/or diagnosis and OS were evaluated using Cox models. Cause of death was evaluated using a competing risk approach. Results: Overall, 328 patients were confirmed with HT during the study period, 41% were female, and the median age at HT was 63 years (interquartile range [IQR] 56-70). The median time from diagnosis to transformation (TDT) was 35 months (IQR 12-66). At HT, 88% had advanced stage disease (III-IV) and LDH was elevated in 49%, while few patients exhibited B symptoms (5%) and ECOG performance status was &amp;gt;2 in 9%. 23% did not receive systemic therapy prior to HT. For those with prior therapy, the median time from prior therapy to HT was 15 months (IQR 7-39). The most frequent treatment regimens following HT were CD20-CHOP (42%), followed by platinum-based salvage therapy (20%), R-EPOCH (10%), CD20-Benda (8%), R-Mono (4%), and R-Gem-Ox (3%). 50 (15%) patients underwent consolidation with autologous stem cell transplant, 3 underwent allogeneic transplant (30 platinum-based, 15 CD20-CHOP, 5 R-EPOCH, 3 Other), and 2 received CAR T-cell therapy (Figure 1). After median follow-up of 85 months from HT, 170 patients had died; 5-year OS was 52% and median OS was 65 months (95% CI: 55-107). Among 160 patient deaths, cause was most often lymphoma-related (progression, n=107 [63%]; therapy-related, n=14 [7%]) compared to non-lymphoma (n=20, 13%) or missing/unknown causes (n=29, 17%). Clinical factors at the time of HT that were associated with worse OS include: ECOG PS &amp;gt;2, age ≥70, IPI 3-5, and shorter TDT (&amp;lt;24 months), hemoglobin &amp;lt;10 g/dl and elevated LDH. A transformation to HGBCL was also associated with inferior OS (Table 1). OS did not significantly differ by gender, BMI, stage, presence of B-symptoms, absolute lymphocyte count, number of extranodal groups, presence of bulky disease at HT, or response to prior FL treatment. Factors at the time of FL diagnosis that were associated with decreased OS after HT included FLIPI score 3-5 (high risk), FLIPI 2 (moderate risk), and FL grade 3A at diagnosis. Exposure to any systemic therapy for FL prior to HT was associated with shorter OS, with the worst outcomes in patients receiving an anthracycline prior to HT. POD24 to frontline immunochemotherapy was associated with inferior OS after HT (Table 1). Conclusions: Patterns of care in Transformed FL are heterogeneous and vary greatly in intensity. These data confirm previous reports that age, early HT, and any systemic therapies prior to HT are negative prognostic indicators for OS. At HT elevated LDH, low hemoglobin, POD24 status, poor performance status, and HT to HGBCL were associated with poor outcomes following HT. These data provide a basis for future prognostic indices to identify patients with highest risk of lymphoma related mortality for whom study of novel treatments is greatly needed.

Improved Survival of R/R Double Hit/Triple Hit Lymphoma in the Era of CD19 Chimeric Antigen T Cell (CART) Therapy

Introduction: DH/THL also classified as high-grade B cell lymphomas (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements have higher risk of progression after initial treatment and poor response to salvage therapies compared to diffuse large B cell lymphoma (DLBCL), NOS. Recently, CART cell therapy has shown encouraging responses in treatment of relapsed refractory (R/R) DLBCL. In this retrospective study, we evaluated whether survival of (R/R) DH/THL is improved in the CART era. Methods: In this multicenter retrospective study, adult pts (pts) with R/R DH/THL after anthracycline-based therapy were included. Demographic and clinical variables were obtained from electronic health records. Study objectives was overall survival (OS) at 2 year landmark. We utilized full propensity score matching to compare progression free survival (PFS) and OS of CART with 2 nd line chemoimmunotherapy. Results: 278 DH/THL pts treated between 2010-2020 were included. Median age was 63 years (range 52-74), 163 (58%) were male, 119 (43%) were classified as DLBCL and 116 (42%) as HGBCL; 40 (14%) were transformed from follicular lymphoma. 225 (82%) had advanced stage, 161 (67%) had elevated LDH, 85 (33%) had bulky disease, 74 (59%) had B symptoms. 105 (38%) pts treated for relapsed disease before 2018 were included in the pre-CART era cohort. 168 (60%) pts treated from 2018 onwards were included in the CART era cohort. 102 (60%) pts in CART cell era received CART cells, 40 (14%) received polatuzumab vedotin (pola), 10 (3.5%) received loncastuximab tesirine, tafasitamab and bispecific antibody each. Characteristics at relapse were similar in both groups. Median follow up was 8.9 (0.2-146) months. 2-year OS estimate was 36% (CI 95: 30-42%) in entire population. Patients treated in CART cell era had significantly higher OS (2 yr OS: 43% [CI 95: 35-53]) compared to pts treated in pre-CART cells era (2-year OS: 24% [CI 95: 16-34], p=0.0006) (Figure 1). In multivariable analyses, increasing age (HR = 1.02 (CI 95: 1.01, 1.04), p=0.003), extranodal disease (HR = 1.41 (CI 95: 1.00, 1.99), p&amp;lt;0.001), elevated LDH (HR = 1.57 (CI 95: 1.11, 2.24), p=0.01) were associated with inferior OS. Increasing time to relapse (HR = 0.98 (CI 95: 0.97, 0.99), p&amp;lt;0.001) was associated with superior OS. BCL6 rearrangement did not affect OS. When adjusted for these factors, treatment with CART cells was associated with higher 2 yr OS (HR = 0.33 (CI 95: 0.22, 0.49), p&amp;lt;0.001). Treatment with polatuzumab (HR = 1.07 (CI 95: 0.71, 1.6), p=0.07) was not significantly associated with OS in univariable analysis. 102 pts underwent CART cell therapy at any point for relapse; 94 (93%) were refractory to prior chemotherapy. 62 (60%) responded and 52 (50%) had CR after CART cells. 2-year PFS and OS after CART cell therapy were 28% (CI 95: 19-40) and 40% (CI 95: 30-53), respectively. Increasing time to CART was associated with inferior OS (HR: 1.02 (CI 95: 1.0-1.03, p=0.03) but not PFS (HR: 1.02 (CI 95: 0.99-1.04), p=0.2). 219 (79%) pts received curative intent salvage chemotherapy for 2 nd line. 2-year PFS and OS were 15% (CI 95: 11-20) and 38% (CI 95: 31-45), respectively. 21 pts received CART cell therapy for 2 nd line. 2 year PFS and OS in this small number of pts were 52% (CI 95: 35-79) and 70% (CI 95: 52-94), respectively. Due in part to the small number of pts who received CART cells in 2 nd line, we utilized full propensity score matched analysis to compare each patient in CART cell group to all possible matched controls in salvage chemotherapy group. Variables matched were age, LDH, extra nodal disease and time to relapse. In propensity score matched analysis, pts who received CART cells had significantly higher 2 year PFS (HR: 10.5 (CI 95: 3.4-17.5), p=002) and 2 year OS (HR: 7.5 (CI 95: 1.4-13), p=0.01). Conclusions: Survival of r/r DH/THL appears to have improved in the era of CART cell therapy. About 2/3 of pts refractory to chemotherapy respond to CART cells, and in multivariable analysis, receipt of CART cells was associated with improved OS. Increasing time to CART cells was associated with inferior survival. In a propensity score matched analysis utilizing full matching, CART cell therapy in 2 nd line was associated with significantly higher 2 year PFS and OS compared to curative intent salvage therapy. Other CD 19 and CD 20 targeting agents approved after CART cell therapy might contribute to favorable survival, effect of these agents could not be assessed because of small numbers.

Heterogeneity of TP53 Mutations in Mantle Cell Lymphoma- Challenges in Risk Stratification and Subclassification

Introduction: Somatic mutations in TP53 occur in approximately 10-20% of mantle cell lymphoma (MCL) patients (pts) at diagnosis. Eskelund and colleagues (Blood 2017) demonstrated poor survival among 20 pts with TP53-mutated MCL following intensive induction and transplant, and reported sequence-level variant data. However, TP53 mutations are heterogeneous, and few studies in MCL provide detailed sequencing data or variant allele frequency (VAF). Furthermore, the clinical impact of TP53 mutations may vary, and there is no algorithm shown to predict outcome for a given variant. We hypothesized that high VAF, or presence of a “disruptive” TP53 mutation as reported in squamous cell carcinoma (SCC; Poeta NEJM 2007), may adversely impact prognosis in MCL. To address this, we analyzed all MCL pts with available TP53 sequencing data at our center, including exact TP53 variant data and VAF, sMIPI score, and classification as disruptive vs not, and impact on survival from time of testing. Methods: Institutional records were analyzed with IRB approval, identifying 65 MCL pts who underwent sequencing for TP53 mutation from any tumor sample, as a single-gene assay or part of a panel. We analyzed VAF, type of mutation, and sMIPI score at time of TP53 testing. We classified TP53 mutations as “disruptive” or not according to method of Poeta and colleagues; these mutations result in a STOP codon, or an amino acid polarity change in the L2-L3 DNA binding domain of the TP53 protein (Poeta NEJM 2017). The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) from time of TP53 testing to death or last follow up, and the log-rank test was used to compare outcomes based on TP53 mutational status. Among TP53 mutated cases, Cox proportional analyses were performed to explore the impact of the following covariates on survival: disruptive status, VAF, sMIPI score at time of TP53 testing, and presence of complex cytogenetics. Results: Sixty-five pts underwent TP53 sequencing, and 23 (35%) had a TP53 mutation (mTP53+). mTP53+ pts had inferior PFS (p=0.03) compared to TP53 wild-type, and a trend toward inferior OS (p=0.07); median OS was 26 months (95% CI: 8.1, NA) from time of TP53 testing. Ki-67 index, blastoid histology, and age were similar between mTP53+ and wild-type status, but mTP53+ pts had a higher rate of complex cytogenetics (&amp;gt; 3 lesions; 48% vs 26%). SMIPI was also higher in mTP53+ pts (median score 6, interquartile range (IQR) range 4-7) vs TP53 wild-type pts (median 4, IQR range 3-5.2). MTP53+ pts were more likely to have received a BTK-inhibitor (BTK-I) (91 % vs 64%) and CAR-T therapy (39% vs 18%). Details of the mTP53+ subset are shown in Table 1; 4 pts had &amp;gt;1 TP53 mutation, median VAF was 40%, and 30% of pts had a disruptive mutation. Among mTP53+ pts, on univariate analysis, higher sMIPI at time of TP53 testing (p=0.003) was associated with worse OS (Table 2). In a multivariable Cox model including VAF &amp;gt;= 40%, presence of disruptive mutation, sMIPI, and complex cytogenetics, only sMIPI at time of TP53 testing was associated with inferior OS (p=0.02). Conclusion: TP53 variants in MCL are diverse, and in our cohort were largely unique from those reported by Eskelund and colleagues (Blood 2017). Despite now-routine application of sequencing and improvements in therapy, both of which may attenuate the negative prognostic impact of TP53 mutation, we confirmed poor outcomes in mTP53+ MCL. Among mTP53+ pts, only sMIPI predicted inferior OS on both univariate and multivariate analysis. Higher VAF and adoption of a clinical algorithm from SCC failed to discriminate among TP53 variants in terms of prognosis. Larger datasets of uniformly tested MCL pts are needed to elucidate prognosis among TP53 mutation variants, and improve understanding and management of mTP53+ MCL.

Immunohistochemical Tumor Expression Predicts Response to CD3xCD20 Bispecific Antibodies in Patients with Relapsed/Refractory B Cell Lymphoma

Introduction Several studies show that CD3xCD20 bispecific antibodies show promising results in relapsed or refractory B-cell lymphomas and may have a milder adverse effect profile compared to chimeric antigen receptor T cell therapy (CAR-T). Tumor loss of antibody target (i.e. CD19 or PD1) have shown to negatively affect treatment outcomes in CD19-CAR-T cell therapy in DLBCL, and anti-PD1 therapy in Hodgkin lymphoma. It has, to our knowledge, not been reported how loss of CD20 expression and other immunohistochemical (IHC) expression patterns affects treatment outcomes in patients treated with CD3xCD20 antibodies. Methods We collected data on all patients in Denmark who received CD3xCD20 bispecific antibodies from 2017 to 2023. Electronic health records were assessed for general baseline characteristics and response according to Lugano criteria. Pathology reports on pre- and post-CD3xCD20 therapy lymphoma samples were collected and assessed on IHC analysis of CD20, Ki67, CD10, Bcl2, Bcl6, MUM1, germinal center B-cell (GCB) subtype and non-germinal center B-cell subtypes (non-GCB) according to Hans algorithm, as well as reports on cytogenetic FISH analysis regarding MYC with BCL2 and/or BCL6 rearrangements. To determine whether an expression was weak, negative, or strong the assessment of the original pathology reports was used. Results Pre-treatment IHC assessments were available in 122 patients. These were distributed across 81 patients with DLBCL, 32 with FL and 9 with other lymphoid neoplasms (MZL, HL, CLL). Of these, 109 had a strong CD20 expression, 10 had a weak CD20 expression, while 3 had no expression of CD20. Patients with a weak CD20 expression before treatment had an overall survival (OS) rate after 12 months at 40% (95% CI, 9.5-70) compared to 69% in patients with strong CD20 expression (95% CI, 45-61) (Figure 1, p=0.08). In a univariable Cox regression, we found that negative CD20 expression and higher Ki67 was significantly associated with inferior OS (Table 1, respectively HR=2.11 and HR=1.02 (per %-change in Ki67)). Worse performance status and a higher number of previous lines of treatment were also significantly associated with inferior overall survival (respectively HR=1.85 and HR=1.20). Surprisingly, BCL6 rearrangement was significantly associated with superior OS (HR=0.46). In a multivariable cox regression using OS as the endpoint, weak and negative IHC expression of CD20 was significantly associated with inferior OS (respectively HR=3.29, 95% CI 1.32-8.23, p=0.011 and HR=6.79 95% CI 1.25-36.76, p=0.026). Positive BCL6 compared to negative was associated with increased OS (HR =0.48, 95% CI 0.24 - 0.94, p=0.032). Analyzing only patients with DLBCL (n=81), weak and negative IHC expression of CD20 were the only factors to remain significantly associated with inferior overall survival (respectively HR=3.01, 95% CI 1.10-8.28, p=0.032 and HR=7.26, 95% CI 1.35-43.35, p=0.026). BCL6 rearrangement was associated with an increased overall survival, however only borderline statistically significant (HR=0.53, 95% CI 0.26-1.08, p=0.082). With regards to treatment response weak CD20 expression, worse performance status, higher Ki67 and a higher number of prior lines of treatment was in univariable analysis significantly associated with not being in a complete remission (CR) (respectively HR=2.28, HR=1.73, HR=1.01(per %-change in Ki67), HR=1.23 (per prior line of treatment). In a multivariable cox regression only weak and negative CD20 expression remained significantly associated with not being in CR (respectively HR=2.40, 95% CI 1.1-5.25, p=0.028 and HR=5.7 95% CI 1.14-28.58, p=0.034). Of the 48 patients who had biopsy-confirmed relapse, 29 had a weak or negative IHC CD20 expression (24 with a negative expression and 5 with a weak expression). Of these 29 patients, 24 had a strong pre-treatment IHC CD20 expression. Conclusions To our knowledge, we here present the first long-term analysis of the prognostic effect of tumor immunohistochemistry properties in patients treated with CD3xCD20 bispecific antibodies. We find that CD20 expression before treatment is an important prognostic factor, as patients with lymphomas with weak CD20 expression yield significantly poorer responses and decreased overall survival. Additionally, we find that BCL6 rearrangement is associated with superior overall survival in patients treated with CD3XCD20 bispecific antibodies.

Impact of Letermovir Prophylaxis for Cytomegalovirus Reactivation on Post-Transplant Outcomes 100 Days before and after Allogeneic Hematopoietic Cell Transplantation

Background: Cytomegalovirus (CMV) infection is a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Although letermovir (LMV) prophylaxis dramatically reduces the incidence of early clinically significant CMV (csCMV) infection, it remains unclear whether it has a beneficial effect on nonrelapse mortality (NRM) and overall survival (OS). Additionally, because the incidence of csCMV infection increases after completing LMV prophylaxis, the impact of late csCMV infection beyond 100 days after transplantation on posttransplant outcomes should also be verified. Study Design: We included adult patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS) aged ≥16 years who underwent allo-HCT between 2017 and 2019. These patients' data were obtained from the registry database of the Japanese Society for Transplantation and Cellular Therapy (JSTCT). Results: Donor CMV seronegativity (D-CMV −)/recipient CMV seronegativity (R-CMV −) was recorded in 558 cases (9.3%), and R-CMV +/D-CMV + or - was recorded in 4,562 cases (78.0%). The median age was 51 (range, 16-80) years. The median follow-up length was 389 (range, 0-1,334) days. LMV prophylaxis was administered to 1,640 patients (LMV group), and the median duration of LMV prophylaxis was 85 (range, 2-152) days. LMV prophylaxis significantly reduced the incidence of early csCMV infection compared with those not administered LMV prophylaxis (15.4% vs. 54.1%; p&amp;lt;0.01, hazard ratio [HR], 0.30; p&amp;lt;0.01)). However, LMV prophylaxis did not have any beneficial effect on the 1-year NRM (HR, 0.93; p=0.40) and OS (HR, 0.96; p=0.49) in multivariate analysis. The possible causes were breakthrough csCMV infection within 100 days after transplantation during LMV prophylaxis and late csCMV infection after 100 days after transplantation after completion of LMV prophylaxis. Breakthrough csCMV infection during LMV prophylaxis developed in 74 (4.5%) of the 1,640 patients who had received LMV prophylaxis. Breakthrough csCMV infection occurred at a median of 33 (range, 6-139) days after transplantation. R-CMV +, prior transplantation, cord blood (CB) transplants, anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY) use for GVHD prophylaxis, and grade II-IV acute GVHD were associated with an increased risk of breakthrough csCMV infection. The breakthrough csCMV infection group showed inferior NRM (HR, 3.44; p&amp;lt;0.01) and OS (HR, 1.93; p=0.02) compared with those without infection among LMV prophylaxis group. After completing LMV prophylaxis, 252 patients had late csCMV infection at a median of 134 (range, 101-405) days after transplantation. In multivariate analysis, R-CMV +, older age, CB transplantation, ATG and/or PTCY use for GVHD prophylaxis, grade II-IV acute GVHD, and LMV prophylaxis before day 100 after transplantation were associated with an increased risk of late csCMV infection. Late csCMV infection showed inferior NRM (HR, 1.83; p&amp;lt;0.01) and OS (HR, 1.58; p&amp;lt;0.01) in multivariate analysis. Conclusion: LMV prophylaxis efficiently suppressed the development of early csCMV infection; however, this effect did not translate into improved posttransplant outcomes. Breakthrough csCMV infection during LMV prophylaxis and the development of late csCMV infection after completing LMV prophylaxis worsened transplant outcomes in the LMV prophylaxis group. Further improvements in posttransplant CMV management will be required to address these issues.

Meta-Analysis of the Prognostic Significance of BCL6+/CD10+ Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL), classically characterized by the translocation of t(11;14). MCL is typically CD10 negative, often attributed to its pre-germinal nature arising from naïve B cells. Increasing cases of CD10+ MCL suggest the possibility of germinal center-derived pathology. Moreover, a unique and rarer BCL6+/CD10+ immunophenotype has been reported in the literature and warrants investigation into its clinicopathologic significance. This meta-analysis was conducted to further investigate the relationship between MCL immunophenotypes and their clinical outcomes. Methods: A meta-analysis was conducted to investigate the relationship between MCL immunophenotypes and clinical outcomes. Endpoints collected included clinical features, overall survival (OS), morphology, immunophenotypes , Ki67%, and cytologic variants. OS data was pooled from multiple studies and assessed using the R programming package survival. A log-rank test was performed to compare OS. The mean differences in OS between BCL6+ and BCL6- MCL for individual studies were calculated and combined to minimize the batch effects. If individual Ki67 indexes were not available, the standard deviation (SD) of the mean difference was calculated based on normal distribution and the sample size of the particular study. The summary statistics across all studies was calculated by averaging all mean differences and pooling individual SDs. The correlations between CD10 &amp; BCL6, BCL6 &amp; blastoid morphology, and BCL6 &amp; SOX11 were tested using Fisher's exact test. Statistical significance was determined by setting the alpha (α) level at 0.05. Results: The meta-analysis included 537 patients (425 males and 112 females). The median age of diagnosis in CD10+ and CD10- MCL was 69 and 61.5 years old, respectively. There were 70 CD10+, 467 CD10-, and 22 BCL6+/CD10+ patients. BCL6 positivity had an odds ratio of 5.11 (95% CI [2.49, 10.46]; p=0.00002386) for CD10 positivity compared to CD10 negativity. The subgroup analysis showed a higher frequency of blastoid/pleomorphic/small morphology variants in BCL6+/CD10+ MCL. Correlation analysis between BCL6 positivity and blastoid/pleomorphic/small morphology did not demonstrate significant correlation (p=0.2423). However, positive correlation was seen between BCL6 and SOX11 (p=0.013). BCL6+ MCL was associated with an inferior median OS compared to BCL6- MCL (BCL6+: 14 months vs. BCL6-: 43 months; p=0.01). Furthermore, BCL6+/CD10+ co-expression was associated with an inferior median OS compared to BCL6-/CD10+ MCL (BCL6+/CD10+: 20 months vs. BCL6-/CD10+: 55 months; p&amp;lt;0.01). Conclusion: Based on the analysis, it was found that BCL6 expression positivity negatively impacts overall survival (OS) in MCL, regardless of CD10 expression. The higher Ki67% observed in BCL6 expression positivity compared to BCL6 negativity suggests the prognostic value of the BCL6 immunophenotype in MCL. Additionally, BCL6 expression was found to be correlated with CD10 and SOX11 expression, indicating the clinical significance of these variables when combined with BCL6 positivity. It is suggested that prognostic scoring systems adjusted for BCL6 could provide further insights into the prognostic categorization, management, classification, and future tailored treatment of MCL variants.

A Novel and Cost-Efficient Measurable Residual Disease (MRD) Detection Assay Using a Single Molecule Molecular Inversion Probe-Based Next Generation Sequencing (NGS) Assay Predicts Overall Survival in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction Relapse remains the main reason for poor outcomes of patients (pts) with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred post-remission treatment in pts at high risk of relapse. The presence of measurable residual disease (MRD) after intensive frontline treatment or before or after HSCT has emerged as an important predictor of relapse. Various methods are used for MRD detection, including flow cytometry and molecular assays detecting individual gene mutations (mut) such as NPM1mut. Next generation sequencing (NGS)-based assays covering multiple genes commonly mutated in AML may allow sensitive MRD detection in a broad range of pts with diverse genetic characteristics. Methods We established a targeted, error corrected NGS MRD assay utilizing single-molecule molecular inversion probes (smMIPs). The smMIP protocol uses a hybridization-capture approach to selectively enrich and amplify both DNA strands of 92 regions in 32 genes in a single reaction. Unique molecular identifiers (UMIs) facilitate computational correction of sequencing errors to enable reliable detection of variants ≥0.5% variant allele frequency (VAF), with the additional advantage of relatively low reagent and sequencing costs of &amp;lt; $100 per sample. The smMIP assay was used to evaluate MRD status on pre-HSCT bone marrow samples from 98 AML pts who received an HSCT in first (n=83) or second (n=15) complete remission with or without count recovery. Median age at HSCT was 59 (range 20-75) years, 42% were female; 70% had de novo AML, 19% had an antecedent myeloid neoplasm and 11% had AML post cytotoxic therapy. European LeukemiaNet (ELN)-2022 risk groups at diagnosis were favorable in 11%, intermediate in 33%, adverse in 20% and unknown in 22%. All pts had received intensive induction chemotherapy. Twenty-nine percent received a myeloablative conditioning regimen (MAC), while 23% received reduced intensity conditioning (RIC) and 48% a non-myeloablative (NMA) conditioning regimen. Donors were matched related (18%), haploidentical (6%), or matched (55%) or mismatched (21%) unrelated. The median follow-up for pts alive was 34.8 months. Results Overall, we detected 190 variants in 71 (72%) of 98 pre-HSCT remission samples. The most commonly affected genes were DNMT3A (in 37% of pts), TET2 (21%), PPM1D (12%), IDH2 (10%) and TP53 (5%). Twenty-nine percent of pts had only variants affecting the clonal hematopoiesis-related genes DNMT3A, TET2 or ASXL1 (‘DTA‘), while 44% of patients had ≥1 variant involving a non-DTA gene. MRD-positive pts, defined as those with ≥1 non-DTA variant, had similar baseline and HSCT-related characteristics (includingage, sex, ELN risk group, de novo vs. secondary AML) compared to pts without non-DTA variants. Overall survival (OS) was significantly inferior in NGS MRD-positive pts compared to those with no non-DTA variant (Figure A, 5-year OS, 49% vs. 85%, P=.011). MRD-positive pts also had a non-significant higher cumulative incidence of relapse at 5 years (46% vs. 24%, P=.14), while non-relapse mortality was similar in both groups (P=.72). We next performed multivariable analyses, considering variables associated with OS at an univariable P&amp;lt;.10 (MRD status, patient sex, therapy-related AML, conditioning intensity), and using stepwise backward variable selection to identify factors significantly associated with OS (Figure B). In the final multivariable model, pre-HSCT MRD detection remained associated with inferior OS (hazard ratio 2.51; 95% confidence interval, 1.07 - 5.91; P=.035). Female sex associated with favorable OS, while myeloablative conditioning (MAC) showed a borderline significant association with superior OS. Of note, we did not detect an interaction between conditioning intensity and detection of MRD with regard to OS, i.e. the prognostic association of MRD detection was not different between pts receiving myeloablative or less-intensive conditioning. However, this analysis was limited by the small patient number. Conclusion Detection of MRD by targeted NGS using the smMIPs approach provides prognostic information in pts undergoing allogeneic HSCT, including those without established molecular markers such as NPM1mut. This method is applicable to a large proportion of AML pts and is cost-efficient for broad clinical use. S.M.K. and T.H., and M.J. and K.H.M. contributed equally to this abstract.

Risk Factors and Outcomes for Hematotoxicity Following Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia

Background: Hematotoxicity following chimeric antigen receptor (CAR) T-cell therapy is increasingly recognized as a distinct adverse event. The CAR-HEMATOTOX score has been developed as a prognostic tool for subsequent development of prolonged cytopenias in adults with lymphoma. However, risk factors in children and young adults (CAYA) with B-acute lymphoblastic leukemia (B-ALL) receiving CAR T cell therapy are less well-defined. We sought to describe incidence, outcomes, and risk factors for prolonged severe neutropenia in CAYA treated with tisagenlecleucel. Methods: This was a multi-institutional retrospective study involving CAYA ≤26 years of age with B-ALL treated with tisagenlecleucel who underwent leukapheresis and manufacturing between August 2017 and March 2020, with data collected through the Pediatric Real World CAR Consortium (PRWCC). Of 185 patients infused, 41 patients were excluded from analysis due to missing data (n=10), refractory disease/death from leukemia (n=27) or non-relapse mortality (n=4) prior to day 35 post-CAR T. Severe prolonged neutropenia was defined as absolute neutrophil count (ANC) &amp;lt;500 cells/mm 3 for ≥30 days. For those with severe neutropenia pre-CAR T, day 0 of severe neutropenia was considered the day of CAR T-cell infusion. Statistical analyses included comparisons using Mann-Whitney and Fisher's exact tests, receiver operating characteristic (ROC) curves to determine cut points with optimal sensitivity and specificity, univariate logistic regression, Kaplan-Meier curves for recovery from neutropenia, overall survival (OS) and relapse free survival (RFS). Results: Of 144 patients, 23 (15.9%) met the definition of severe prolonged neutropenia and 121 (84%) did not. For lymphodepleting chemotherapy, 139 (96.5%) received standard fludarabine (30mg/m 2/dose x 4) and cyclophosphamide (500mg/m 2 x 2). Pre- and post-infusion characteristics are shown in Table 1. Pre-infusion, higher pre-infusion C-reactive protein (CRP), ferritin, bone marrow disease burden, and lower ANC and platelet counts were associated with severe prolonged neutropenia. Post-infusion, any grade cytokine release syndrome (CRS), severe CRS, CRS with hemophagocytic lymphohistiocytosis (HLH)-like manifestations, any grade neurotoxicity, peak CRP and ferritin, use of tocilizumab and steroids, and presence of infections within 30 days were associated with severe prolonged neutropenia. With univariate logistic regression, pre-infusion inflammatory markers, cytopenias, and bone marrow disease burden associated with severe prolonged neutropenia and of these, disease burden &amp;gt;15% had the highest odds ratio (Figure 1). Post-infusion infections and inflammatory toxicities, particularly CRS with HLH-like toxicities, as well as peak CRP, and peak ferritin, were associated with severe prolonged neutropenia. Peak ferritin &amp;gt;3800 ng/ml had the highest odds ratio. In patients with severe prolonged neutropenia, OS was inferior (p&amp;lt;0.0001) and RFS trended towards being inferior (p=0.052), compared to those without. Groups with or without severe prolonged neutropenia were also subdivided into &amp;gt;15% or ≤15% pre-infusion bone marrow disease burden subgroups. OS was similar between patients without severe prolonged neutropenia that had &amp;gt;15% or ≤15% pre-infusion disease burden, but patients with severe prolonged neutropenia and &amp;gt;15% disease burden had inferior OS, suggesting prolonged severe neutropenia may have independent prognostic value. Conversely, RFS was inferior in patients in the subgroups with &amp;gt;15% disease burden compared to those with ≤15%, regardless of occurrence of severe prolonged neutropenia. Discussion/Conclusions: We describe incidence, risk factors and outcomes for the development of severe prolonged neutropenia in CAYA with B-ALL following tisagenlecleucel. While there are similarities in risk factors with the CAR-HEMATOTOX score that has been validated in adults, in CAYA with B-ALL high disease burden pre-infusion and severe inflammation post-infusion were identified as the strongest risk factors for prolonged neutropenia. Identification of risk factors unique to the CAYA B-ALL population allows for tailored risk mitigation in higher risk patients and may help improve outcomes in CAYA at increased risk of prolonged severe neutropenia following tisagenlecleucel.

Longitudinal Screening of Mutant Hematopoietic Progenitor Cells (HPC) in Multiple Myeloma (MM) and Its Association with Secondary Primary Malignancies (SPM)

Background: The incidence of SPM in transplant eligible MM patients (pts) receiving lenalidomide maintenance is ≥ 12% and is associated with inferior overall survival (OS). Recent evidence suggests that while clonal hematopoiesis does not increase the risk of SPM, specific TP53 mutant HPC may expand under lenalidomide treatment and give rise to therapy related myeloid neoplasms and acute lymphoblastic leukemia. Genetic screening may facilitate personalized treatment to minimize the risk of SPM. However, there are no longitudinal studies in purified HPC to inform on the evolution of specific gene mutations and its association with clinical outcomes. Aim: Analyze the mutational landscape of HPC at diagnosis and throughout lenalidomide based regimens. Methods: This study included 335 pts: 43 with high risk smoldering MM, 223 transplant eligible and 69 ineligible active MM respectively enrolled in the CESAR, GEM2012MENOS/GEM2014MAIN and CLARIDEX clinical trials. Of the 335 pts analyzed at diagnosis, 60 were further investigated after induction, 30 at day 100 after autologous transplant (ASCT) and 47 during maintenance. Two or more studies were available throughout treatment in 36 pts. Fluorescence activated cell sorting of CD34+ HPC was performed in a total of 500 bone marrow aspirates. DNA was analyzed with a panel of 55 genes recurrently mutated in myeloid neoplasms. Sequencing depth was &amp;gt;1000x in 95% of nucleotides. Criteria to filter out included synonymous, intronic, invalid-transcript, 5'UTR, panel error and single nucleotide polymorphisms. The criteria to filter in was a AMP/ACMG classification of uncertain significance, likely pathogenic or pathogenic. Only the latter two were included in downstream analysis. Results: HPC from 184 of the 335 (55%) pts were mutated. The frequency in high-risk smoldering MM, transplant eligible and ineligible active MM was 46%, 26% and 35%, respectively. The genes more frequently mutated were DNMT3A (n=94, 52%), TP53 (n=29, 16%) and TET2 (n=28, 15%). The median variant allele frequency was 4.9, 7.5 and 7.0, respectively. In a pt-paired analysis between diagnosis and induction, 8 mutations were present in both time points, 25 became undetectable and 22 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 14 of the 60 (23%) pts. In the 30 pts with paired samples at diagnosis and at day 100 after ASCT, 4 mutations were present in both time points, 48 became undetectable and only 3 were acquired during treatment ( ATRX, MPL and SAMDL9). Thus, the frequency of mutant HPC was higher at diagnosis vs ASCT (23% vs 5%, P &amp;lt;.001). In a pt-paired analysis between diagnosis and maintenance, 13 mutations were present in both time points, 12 became undetectable and 30 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 24 of the 47 (51%) pts screened at both time points, and after a median of 5 years since diagnosis. With a median follow-up of 6 years, 17 of the 335 (5%) pts developed SPM. Mutant HPC were detected in 13 of the 17 pts. Accordingly, presence of mutant HPC was associated with a 2-fold increased risk of SPM (OR: 2.3; P = .03). Of the 13 pts, 3 showed mutations at diagnosis and in 8 these emerged during maintenance. The only case developing a myeloid neoplasm had a TP53 mutation present during maintenance that was undetectable at diagnosis. Pts with mutant vs non-mutated HPC at diagnosis showed similar OS (6y rates of 86% and 81%, respectively; P =.46). Similarly, there were no differences in OS of pts with emerging mutations vs those without mutant HPC after treatment (6y rates of 85% and 83%, respectively; P =.65). Specific mutations in DNMT3A, TP53 and TET2 and were not associated with inferior OS. Conclusions: To our knowledge this is the first study analyzing the mutational landscape of purified HPC throughout lenalidomide based regimens in high risk smoldering MM as well as transplant eligible and ineligible active MM. Deep sequencing of CD34+ HPC uncovered that the frequency of mutations is similar between precursor and malignant disease, and that TP53 is amongst the top mutated genes. There was considerable volatility with presence of both transient and emerging mutations throughout treatment. Importantly, the detection of mutant HPC was associated with increased risk of SPM without differences in survival. Thus, this study supports the longitudinal screening of HPC for the identification of patients at risk of developing SPM.

The Prognostic Value of Dynamic Change of NK-Cell Counts in Diffuse Large B-Cell Lymphoma Treated with R-CHOP

Key words: Diffuse large B-cell lymphoma, Natural killer cell count, prognosis. Introduction Natural killer (NK) cell counts at diagnosis have been reported to be associated with poor outcomes, but the dynamic change and prognostic value of NK cell counts after treatment in diffuse large B-cell lymphoma (DLBCL)remain unknown. NK cell count was test by flow cytometry at diagnosis, interim and the end of treatment. Receiver operating characteristic (ROC) curve was used to determine the best cutoff value for survival analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed by the method of Kaplan-Meier and Cox proportional hazard regression model. A total of 175 DLBCL patients were analyzed and 45 of them were divided into the low NK cell counts with the cut-off value was 94.5/ul. Patients with low NK cell counts were associated with B symptoms (p &amp;lt; 0.001), high LDH (p=0.002), advanced stage (p &amp;lt; 0.001) and high IPI scores (p=0.001). Survival analysis showed patients with low NK cell counts at diagnosis showed more inferior OS and PFS than those with high NK cell counts (p &amp;lt; 0.001 and p &amp;lt; 0.001). There were 60 patients showed low NK cell counts at the interim, consist of 31patients with low and 29 with high NK cell counts at diagnosis and 65 patients had low NK cell counts at the end of the treatment, consist of 31patients with low and 34 with high NK cell counts at diagnosis. But NK cell count at the interim or end of treatment had no impact on the PFS (p = 0.415 and p = 0.011) and OS (p = 0.537 and p = 0.836) of DLBCL patients. Multivariable analysis revealed that NK cell counts was an independent prognostic factor OS [relative risk (RR);95% confidence interval (CI),0.157-0.984, p = 0.046] and PFS (RR,0.335;95%CI,0.191-0.588, p &amp;lt; 0.001） in all DLBCL patients independent of IPI. In conclusion, low NK cell counts at diagnosis is a simple and effective adverse prognostic factor in DLBCL patients treated with R-CHOP. However, the NK cell counts at the interim and the end of the treatment showed no impact on outcome.

Neighborhood Disadvantage Is Associated with Inferior Overall Survival for Acute Myeloid Leukemia Patients Treated with Standard Intensive Induction

Background: Identifying biologic and socioeconomic contributors to disparities in outcomes is critical for the management of acute myeloid leukemia (AML). Prior studies in AML revealed that Black patients (pts) have inferior survival compared to White pts, with more striking disparity for Black pts aged &amp;lt;60. We previously explored our large and diverse AML cohort from urban and large rural areas and did not identify inferior survival for pts with self-reported Black race or Hispanic ethnicity. Although no surrogates for social determinants of health (SDOH) or insurance status were recognized as contributing to survival differences, oncology nurse navigation (ONN) was associated with a survival benefit, with no significant difference in access to ONN among racial or ethnic groups. To further evaluate socioeconomic drivers of disparities in this population supported by ONN, we aim to use the Area Deprivation Index (ADI) to determine the impact of neighborhood disadvantage on survival in AML. Methods: AMLpts diagnosed at Levine Cancer Institute between 12/2015 and 12/2020 were included. Pts with acute promyelocytic leukemia (APL) were excluded from this analysis. Details regarding insurance coverage, ONN services, induction therapy, stem cell transplant (SCT) status, and survival outcomes were collected. Race and ethnicity were self-reported. European LeukemiaNet (ELN) 2017 criteria were used to assign AML risk. Pt and disease characteristics were summarized, described, and compared with Fisher exact tests and Wilcoxon rank-sum tests for categorical and continuous data, respectively. Pts were grouped into 4 quartiles based on ADI national percentile. Subsequent models were fit with ADI dichotomized at the median after adjacent ADI groups were removed with backward elimination. Associations between overall survival (OS) and pt and disease characteristics, insurance status, race, ethnicity, ONN services, and ADI were investigated. OS was defined as the time from diagnosis (dx) to death from any cause, with surviving subjects censored at the time of last follow-up. Kaplan-Meier methods were used to summarize OS and calculate landmark survival rates. Survival was compared with unadjusted log-rank tests. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) associated with OS. Results: Three hundred eighty pts with available baseline characteristics were included in our analysis ( Table 1) . For pts &amp;lt;60 who received intensive induction and had available ADI (N=86), there was a significant difference in OS amongst the quartiles of ADI (P=0.007), with differences even more pronounced with dichotomized ADI (P&amp;lt;0.001) ( Figure 1). With a median follow-up of 38.1 months for the intensively treated pts &amp;lt;60, the estimated two-year OS was 96.6% for more advantaged/low ADI pts and 55.4% for less advantaged/high ADI pts (HR 5.21; 95% CI 1.82 to 14.95). Within the cohort of pts &amp;lt;60 who received intensive induction, sixty-eight percent were Non-Hispanic White and 28% were Non-Hispanic Black. Many (66%) were privately insured at dx, with 24% uninsured or with Medicaid. ONN services were accessed by most (72%) pts with known ADI. Care barriers were expressed by pts of all ADI quartiles, with transportation being the only barrier most reported by pts of increased disadvantage (P&amp;lt;0.01). Forty-two percent of pts received SCT (N=38). Nearly 60% of socially advantaged pts (ADI≤51) received SCT versus 33% of socially disadvantaged pts (P=0.03). In univariate models, receipt of SCT (P=0.016) was associated with improved OS while receiving navigation services (P=0.32) was not. Conclusions: Higher ADI was associated with inferior OS in AML pts &amp;lt;60 who received intensive induction. Receipt of SCT was observed more often in pts with more neighborhood advantage, which is of great importance since SCT improved OS in this cohort. Although insurance status is often linked to SCT access, insurance status did not significantly impact OS. Of the ONN reported barriers to care, transportation issues had a greater impact on pts with more neighborhood disadvantage. Expanding access to SCT and addressing barriers to care, such as transportation, is necessary to overcome the detrimental impact of neighborhood disadvantage on survival in AML.

Obesity after Induction Is Associated with Poor Overall Survival in Adults with Acute Lymphoblastic Leukemia: Results from a Peruvian Adaptation of the CALGB10403 Protocol

Background:Acute lymphoblastic leukemia (ALL) is a lymphoid malignancy with wide racial disparities. Indeed, ALL is more frequently diagnosed among the Latino population who classically achieve lower remission rates and experience worse survival than other racial and ethnic groups. Several high-risk features including genetic polymorphisms and metabolic issues have been implicated in Latino ethnicity, including obesity. A high body mass index (BMI) at different stages of treatment represents a well-known risk factor in several prospective studies mainly based on white populations. It is unclear whether these findings are consistent in other racial and ethnic unrepresentative groups. We aimed to evaluate the effect of BMI at the end of induction on the overall survival (OS) of Latino adults with ALL. Methods:We conducted a retrospective cohort study among adult patients diagnosed with ALL in an academic cancer center (Instituto Nacional de Enfermedades Neoplasicas - INEN) from 2017 to 2019, with follow-up through July 2023. The INEN is a national tertiary referral center in Lima-Peru that provides leukemia treatment for approximately 85% of the insured population in Peru. Patients aged 20-65 who successfully achieved complete remission after 4 weeks of intensive induction treatment were included. Patient data were manually abstracted from the medical records. BMI was classified as underweight, healthy weight, overweight and obese according to the CDC and WHO recommendations. Vital status was ascertained with the National Vital Registry. The Kaplan-Meier method and the Log-rank test were used to estimate OS probabilities. Multivariable Cox regression was used to evaluate the effect of BMI on OS, adjusting for sex, age, risk, and immunophenotype. Results: Of 784 patients identified in the electronic records of the INEN, we excluded 578 because they didn't achieve complete remission, yielding 206 patients for analysis. The median age at diagnosis was 33 years, most were aged 20-40 years old (68%), and female (54%). 160 (78%) were ALL-B Ph- and 126 (61%) corresponded to the high-risk stratification. At the end of the induction, 119 patients presented a healthy weight (58%), 49 (24%) overweight, 26 (13%) obese, and 12 (6%) underweight (Table 1). With a median follow-up of 55 months, the median OS was 18 months (95% CI: 16-23), and the 5-year OS was 23% for all patients. The 5-year OS was lower in patients with obesity (12%), followed by patients with overweight (20%), healthy weight (26%), and underweight (33%), as evidenced by the Kaplan-Meier curve (Figure 1, p=0.036). In the multivariable analysis, obesity (p-value=0.006) was associated with an increased risk of all-cause mortality (adjusted Hazard Ratio [aHR]: 1.93; 95% CI: 1.21-3.08). A very high-risk disease was also associated with poor OS (aHR:2.69; 95% CI: 1.15-6.26) (Table 1). Conclusion: This study identified that obesity at the end of induction is associated with inferior OS among Peruvian patients who achieved complete remission. Our real-world findings should be validated in prospective studies including other Latino populations to recommend the feasibility of weight reduction strategies.

Impact of Diagnosis to Treatment Interval on Outcomes in Patients with Newly Diagnosed Marginal Zone Lymphoma - a US Multisite Study

Introduction Diagnosis to treatment interval (DTI) is an important prognostic factor in patients with newly diagnosed diffuse large B-cell lymphoma (Maurer M et al, JCO 2018) and mantle cell lymphoma (Epperla N et al, Blood Adv 2023) where patients with shorter DTI consistently show inferior survival. In marginal zone lymphoma (MZL), the use of first-line bendamustine and rituximab (BR) therapy may enhance progression-free survival (PFS) compared to cyclophosphamide-based regimens such as RCHOP/RCVP. However, the differences in outcomes may be influenced by other factors, such as the DTI, especially in observational studies. Until now, the prognostic significance of DTI in MZL has not been explored. Therefore, our objective was to assess the impact of DTI on outcomes for patients with newly diagnosed MZL. Methods This is a substudy of a previously reported multicenter, retrospective cohort that included adult MZL patients treated at 10 US medical centers on or after 1/1/2010. In this substudy, we included patients who initiated first-line BR, RCHOP, or RCVP within 120 days of diagnosis. Patients who were on observation or received antibiotics, local therapy (surgery or radiation therapy), or rituximab monotherapy were excluded. DTI was defined as the number of days from the MZL diagnosis to the start of immunochemotherapy (IC). Using concordance statistics for different DTI cutoffs, we determined 60 days as optimal for analysis. Patients who received treatment within 60 days from their diagnosis were classified into the short DTI group. To compare clinical characteristics between the two groups, univariable and multivariable (MV) logistic regression analyses were performed, accounting for missing data through multiple imputations. The primary endpoint of this analysis was PFS, while secondary endpoints included overall survival (OS) and the cumulative incidence of histologic transformation (HT). Predictors of PFS and OS were identified using Cox regression analysis. Results Of the 900 patients with newly diagnosed MZL included in the main study, 177 patients met the inclusion criteria and were included in this analysis, including 144 (81%) in the short DTI group and 33 (19%) in the long DTI group. The median time to treatment initiation was 27 days (range: 1-60) for the short DTI group and 81 days (range: 61-112) for the long DTI group. The median age was 61 years with 43% EMZL (n=77), 38% NMZL (67), and 19% SMZL (33) patients. Among the patients, 75% received BR as first-line treatment followed by R-CHOP (15%), and R-CVP (10%). A higher proportion of patients in the short DTI group had B symptoms compared to long DTI group (27% vs 3%, p=0.03, respectively). No significant differences were observed between the two groups in regard to MZL subtype, ECOG performance status, stage, LDH, or the choice of first-line IC. In the MV model, presence of B symptoms remained significantly associated with short DTI (OR=12.63, p=0.02). Short DTI was not associated with a statistically different PFS in a univariable assessment (HR=0.86, 95%CI=0.47-1.56), or in the MV model, adjusting for other prognostic factors (aHR=0.87, 95%CI=0.47-1.61, p=0.65, Figure 1A), while high LDH (aHR=2.07, 95%CI=1.06-4.07, p=0.034) and low albumin (aHR=2.31, 95%CI=1.10-4.85, p=0.027) at diagnosis were associated with significantly inferior PFS in the MV model. Additionally, the MV model indicated that patients who received BR had significantly better PFS compared to those who received R-CHOP/RCVP (aHR=0.50, 95% CI=0.29-0.86, p=0.01, Figure 1B). Short DTI was not associated with inferior OS in either univariable or MV models (MV: aHR=0.74, 95%CI=0.26-2.08, p=0.57). There were 12 transformation events in the study: 8 in the short DTI group and 4 in the long DTI group. The cumulative incidence of HT was not significantly different between the two groups (10-year CIF 13% versus 12%, respectively, p=0.22). Conclusion In MZL, a short DTI does not correlate with an inferior prognosis, despite being associated with certain unfavorable characteristics such as the presence of B symptoms. This lack of prognostic utility of DTI in newly diagnosed MZL, in contrast to aggressive B-cell lymphomas, may be intrinsically linked to the underlying biology of the disease. Furthermore, the observed improvement in PFS with BR compared to RCHOP/RCVP, as demonstrated in clinical trials like STiL and BRIGHT, cannot be attributed to differences in DTI.