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ABSTRACT As the treatment paradigm for Waldenström macroglobulinemia (WM) continues to evolve, the debate surrounding the prioritization of depth of response versus disease control as therapeutic goals gains significant relevance. However, the impact of depth of response from fixed‐duration therapy on overall survival (OS) was unclear. This multicenter study evaluated the prognostic impact of depth of response using a landmark survival analysis. A total of 440 patients with WM treated with frontline fixed‐duration regimens were included. Attaining a major response (MaR) was associated with superior outcomes, including significantly longer OS. The estimated 5‐year PFS rates for patients with MaR at 6 months versus not were 50% versus 32%, respectively, p < 0.001, and the estimated 5‐year OS rates for patients with MaR at 6 months versus not were 89% versus 70%, respectively, p < 0.001. In a multivariable analysis, MaR at 6 months was independently associated with superior PFS (HR 0.66, p = 0.007) and OS (HR 0.28, p < 0.001). Similar results were seen when considering deeper responses (CR + VGPR vs. PR). Depth of response at 6 months is an important prognostic marker in WM and an independent predictor of PFS and OS. These results support its utilization as a suitable endpoint in clinical studies in WM.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Oncoprotein-driven human cancers exhibit replication stress (RS), leading to an increase in DNA double-strand breaks (DSB). These DSBs are repaired by one of the three main pathways - homologous recombination repair (HR), non-homologous end-joining (NHEJ), and microhomology-mediated end joining (MMEJ). Cyclin D1 (CCND1) is one of the most overexpressed oncoproteins and is universally overexpressed in mantle cell lymphoma (MCL). While CCND1 overexpression drives cells into the S-phase, its specific effects on RS and DSB repair pathways are poorly understood. Here, we investigated the impact of CCND1 overexpression on RS and DSB repair mechanisms in MCL. First, the expression level of CCND1 positively correlated with heightened RS, as indicated by elevated p-RPA-S33 and p-RPA S8 levels, and increased DNA damage, assessed by g-H2AX, especially in the mitotic phase, across diverse cell models, including MCL. Since CCND1-overexpressed cells proliferate rapidly, we hypothesized that some DNA repair pathways might be upregulated to meet the demand for repairing the excess RS-driven DSBs. Reporter assays demonstrated that the MMEJ pathway was specifically upregulated upon CCND1 overexpression, whereas no significant changes were observed in the HR and NHEJ pathways. Furthermore, CRISPR interference (CRISPRi)-mediated knockdown of CCND1 in MCL cells led to a significant reduction in MMEJ activity. This finding suggests the specificity of CCND1 in mediating the upregulation of the MMEJ pathway. Consistent with this, increased MMEJ activity, assessed via foci formation and immunoblotting of DNA polymerase theta expression (POLQ, encoded by POLQ gene), the primary polymerase for the MMEJ pathway, correlated with CCND1 overexpression, suggesting the crucial role of MMEJ in DSB repair processes under CCND1-overexpressed conditions. Sincethe MMEJ pathwayplays a pivotal role in repairing DSB during mitosis, we assessed the dependency of MCL cells on MMEJ-mediated DSB repair for cell survival. As expected, genetic deletion or pharmacological inhibition (ART558 and novobiocin) of POLQ in MCL cells led to increased RS and increased unrepaired DNA damage during mitosis, ultimately leading to chromosomal instability, mitotic catastrophe, and apoptosis. Additionally, the deficiency of POLQ in MCL cells resulted in increased levels of single-strand DNA, another critical biomarker for RS. Second, we found that ATM deficiency, the second most common genetic alteration after CCND1 overexpression in MCL, further increased the cellular dependence on MMEJ. Interestingly, the accumulation of unrepaired DNA damage during mitosis was notably increased in ATM-deficient CCND1-overexpressed cells. When POLQ was inhibited, a significant antitumor effect was evident in MCL cells, including ibrutinib-resistant MCL, both in vitro and in vivo, and this effect was enhanced by ATM deficiency. Further, simultaneous inhibition of both ATM (AZD0156) and POLQ was synthetic lethal in MCL cell lines and primary tumor cells from patients with MCL. Mechanistically, we observed the direct binding of CCND1 to the POLQ promoter and a corresponding upregulation of POLQ mRNA in CCND1-overexpressing cells. Consistently, a significant overexpression of POLQ mRNA was observed in primary MCL cells, compared to other non-Hodgkin lymphoma cells without CCND1 overexpression. Moreover, the positive correlation between POLQ and CCND1 expression was further validated using syngeneic B-lymphoma cells with and without CCND1 overexpression. Importantly, CRISPRi-mediated CCND1 knockdown reduced POLQ mRNA expression and the dependency of MCL cells on the MMEJ pathway for survival. In addition, ATM deficiency showed a further increase of endogenous POLQ expression and foci formation in cells with CCND1 overexpression, suggesting ATM negatively regulates the MMEJ pathway, especially in the CCND1 overexpressed background. In summary, CCND1 overexpression leads to a substantial increase in RS, intensifying the reliance on MMEJ-mediated mitotic DSB repair. Within MCL, POLQ is crucial in mitigating the adversities of CCND1-driven RS. Our data suggest that targeting the MMEJ pathway via POLQ inhibition, particularly in the presence of CCND1 overexpression and ATM deficiency, emerges as a promising therapeutic approach in oncoprotein-driven hematologic malignancies such as MCL.

Background Advancements in imaging techniques, diagnostic procedures, and increased routine health care visits are anticipated to lead to a higher number of patients with an incidental diagnosis of cancer, including the most common lymphoma DLBCL. In parallel, multiple cancer early detection (MCED) blood assays are emerging to screen for cancer in asymptomatic, average risk individuals. Assays that use methylated DNA markers (MDM) are of special interest and have been shown to detect evidence of DLBCL in the blood in 80% of DLBCL cases (Witzig TE et al ASCO 2022). While these MDMs are candidates for inclusion in MCED assays, the impact of early detection of lymphoma in general and DLBCL specifically remains controversial. Since the outcomes for patients with an incidental diagnosis of DLBCL have not been previously studied and to give further insight to the early detection question, we investigated clinical characteristics and outcome differences between patients with DLBCL found incidentally and those with symptoms or obvious signs of disease that led them to seek medical evaluation. Methods We conducted a retrospective analysis of newly diagnosed DLBCL patients enrolled into the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence from 2002-2015. We reviewed the medical records of the Mayo component to assign a mode of diagnosis (incidental vs symptomatic). We examined disease characteristics and impact on event-free survival (EFS) and overall (OS) survival according to the mode of diagnosis. EFS was the time from diagnosis to relapse, progression, retreatment, or death from any cause. OS was defined as the time from diagnosis to death from any cause. Results 1140 patients with DLBCL (90.6%), high grade B cell lymphoma (2.4%) or primary mediastinal B cell lymphoma (7.0%) were reviewed; 85 (7.5%) patients presented incidentally (incidental group), while 1055 (92.5%) presented with a lymphoma-related symptom or sign, e.g., palpation of a lump/mass, B symptoms and/or other symptoms caused by the lymphoma such as abdominal pain (symptomatic group). In the incidental group, 67.5% (65/85) of patients were diagnosed after an incidental finding on imaging or diagnostic/surgical procedure, 14.1% (12/85) were diagnosed after an incidental lab finding, and 9.4% (8/85) were diagnosed after a clinical health care professional incidentally identified a lump/mass. Compared to the symptomatic group, patients with incidental diagnosis were older at diagnosis (median age 66 vs 63 years, P=0.01) and more likely to present with an earlier stage I/II (62.4% vs 38.9%, P&lt;0.001). Patients who presented with symptoms were more likely to have ≥ 1 extra-nodal site involvement (29.8% vs 15.5%, P=0.005), elevated LDH level (55.4% vs 40.8%, P=0.01), and high-risk IPI score (13.7% vs 5.9% P=0.03) compared to the incidental group. The median diagnosis to treatment interval (DTI) was significantly longer in the incidental group (21 days, IQR 12-34) compared to the symptomatic group (15 days, IQR 9-24) (P = 0.0014). The median follow-up time was 152.3 months in the incidental group and 123.7 months in the symptomatic group. We observed no difference in early failure rates as measured by failure to achieve event-free status at 24 months (EFS24) for incidentally vs symptomatic diagnosis (25.9% vs 31.9%, P=0.25). There was no difference in EFS between the two groups in univariate (HR=1.08, 95%CI=0.8-1.45) or multivariable analysis adjusted for IPI (aHR=0.97, 95%CI=0.72-1.31). There was also no difference in OS in univariate (HR=0.98, 95%CI=0.72-1.34) or multivariable analysis adjusted for IPI (aHR=0.87, 95%CI=0.64-1.19). Conclusion In this large cohort of aggressive B-cell lymphoma, incidental diagnosis occurred in only 7.5% of cases and these patients had earlier stage, lower IPI score, lower LDH levels and less extranodal involvement. These differences in clinical characteristics did not translate into EFS or OS differences. Our findings are the first to describe presentation and outcomes of incidentally diagnosed DLBCL and provide data regarding what investigators may find with MCED assays. Finding more early stage DLBCL patients with lower tumor burden may influence type of treatment, enable the use of fewer chemotherapy cycles, and avoid symptoms and complications of advanced stage disease such as tumor lysis syndrome and organ compression.

Introduction: Diffuse large B cell lymphoma (DLBCL) patients experience favorable outcomes following frontline immunochemotherapy, however, 30-40% of patients will exhibit primary refractory disease or relapse (rrDLBCL). Recent studies have expanded upon well-defined characteristics of newly diagnosed DLBCL (ndDLBCL) to elucidate genomic landscapes underlying rrDLBCL; yet, high-throughput examination of resistance and relapse mechanisms within rrDLBCL subtypes, including the newly defined dark zone signature (DZsig) addition to cell of origin (COO), have yet to be described. To expand upon the current tumor etiology and define subtype-specific driving mechanisms, we describe a multi-omic analysis leveraging clinical and biologic variables in rrDLBCL. Methods: Tumor biopsies (N=228) collected at the time of relapse were obtained from n=85 participants in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource (MER), n=73 in the Mayo Clinic Biobank, and n=38 from CC-122-DLBCL-001 or n=32 CC-122-ST-001 trials. Tumor samples were analyzed by WES (n=158) or WGS (n=70) and by RNAseq (n=145). Comparative analysis against ndDLBCL MER samples (N=444) utilized WES (n=404) and RNAseq (n=321). Chi Square or Fisher's exact test was used for enrichment analysis of categorical variables, while Wilcoxon or Kruskal-Wallis test was used for continuous variables. Results: rrDLBCL samples were enriched for ABC (46% vs 33% in ndDLBCL, p=0.01), and fewer GCB (27% vs 40%, p=0.006). Amongst rrDLBCL patients, variance in overall survival (from time of original diagnosis; log-rank p=0.001) was observed between COO subtypes, with poor outcomes in patients with DZsig (median 15.0 mo) and GCB (36.5 mo) compared to ABC tumors (74.4 mo). Patients with progression or relapse within 6 months featured a more even COO distribution (ABC - 22%, GCB - 34%, DZsig - 28%) than patients with early (6-24 mo; 51%, 22%, 22%) or late relapses (&gt;24 mo; 62%, 19%, 4%), which were predominantly ABC. Comparing mutation frequency within subtypes, rrDLBCL GCB tumors were enriched for B2M (41% vs 15% in ndDLBCL, p=0.002), EP300 (19% vs 7%, p=0.059), CIITA (19% vs 5%, p=0.02), PRKCB (11% vs 2%, p=0.035), CD79B (11% vs 0%, p=0.004), and CD83 (8% vs 1%, p=0.049) mutations, and CNV events including gains at 8q24.21 (MYC locus; 48% vs 14%, p&lt;0.001) and 18q21.33 (BCL2, TCF4 locus; 36% vs 15%, p=0.021), and losses at 17p13.1 (TP53 locus; 40% vs 19%, p=0.035). rrDLBCL DZsig tumors featured enrichment for BCL6 (22% vs 3%, p=0.025), and SPEN (17% vs 3%, p=0.062) mutations and 2q22.2 losses (LRP1B locus; 20% vs 0%, p=0.019). Despite differential mutation and CNV profiles, gene expression analysis revealed minimal variance within COO subtypes in rrDLBCL and ndDLBCL, however upregulation of lymphoma driving genes including MYBPC2 (LogFC=1.68, FDR&lt;0.001), MYOM2 (LogFC=1.33, FDR=0.007), MYC (LogFC=0.61, FDR=0.04), and CELSR2 (LogFC=0.53, FDR=0.02) were observed in ABC rrDLBCL. Increased frequency of LymphGen classifier A53 was observed in ABC (43% vs 17%, p=0.005) and GCB (40% vs 14%, p=0.009) rrDLBCL. Using CIBERSORTx to infer lymphoma microenvironment (LME) cell type abundance, an LME-depleted class was evident in rrDLBCL tumors, including reduction of CD8+ T cells (effect size (r)=-0.78, p&lt;0.001) and T follicular helper cells (r=-0.48, p=0.012) in GCB rrDLBCL and reduction of T follicular helper cells (r=-0.43, p=0.023) and Tregs (r=-0.32, p=0.065) in DZsig rrDLBCL. Significance: We present an update to the genomic landscape of rrDLBCL, highlighting GCB and DZsig tumors with differential biology and advanced clinical course. Our data supports increased implementation of sequencing efforts in rrDLBCL to more broadly evaluate relapse mechanisms, with optimism that a more detailed understanding of r/r disease may guide trials for targeted treatment strategies. For example, rrDLBCL patients may be strong candidates for MYC pathway targeting agents (BETi), or a Lenalidomide-based regimen (R2 or Tafa-Len), as Lenalidomide has been shown to reprogram the LME via PD-L1 expression in addition to downregulation of MYC and MYC target genes. Or, due to enrichment of variants affecting anti-apoptotic proteins including BCL6 or BCL2 in DZsig and GCB rrDLBCL, a venetoclax-based therapeutic may be considered. Further targeted strategies should be considered as development of a more personalized approach remains an unmet need.

Background: Immunochemotherapy is the current standard-of-care frontline therapy for diffuse large B-cell lymphoma (DLBCL). Our group previously reported that addition of the mTOR inhibitor everolimus to R-CHOP resulted in excellent efficacy in the Alliance N1085 trial (Witzig TE et al, Blood Cancer J, 2017, 7(6):e576), with 23 of 24 patients achieving event-free survival at 24 months (EFS24), supporting further investigation of PI3K/mTOR targeting in DLBCL. New insights into molecular classification of DLBCL suggest that multiple genetic subtypes of DLBCL (eg, MCD, BN2, ST2, and EZB per LymphGen classification) may be susceptible to PI3K/mTOR targeting. Therefore, we conducted a phase 1/1b trial to investigate the safety and efficacy of combination therapy with a novel PI3K inhibitor parsaclisib and standard immunochemotherapy. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) protein expression of either MYC (≥40%) or BCL2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. Patients with high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements were also eligible. Phase 1 followed a 3+3 design to determine the maximum tolerated dose (MTD) of parsaclisib (plus R-CHOP) to be used in Phase 1b (dose expansion). The primary efficacy endpoint in phase 1/1b was complete response (CR) rate by PET. A polatuzumab vedotin (Pola) safety lead-in cohort was added later to explore the safety and efficacy of parsaclisib (at MTD) plus Pola-R-CHP. Results: From July 2020 to May 2023, 50 patients were enrolled; 1 patient withdrew consent before study treatment and was excluded from this analysis. Nine patients were treated in Phase 1, 33 in Phase 1b, and 7 in the Pola cohort. The median age at diagnosis was 66 years (range 20-86), and 20 (41%) were female. Two (4%) patients had ECOG PS ≥2, 26 (53%) had elevated LDH, 19 (39%) had &gt;1 extranodal site, 37 (76%) had stage III/IV, and 25 (51%) had high-intermediate or high-risk International Prognostic Index (3-5). 23 (47%) had non-GCB subtype, 23 (46.9%) had MYC or BCL2 single expression, 21 (42.9%) had MYC/BCL2 double expression, and 6 (12%) had MYC rearrangement (2 with BCL2 and/or BCL6 rearrangements). In Phase 1, 3 patients were treated at dose level 1 (parsaclisib 20 mg QD, d1-10) and 6 at dose level 2 (parsaclisib 20 mg QD, d1-14). No dose limiting toxicity was observed. Therefore, dose level 2 for parsaclisib was the MTD and was used in Phase 1b. In the Pola cohort (n=7), only 1 of 6 evaluable patients experienced significant toxicity (grade 3 diarrhea). Among all 49 patients, the most common treatment-related adverse event (TRAE) of any grade included neutropenia (83.7%), thrombocytopenia (79.6%), leukopenia (77.6%), lymphopenia (71.4%), anemia (71.4%), nausea (63.3%), fatigue (40.8%), peripheral sensory neuropathy (36.7%), constipation (24.5%), and diarrhea (22.4%), and the most common grade ≥3 TRAE included neutropenia (71.4%), leukopenia (69.4%), lymphopenia (49.0%), thrombocytopenia (20.4%), anemia (16.3%), febrile neutropenia (6.1%), and diarrhea (6.1%). In Phase 1/1b (n=42), the overall response rate (ORR) to parsaclisib plus R-CHOP was 97.6%, and the CR rate was 90.5%. After a median follow-up of 28.5 months (95% CI 27.7-32.7), the estimated 2-year progression-free survival (PFS) rate was 84.6% (95% CI 73.9-96.8), and the estimated 2-year overall survival (OS) rate was 95.1% (95% CI 88.7-100.0). In the Pola cohort, the ORR to parsaclisib plus Pola-R-CHP was 100% and the CR rate was 100%. After a median follow-up of 15.6 months (95% CI 13.5-NE), 1 patient had disease relapse at 11.95 months, and all patients were alive. Conclusions: Addition of the PI3K inhibitor parsaclisib to R-CHOP or Pola-R-CHP immunochemotherapy is considered safe in patients with newly diagnosed DLBCL. Combination of parsaclisib and standard immunochemotherapy resulted in high ORR and CR rate and encouraging preliminary PFS and OS outcomes patients with high-risk DLBCL. These data support further investigation of PI3K/mTOR targeting in newly diagnosed DLBCL in future trials.

In 2023, Mayo Clinic in Rochester, MN, cared for over 20,000 patients with hematologic malignancies, roughly 42% of whom were rural. Patients residing in rural areas can face challenges in access to care, financial and time burdens due to treatment-related travel, and limited opportunities to participate in clinical trials. In 2021, The Leukemia & Lymphoma Society launched its IMPACT (Influential Medicine Providing Access to Clinical Trials) grant with Mayo Clinic being among its first recipients. The program provides funding to major cancer centers, in partnership with local community oncology centers, to help increase participation of patients traditionally underrepresented in clinical trials, including those who are rural, minority and/or economically disadvantaged. The award allowed significant changes to be made to clinical trial selection and facilitation models increasing access to trials within the rural setting and reducing the socioeconomic barriers noted above. This program included Rochester (IMPACT Hub) and Mayo Clinic Health System (MCHS) sites in Albert Lea, MN (65 miles to Hub), Eau Claire, WI (96 miles to hub), La Crosse, WI (73 miles to Hub), and Mankato, MN (84 miles to Hub). Methods: Two models were deployed; the full activation model where clinical trials were fully opened at MCHS sites, and the hybrid model where clinical trial participants are consented at the Hub and portions of participant care are conducted at MCHS sites. Initial barriers included limitations in clinical trials support staff, insufficient specimen processing equipment, medication storage and shipping limitations, MCHS catchment population unalignment with the Hub trials portfolio, and reduced bandwidth of providers due to patient care responsibilities. To address barriers to trial conduct, community center site champions were identified to streamline trial review and increase collaboration to better define site catchment areas, trial constraints, and site needs. A feasibility specialist was hired to support the program in trial design/implementation, barrier tracking, and to serve as a liaison between community site providers, study staff, and the program. Results: Since 2021, 20 clinical studies including 14 interventional treatment trials have been activated demonstrating 108 total patients accrued with 42 interventional accruals; 5 within the full activation model (13 accruals) and 15 in the hybrid model (29 accruals). Patients showed an average of 216 miles, with an estimated mileage cost of $142/trip based on the 2023 IRS mileage rate of $0.655/mile to the hub location. Nine of those patients traveled over 260 miles, with an estimated mileage cost of $170/visit to access clinical trials. Under the hybrid model, 8 patients transitioned portions of their care to their home city resulting in reduction of an average of 155 miles/visit, and 7 patients were able to reduce their travel time an average of 216 miles/visit. By estimating at least 10 study visits, the travel burden was reduced by 2,160 miles (4320 driving hours) and $1,420 in driving costs alone for participants. Using participant averages the 108 patients would spend a total of $15,336 in travel costs for just the initial visit, but when factoring in the 10-visit estimate, travel reduction could result in a net savings of $153,360. Based on travel data, it is estimated 11 of these patients would have required overnight accommodation using an average of $149/night hotel stay, a savings of $1,490/patient is estimated for the lifecycle of trial participation or $16,390 for the 11-patient cohort requiring accommodation. These results do not include travel companion and time off work costs. Efforts have been made to further develop the full activation model and 5 clinical trials are in activation. Data gathered from the program is being used to design strategies to reduce the administrative burden of clinical trial participation for community providers and launch screening programs. Conclusion: The Mayo Clinic LLS IMPACT program has demonstrated success in addressing barriers to opening clinical trials in the community-center setting and reduced the travel burden and financial impact to clinical trial participation in a cohort of trial participants. Centralized hub support of study activation and conduct and decentralized care to support treatment of patients in proximity of their home can be extended to other hospital systems and settings.

Background Mantle cell lymphoma (MCL) is more common in males, with a male to female ratio of approximately 3:1. However, it is unclear whether disease characteristics and survival outcomes differ by sex. Additionally, the impact of race and ethnicity in MCL is understudied due to underrepresentation of minorities in clinical studies and trials. In this study, we utilized the National Cancer Database (NCDB) to examine patient and disease characteristics and survival outcomes of MCL by sex, race and ethnicity. Methods Patients diagnosed with MCL in 2004-2020 were identified from NCDB. Patient and disease characteristics were compared between groups using Chi-squared tests. Overall survival (OS) analysis was performed using the Kaplan-Meier method and the Cox proportional hazards model. Results A total of 35,135 patients was included. The median follow-up was 83.0 months (95% CI 81.9-84.1). 24,980 (71.1%) patients were male and 10,155 (28.9%) were female. Females had more elderly (age ≥65: 65.9% vs 59.0%; p&lt;0.001), lower Charlson-Deyo Score (CDS ≥2: 7.0% vs 8.6%; p&lt;0.001) and fewer stage III-IV diagnoses (80.5% vs 82.6%; p&lt;0.001). Females were less likely to receive upfront treatment (80.7% vs 85.3%; p&lt;0.001), treatment at academic centers (36.8% vs 40.9%; p&lt;0.001) or transplant (11.0% vs 13.7%; p&lt;0.001). Compared to males, females were more likely to live in metropolitan areas (83.7% vs 81.6%; p&lt;0.001), had similar incomes, had more Medicare (60.4% vs 53.1%) and fewer private insurance (33.2% vs 38.6%; p&lt;0.001). Female patients had better OS, with a median OS of 76.0 (95% CI 72.4-79.6) vs 67.8 months (95% CI 65.9-69.6; p&lt;0.001). In the multivariable Cox model adjusting for age, race, ethnicity, CDS, stage, upfront treatment (vs surveillance or no treatment), facility (academic vs nonacademic), transplant, residence (metropolitan vs urban or rural) and insurance, female sex remained associated with superior OS (HR 0.84, 95% CI 0.793-0.890; p&lt;0.001). For race, 32,399 (92.2%) patients were White, 1,465 (4.2%) were Black, 942 (2.7%) were others and 329 (0.9%) were unknown. Compared to White patients, Black patients had fewer elderly (52.9% vs 61.7%; p&lt;0.001), higher CDS (≥2: 11.4% vs 7.9%; p&lt;0.001), similar stage III-IV (80.7% vs 82.1%; p=0.276) and upfront treatment (84.7% vs 84.0%; p=0.074), were more likely to be treated at academic centers (50.6% vs 38.9%; p&lt;0.001), were less likely to receive transplant (11.1% vs 13.0%; p=0.042), were more likely to live in metropolitan areas (91.0% vs 81.5%; p&lt;0.001), had lower income, had more uninsured (4.4% vs 2.0%) and Medicaid (9.8% vs 3.7%) and fewer Medicare (47.4% vs 56.0%; p&lt;0.001). Black and White patients had similar OS, with a median of 67.9 (95% CI 57.5-78.2) vs 69.6 months (95% CI 67.8 vs 71.3; p=0.697). In the multivariable Cox model, Black vs White race was not associated with OS (HR 1.086, 95% CI 0.952-1.240; p=0.219). For ethnicity, 31,717 (90.3%) patients were non-Hispanic, 1,894 (5.4%) were Hispanic and 1,534 (4.3%) were unknown. Hispanics had fewer elderly (51.3% vs 61.5%; p&lt;0.001), lower CDS (≥2: 6.4% vs 8.2%; p=0.018), similar stage III-IV (81.2% vs 82.1%; p=0.467), were more likely to receive upfront treatment (86.0% vs 83.9%; p&lt;0.001), more likely to be treated at academic centers (49.9% vs 39.5%; p&lt;0.001), equally likely to receive transplant (13.0% vs 13.1%; p=0.943), more likely to live in metropolitan areas (95.4% vs 81.6%; p&lt;0.001), had lower income, had more uninsured (9.6% vs 1.8%) and Medicaid (15.2% vs 9.6%) and fewer Medicare (40.3% vs 55.9%; p&lt;0.001). Hispanics had better OS, with a median OS of 84.4 (95% CI 71.7-97.1) vs 70.5 months (95% CI 68.7-72.2; p&lt;0.001). However, in the multivariable Cox model, Hispanic ethnicity was not associated with OS (HR 0.952, 95% CI 0.839-1.080; p=0.448). Conclusion This study is the first of its scale to demonstrate that female MCL patients have superior survival outcomes compared to males. It also demonstrated that neither Black race nor Hispanic ethnicity appears to be associated with worse survival outcomes. Despite its size, the NCDB is limited in the treatment information and disease characteristics it provides, including MIPI score, Ki-67, blastoid/pleomorphic morphology, and TP53 status. Thus, additional real-world dataset studies are needed to gain a deeper understanding of potential differences in sex, race and ethnicity with regards to disease characteristics and survival outcomes.

Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN), further categorized as MD (WBC &lt; 13 x 109/L) and MP (≥ 13 x 109/L) subtypes with an inherent risk for AML transformation (Am J Hematol 2024; 99: 1142). Hypomethylating agents (HMA), decitabine (DAC) and azacitidine, are the only FDA approved agents for the management of CMML, with complete remission rates of &lt;20%, and a recent prospective study showing no event free survival benefit of DAC over hydroxyurea in MP-CMML (J Clin Oncol 2023; 41: 1888). TET2 mutations (TET2MT) occur in approximately 60% of CMML cases. TET2 converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), resulting in DNA demethylation (Nat Rev Gen 2017; 18: 517). IV ascorbic acid (AA) at pharmacologic concentrations demonstrates anti-cancer activity via H2O2-induced oxidative stress and DNA demethylation mediated by TET-activation. AA, a cofactor of TET2, binds to its catalytic domain, restores, and enhances TET1/2/3 activity. Given the synergistic impact of IV AA and HMA on DNA methylation, we designed a phase II clinical trial testing the safety and efficacy of standard dose decitabine and high dose IV AA in HMA-naïve CMML patients. Methods: LS1781 (NCT03418038) is an investigator-initiated, prospective, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of high-dose IV AA in combination with DAC for patients with TET2MT CMML. DAC 20 mg/m2 Days 1-5 of each 28-day cycle is given as standard of care. With each cycle, IV AA (1g/kg, maximum 100g) is given 3 times on Days 1, 3, 5 via central line within 2 hours after DAC. Patients are encouraged to take oral AA 1000 mg once daily on non-treatment days. The primary endpoint is overall response rate determined by IWG MDS/MPN 2015 criteria after 4 cycles of therapy. Secondary endpoints include safety and side effects. Exploratory endpoints include the impact of AA on TET2MT variant allele fraction, plasma cytokine levels, DNA methylation and hydroxymethylation (as measured by Infinium MethylationEPIC array), and hematopoietic progenitor colony forming assay assessment (colony counts and impact on differentiation). Inclusion criteria include patients ≥ 18 years with TET2MT CMML, ≤1 cycle of HMA or ESA (hydroxyurea allowed), platelets ≥ 20,000/m3, ANC ≥ 500/mm3, and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Twenty-three patients will be enrolled at Mayo Clinic Rochester and the Mayo Clinic Health System, based on power calculations to demonstrate enhanced complete response and overall response rates, in comparison to those seen historically with decitabine alone. Dose modifications have been established and will be considered based on adverse events. Treatment will be discontinued for disease progression or in the event of ≥ Grade 3 adverse events that do not resolve promptly. After completion of up to 12 cycles, patients with stable disease or better may continue single agent DAC with or without oral AA. Enrollment to the trial began in February 2024, with 2 patients enrolled at the time of abstract submission.