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Abstract Introduction: Elranatamab (Elra) is a bispecific antibody (BsAb) targeting BCMA that is approved for patients with triple class exposed relapsed refractory myeloma (RRMM) on the basis of the MagnetisMM-3 phase 2 trial. For BCMA naïve patients, an overall response rate (ORR) of 61.0% and median progression free survival (PFS) of 17.2m was observed with a median overall survival (OS) of 24.6m. However, efficacy and safety information in the real world is lacking. Methods: This was an international retrospective study of patients with RRMM treated with Elra monotherapy outside of clinical trials. Data was collected through the International Myeloma Foundation Immunotherapy Database from 7 countries (UK, USA, Canada, Greece, Spain, Czech Republic and Singapore). High-risk cytogenetic abnormalities (HRCA) were defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (range). PFS, OS were evaluated using the Kaplan-Meier method and reported with 95% confidence intervals. Results: 79 patients were included. Median age was 67 years (range: 41-95y) with 20% ≥75 years. Racial distribution was: 75% White, 16% Black/African American, 8% Asian/Pacific. 55% were ECOG performance status (PS) 1-2. Patients received a median of 5 prior lines (range 1-11), and 35% were BCMA exposed (9% CAR-T, 5% ADC, 7% BsAb, 8% BsAb plus CAR-T, 4% ADC plus BsAb). Of those with available data, 45% had HRCA,13% had extramedullary disease (EMD) and 32% had penta-drug refractory RRMM. Overall, 48% would not have been eligible for the MagnetisMM-3 trial. Median follow-up was 6.3m (range 0.5-35.0). ORR was 53% (PR 11%, VGPR 33%, CR 8%, sCR 1%) and 67% for BCMA naïve patients. Responses were significantly lower for BCMA exposed patients (ORR 31%) but did not differ by age (51% <75yrs vs 60% ≥75yrs). On univariate analysis, prior BCMA exposure, platelets <50, presence of HRCA and penta-refractoriness were significantly associated with a lower response rate. PFS for the whole cohort at 6 and 12m was 64% (95%CI, 54-77%) and 52% (40-67%); for BCMA naïve patients, it was 77% (65-90%) and 67% (54-84%), respectively. Within the whole cohort, PFS was shorter for: BCMA exposed (median 4.0m vs not reached (NR)), platelets <50 (2.0 vs 21.7m), HRCA (7.2m vs NR), penta-refractory (4.3m vs NR). PFS did not differ significantly by EMD, PS, age, or creatinine clearance. OS for the whole cohort at 6 and12m was 74% (64-85%) and 58% (45-74%); for BCMA-naïve patients, it was 80% (43-85%) and 70% (57-87%), respectively. Within the whole cohort, OS was shorter for: BCMA exposed (median 10.3m vs NR), platelets <50 (4.3m vs NR), HRCA (10.7m vs NR) and penta-refractory (10.3m vs NR). Univariate regression analysis demonstrated that prior BCMA exposure, platelets <50 and penta-refractoriness were significantly associated with a worse PFS and OS, and HRCA predicted poorer survival CRS was observed in 41% of patients (grade(G)1: 35%, G2: 5%, ≥G3: 0%) with most occurring with the first step up dose (SUD): SUD1: 29%, SUD2: 15%, full dose: 4%. Tocilizumab was used in 20% and steroids in 3%. ICANS was observed in 4 cases (5%): G1: 2, G2: 1, G4: 1. Treatment was with steroids (n=3) and tocilizumab (n=2). G3-4 thrombocytopenia was observed in 19% and 14% required platelet transfusions. G3-4 neutropenia occurred in 25% with overall 31% requiring GCSF. Infections were reported in 33 (42%) patients with median time to infection of 41 days. A total of 94 infection episodes were observed over 581 personal months. There were 2 infection-related deaths reported (1 had IVIG, 1 did not). 64% had hypogammaglobulinemia (IgG < 400mg/dl) and IVIG was given in 65% of patients. Conclusions: In this first international real world analysis, Elranatamab achieved a response rate of 67% and a 12m PFS of 67% in BCMA naïve patients, similar to the MagnetisMM-3 trial despite almost half not meeting trial eligibility. However, prior BCMA exposure, platelets <50, high risk cytogenetics and penta refractory status were predictors of poorer outcomes. Acknowledgements: The International Myeloma Foundation, International Myeloma Working Group (IMWG)

Abstract Background: Plasmacytoid dendritic cell-associated acute myeloid leukemia (pDC-AML) is an emerging, rare subtype of AML characterized by the clonal proliferation of plasmacytoid dendritic cells (pDCs) at various stages of maturation. Although infrequent, this leukemia subtype is clinically aggressive and poses significant diagnostic and therapeutic challenges. Objective: This review synthesizes current knowledge on the immunophenotypic, genetic, and clinical features of pDC-AML, explores its prognostic implications, and compares it with the related entity blastic plasmacytoid dendritic cell neoplasm (BPDCN). Methods: A comprehensive literature search was conducted using databases including PubMed, Scopus, and Web of Science. Studies describing the morphology, immunophenotype, cytogenetics, molecular alterations, clinical presentation, and treatment outcomes of pDC-AML were included. Data were extracted and compiled from 16 studies encompassing 231 patients. Results: pDC-AML predominantly affects older adults (median age ~69 years) and exhibits a male predominance (~68%). It presents with diverse AML subtypes, including AML with monocytic differentiation, minimal differentiation, and secondary AML. Bone marrow pDCs range from 2.2% to 30% and exhibit variable maturation, often expressing CD123, CD303, CD304, and variably CD34 and CD117. In contrast to BPDCN, CD56 is rarely expressed, and skin or lymph node involvement is uncommon. Genetically, pDC-AML exhibits a complex landscape. RUNX1 mutations are the most common (14–78%), possibly driving pDC lineage commitment. Additional mutations include ASXL1, DNMT3A, SRSF2, FLT3, and BCOR. Chromosomal abnormalities such as chromosome 7 deletions, trisomy 13, and MLL or CBFA rearrangements are frequently observed. Compared to BPDCN—which shows high CD56 and TCL1 expression and more frequent TET2 mutations—pDC-AML is more genetically and phenotypically heterogeneous. Therapeutic responses are inconsistent. Treatments include induction chemotherapy, hypomethylating agents (e.g., azacytidine plus venetoclax), and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Median overall survival ranges from 9.6 to 20 months, with frequent relapse even post-HSCT. Emerging therapies targeting CD123 (e.g., tagraxofusp) and immune-modulating agents are under investigation. Conclusion: pDC-AML is a clinically aggressive and biologically distinct AML subtype defined by clonal pDC expansion, frequent RUNX1 mutations, and suboptimal responses to current therapies. Accurate diagnosis relies on integrated immunophenotypic and genetic profiling. Despite progress, patient outcomes remain poor, underscoring the need for improved classification, prognostic markers, and targeted therapeutic strategies.

Abstract Background: Leukemia, a type of cancer of the blood forming tissues, compromises the immune system putting the body at risk of aggressive infections like septicemia. This can not only progress to septic shock but also death. The occurrence of the two conditions makes it almost necessary to understand the epidemiological patterns to increase the rates of survival. This study assesses the trends in mortality in patients with leukemia and septicemia in the United States from 1999-2023. Methods : We analyzed death certificates of adults aged 5 to 84 years' from the CDC-WONDER database with Leukemia (ICD-10 codes: C91, C92) and Septicemia (ICD-10 codes: A40, A41) from 1999-2023. Age-adjusted mortality rates (AAMR) per 100,000 population were stratified by gender, race, census region, year and age. Join-Point analysis was performed to estimate annual percent change (APC) and average annual percent change (AAPC) in mortality trends, along with 95% confidence intervals (CIs). Results : Between 1999 and 2023, Leukemia and Septicemia caused 56,497 deaths in patients aged 5 to 84 years. The total AAMR decreased from 0.78 in 1999 to 0.66 in 2023. Demographically, AAMR among the men decreased significantly from 1.04 to 0.85 (AAPC: -0.65; 95% CI: -0.80 to -0.49). Females experienced a decline in mortality from 0.59 to 0.46(AAPC: -0.44; 95% CI: -0.71 to -0.17). In terms of race, a slight decrease in mortality was witnessed in the mortality of Non-Hispanic (NH) Black or African Americans from 0.91 to 0.7 (AAPC:-1.13 ; 95% CI: -1.43 to -0.82), moreover the AAMR in the Hispanics decreased from 0.8 to 0.63 (AAPC: -0.04; 95% CI: -0.04 to -0.58) while those among the white community decreased from 0.78 to 0.68 (AAPC: -0.39; 95% CI: -0.58 to -0.19). Moreover, the Asian community also experienced a declining death rate. Geographically, regions in the Midwest showed the highest overall AAMR (0.75), followed by the West,Northeast and areas in the South with an overall AAMR of 0.72 . Between the urban and rural areas, rural areas had a higher AAMR as compared to the urban areas with an overall AAMR of 0.17. When stratified according to states, AAMRs varied highly from the highest in Kentucky (0.89) to the lowest in Maine(0.26). Conclusion: The overall mortality rates for leukemia and septicemia decreased between the years 1999-2023. The greatest change was seen in males, regions in the Northeast, racially in NH Blacks and the rural areas.

Abstract Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders often complicated by infections due to cytopenias. Sepsis is a frequent cause of hospitalization and mortality in MDS patients. Neutropenia, a common feature in MDS, may predispose patients to specific infectious complications, but its impact on sepsis-related outcomes remains poorly characterized. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (NIS) database from 2016 to 2022. Adult hospitalizations with co-diagnoses of MDS and sepsis were identified using ICD-10-CM codes. Patients were stratified based on the presence or absence of neutropenia. Multivariable logistic regression models were used to evaluate the association between neutropenia and specific in-hospital outcomes, including Clostridioides difficile infection, fungal sepsis, and disseminated intravascular coagulation (DIC). Models were adjusted for age, sex, comorbidities, hospital characteristics, and illness severity. Results: A total of 78,549 hospitalizations involving MDS patients with sepsis were identified, including 11,295 (14.4%) with neutropenia. Neutropenic patients had significantly higher odds of C. difficile infection (adjusted odds ratio [aOR] 1.61, 95% CI 1.30–1.99, p < 0.001) and fungal sepsis (aOR 2.08, 95% CI 1.22–3.54, p = 0.007) compared to those without neutropenia. However, neutropenia was not significantly associated with DIC (aOR 0.84, 95% CI 0.59–1.19, p = 0.322). Conclusion: In this large national cohort, neutropenia was associated with a significantly increased risk of C. difficile infection and fungal sepsis among MDS patients hospitalized with sepsis. These findings highlight the need for early recognition and targeted antimicrobial strategies in neutropenic MDS patients. No significant association was observed between neutropenia and DIC. Future studies should explore preventive strategies and risk stratification tools tailored to this high-risk population. Keywords: Myelodysplastic syndromes, neutropenia, sepsis, NIS, Clostridioides difficile, fungal sepsis, outcomes

Abstract Background: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and an increased susceptibility to infections. Sepsis remains a common and serious cause of morbidity and mortality in this population. While racial disparities in sepsis-related outcomes have been described in the general population, their presence and magnitude among patients with MDS remain poorly understood. Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) from 2016 to 2022 to identify adult hospitalizations with co-diagnoses of MDS and sepsis. Patients were stratified by race into White (reference), Black, Hispanic, Asian, Native American, and Other categories. Multivariable logistic regression models, adjusted for demographics, comorbidities, and hospital characteristics, were used to evaluate associations between race and seven key sepsis-related complications: septic shock, acute renal failure, respiratory failure, encephalopathy, disseminated intravascular coagulation (DIC), Clostridioides difficile infection (CDI), and fungal sepsis. Results: Among 78,549 hospitalizations for MDS with sepsis, significant racial disparities were observed. Asian patients had higher odds of developing septic shock (OR 1.26, 95% CI 1.05–1.50, p = 0.014), and both Black (OR 1.24, 95% CI 1.17–1.31, p < 0.001) and Asian (OR 1.14, 95% CI 1.04–1.24, p = 0.004) patients had increased odds of acute renal failure. Respiratory failure was less likely among Black (OR 0.84, 95% CI 0.79–0.90, p < 0.001) and Hispanic (OR 0.76, 95% CI 0.70–0.82, p < 0.001) patients. Encephalopathy was significantly more common in Black (OR 1.29, 95% CI 1.18–1.41, p < 0.001) and Other (OR 1.20, 95% CI 1.01–1.42, p = 0.042) patients. DIC was more frequent in Asian (OR 2.11, 95% CI 1.37–3.27, p = 0.001) and Hispanic (OR 1.53, 95% CI 1.09–2.14, p = 0.014) patients, with a borderline association in Black patients (OR 1.35, p = 0.082). No statistically significant racial differences were noted for CDI or fungal sepsis, although Asian patients trended toward lower odds of CDI (OR 0.64, p = 0.067), and Native American patients had high but non-significant odds for fungal sepsis (OR 3.03, p = 0.287). Conclusion: Our study highlights significant racial disparities in sepsis-related complications among hospitalized MDS patients. Black and Asian patients were more likely to experience acute renal failure and encephalopathy, while Asian and Hispanic patients had higher odds of developing DIC. Conversely, Black and Hispanic patients had lower risk of respiratory failure. These findings underscore the need for race-conscious approaches in sepsis management for patients with MDS and suggest that tailored interventions may be necessary to ensure equitable outcomes across racial groups. Keywords: Myelodysplastic syndromes, sepsis, racial disparities, acute kidney injury, encephalopathy, DIC, respiratory failure, fungal sepsis, National Inpatient Sample

Abstract Background: Despite advances in LBCL treatment, 35–45% of patients relapse or have refractory disease highlighting an unmet clinical need. Clinical trials are essential to advancing lymphoma treatment, yet participation remains low – especially among certain populations. We hypothesized that participation in clinical trials as part of first-line therapy is associated with improved survival outcomes and conducted this retrospective study in a multi-center cohort. Methods: The LEO cohort prospectively enrolled newly diagnosed patients with LBCL between 2015 and 2020 at 8 academic medical centers in the United States. LBCL histology's included T-cell/histiocyte rich LBCL, Primary mediastinal LBCL, high grade B-cell lymphoma and DLBCL NOS. Pathology was reviewed and classified by a LEO pathologist. Clinical and treatment data (including trial participation) were abstracted from medical records. The primary outcome endpoint is overall survival (OS) defines as the time from diagnosis to death from any cause or last follow up. Univariable and multivariable Cox proportional hazards models were used to evaluate the association between OS and therapeutic trial participation. Univariable models assessed each baseline covariate, with and without interaction with trial participation. The multivariable model adjusted for age, sex, race/ethnicity, diagnosis to treatment interval [DTI], and IPI, including an interaction between IPI and trial participation which was justified per minimal Akaike information criteria. All models clustered on institution. Results: Among the 2636 patients with LBCL, the median age was 63 (range 18 – 99), 57% were male, 75% non-Hispanic white (NHW), 12% Hispanic (H) and 7.3% African American (AA), 62% had Stage III/IV disease, and 214 (8.0%) participated in a clinical trial as part of first line therapy. Overall, between ages 18 – 80, clinical trial participation increased with age (55 % in ages 18-30 vs 11% in ages 71-80) but dropped significantly for patients > 80 (3.4%). There were no significant differences in the rate of trial participation by sex (male 8.6 % vs female 7.5%; p=0.35), race/ethnicity (NHW 8.9% vs H 5.5% vs AA 6.3%; p=0.061), body mass index (underweight [<18.5] 4.5% vs normal [18.5-24.9] 7.7% vs overweight [25-29] 8.3% vs obese (>30) 8.5; p = 0.75) or Rural-Urban Continuum Codes (Metro[1-3] 8.5% vs non-metro Urban [4-6] 7.6% vs non-metro Rural [7-9] 5.4 %; p=0.49). Patients with advanced disease more commonly participated in a trial. Most patients received systemic treatment (98%), with 94% of patients receiving an anti-CD20 antibody and 91% of patients receiving anthracycline-based therapy. Importantly, there was no difference in anthracycline use in trial participants vs nonparticipants (92 vs 91%; p=0.53). Patients with high IPI scores [3-5] were more likely to participate on trials compared to those with low scores [1-2] (8% vs 5.9% respectively, p= 0.012). Patients who participated in clinical trials had significantly longer median DTI (26 days vs 21 days; p <0.0001) and had a significantly lower number of comorbidities compared to non-participants (mean 0.55 vs. 0.69; p=0.032). Among patients with low IPI (0–2), 5-year OS was 89% trial participants (CTP) compared to 82% for non-participants (CTNP). Among patients with high IPI (3–5), 5-year OS was 78% for CTP vs 60%for CTNP. The multivariable Cox model demonstrated a significant interaction between trial participation and IPI, with trial participation with low IPI having a non-significant hazard ratio (HR) of 0.87 with 95% CI (0.57,1.32), while trial participation with high IPI had a significant HR of 0.57 (0.44, 0.74). Additionally, increased age, male sex, black race, and lower DTI were associated with increased hazard. Conclusion: Patients at high risk of poor outcomes such as those with advanced age (80+), higher comorbidities burden, and those needing more urgent therapy (shorter DTI) were less likely to participate in clinical trials. In this multi-institutional cohort of patients with LBCL treated at academic centers, frontline trial participants had outcomes that were equivalent or better than those receiving standard care. These finding underscore the value of clinical trial participation even in the frontline setting and support trial designs that expand inclusion- allowing participation of patients who are older, medically complex or in need urgent therapy.

Abstract Introduction: THRLBCL is a rare disease accounting for less than 10% of all diffuse large B-cell lymphoma (DLBCL) subtypes. THRLBCL was associated with poor outcomes in the pre-rituximab era, with limited contemporaneous data. Optimal frontline treatment remains unclear with some studies advocating for intensive regimens. The goal of this international study is to analyze the survival and treatment-related outcomes in patients with newly diagnosed THRLBCL treated with rituximab-containing chemotherapy and to compare with a DLBCL, not otherwise specified (NOS) cohort. Methods: THRLBCL and DLBCL patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) (NCT02736357) (7/2015 to 5/2020), Molecular Epidemiology Resource (1/2010 to 6/2015), and Czech Lymphoma Study Group project (NiHiL) (NCT03199066) (2/2010 to 11/2023) were analyzed. Diagnosis was made in dedicated hematopathology centers in both registries. We excluded patients with prior nodular lymphocyte-predominant Hodgkin lymphoma, central nervous system involvement, and not treated with rituximab-containing therapy. Event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier.Univariate associations were derived via Cox model and multivariate models were constructed by forward selection of significant variables with P≤0.05. Propensity score matching (1:5, caliper 0.2) between THRLBCL and DLBCL NOS patients was performed using IPI score components and treatment as covariates. Results: We identified 158 patients (LEO: 67 and NiHiL: 91) with THRLBCL. Among them, 140 patients received rituximab-containing regimens and were included in this analysis. Median age was 58 years (range, 19-89) with 57% aged ≤60 years. Most patients were male (n= 88; 63%) and had ECOG performance status (PS) of 0-1 (n= 111; 79%), stage III-IV (n= 111; 79%), elevated LDH (n= 92; 66%), and B symptoms (n= 84; 60%). Fifty (36%) patients had ≥2 extranodal (EN) sites, mostly liver (n= 39; 28%) and lung (n= 16; 11%), bone marrow (BM) involvement was observed in 26% (n= 37). Bulky disease (≥7.5cm) was present in 50 (36%) and IPI score ≥3 in 68 (48%) patients. The median diagnosis-to-treatment interval was 23 days (IQ range, 13-38.5). Frequent regimens were R-CHOP (n= 106; 75.7%), followed by intensive regimens such as R-MegaCHOP/ESHAP, R-HyperCVAD/MA, and R-CODOX-M/IVAC (n= 15; 10.7%), and R-CHOEP/EPOCH-R (n= 10; 7.14%). With a median follow-up of 3.92 years, the 4-year EFS & OS were 71% and 80%, respectively. Lymphoma was the main cause of death (n= 15; 11%) among 30 events. No difference in 4-year EFS (70% vs. 76%; P= 0.55) & OS (80% vs 82%; P= 0.96) were observed between R-CHOP and intensive regimens. Factors associated with shorter EFS and OS in univariate analysis for THRLBCL were ECOG PS 2-4: (HR= 3.3; P<.001 & HR= 5.97, P<.001, respectively); ≥2 EN sites (HR= 1.85, P= 0.043 & HR= 2.54, P= 0.014, respectively); B symptoms (HR= 2.35, P= 0.014 & HR= 2.84, P= 0.023) and IPI score (HR= 1.5, P= 0.002 & HR= 2.16, P<.001). Stage III-IV and BM involvement were associated with shorter OS only (HR= 7.36, P= 0.05 & HR= 2.18, P= 0.036, respectively). Among them, only ECOG PS 2-4 (OS: HR= 3.6, P= 0.003) and B symptoms (EFS: HR= 2.3, P= 0.046) were independent predictors of survival in multivariate analysis. Finally, we compared baseline characteristics and survival between THRLBCL (n= 140) and DLBCL NOS (n= 6099; LEO/MER: 2069 & NiHiL: 4030) treated with rituximab-containing regimens. Patients with THRLBCL were younger (≤60 years: 57% vs. 38%; P<.001), more frequently had ECOG PS 0-1 (79% vs 76%; P= 0.012), stage III-IV (79% vs 63%; P<.001), B symptoms (60% vs 38%; P<.001), and liver involvement (28% vs 7%; P<.001), compared to DLBCL NOS. Subtype was not associated with survival (OS HR= 0.79, P= 0.262 & EFS HR= 0.93, P= 0.662) when adjusted for IPI score. With a median follow-up of 4.89 years in the DLBCL NOS cohort, we observed similar 4-year EFS (71% vs 67%; P= 0.197) & OS between histologies (80% vs 77%; P= 0.125). These results were confirmed in propensity matching for EFS (HR= 0.98, P= 0.897) and OS (HR= 1.07, P= 0.732). Conclusions: In this large international analysis of patients with newly diagnosed THRLBCL contemporaneously treated, we observed similar survival rates compared to DLBCL NOS treated with R-CHOP and intensive regimens. ECOG PS and the presence of B symptoms were independent factors associated with survival.

Abstract Background: Curative therapy for primary central nervous system lymphoma (PCNSL) consists of methotrexate-based induction therapy followed by high-dose chemotherapy consolidation. There is no standard of care for patients unfit for dose-intensive consolidation, leaving these patients at high risk of relapse. Median progression-free survival (PFS) is as low as 7-12 months from the time of induction in newly diagnosed patients treated with methotrexate-based regimens without consolidation (Batchelor et al. J Clin Oncol 2003; Omuro et al. Lancet Haematol 2015). Patients with relapsed disease also have dismal outcomes. Lenalidomide is an immunomodulatory drug (IMiD) with single-agent activity in relapsed and refractory PCNSL. We have previously published our experience with 13 patients receiving low-dose lenalidomide for maintenance of remission in PCNSL (Vu et al. Br J Haematol 2019). Here, we report long-term follow up data from an expanded cohort. Methods: We evaluated low-dose lenalidomide maintenance at a starting dose of 5 mg/day in two cohorts: (1) patients in complete remission after methotrexate-based induction and (2) patients in complete or partial remission after salvage therapy upon first relapse. Patients with PCNSL treated with methotrexate-based induction and subsequently treated with maintenance lenalidomide at a starting dose of 5 mg/day at UCSF between Jan 2011 – Jun 2025 were eligible for inclusion. Retrospective chart review was performed. Cox proportional hazards model was used for survival analysis. Results: A total of 89 patients treated with lenalidomide maintenance were identified. We first evaluated outcomes for 39 patients who did not receive dose-intensive consolidation and were treated with lenalidomide maintenance following first-line methotrexate-based induction. 64% were ineligible for consolidation chemotherapy due to age (>74), 18% due to performance status/co-morbidities, and 18% declined consolidation. Median age at diagnosis was 76 (range: 57-86). 20 patients were male and 19 female. Median International Extranodal Lymphoma Study Group score at diagnosis was 3 (range: 1-4) and median Karnofsky Performance Status was 80 (range: 50-100). With median follow up of 73.9 months, median PFS was 38.5 months from the start of lenalidomide maintenance, and median overall survival (OS) was 64.5 months. 59% of these patients have not relapsed. We next evaluated outcomes for 50 patients treated with lenalidomide maintenance after salvage therapy: methotrexate + rituximab (52%), focal XRT (20%), intraocular therapy (14%), dose-intensive etoposide + cytarabine (8%), ASCT (2%), and WBRT (2%). With median follow up of 91.4 months, median PFS was 13.4 months from the start of lenalidomide maintenance, and median OS was 43.9 months. 30% of these patients have not relapsed. Low-dose lenalidomide was well tolerated, with adverse events consistent with the drug's known toxicity profile. Common toxicities included fatigue, rash, constipation, and mild myelosuppression. One patient experienced reversible bradykinesia and there was one pulmonary embolism. There were no episodes of febrile neutropenia. None of the patients treated with lenalidomide have yet developed a myeloid neoplasm. Strikingly, among 42 patients drawn from both cohorts treated with lenalidomide maintenance who later relapsed, 60% achieved a complete response to the next line of therapy, 26% achieved a partial response, while 14% had refractory disease. 26 patients (62%) went on to receive subsequent IMiD maintenance therapy (27% lenalidomide at doses exceeding 5 mg/day, 73% pomalidomide); median PFS from IMiD re-initiation was 13.3 months. Conclusions: Low-dose lenalidomide maintenance therapy after methotrexate-based induction therapy is an effective strategy for less fit PCNSL patients. Lenalidomide maintenance following salvage therapy likewise demonstrates impressive efficacy, with survival outcomes surpassing published historical values. Low-dose lenalidomide is well-tolerated in both of these settings, with low rates of discontinuation. Importantly, most patients progressing on lenalidomide maintenance achieve remission with salvage therapy and respond to further treatment with IMiDs. While our analysis has limitations including its small sample size and retrospective single-center design, the survival outcomes are encouraging and support further investigations of lenalidomide in PCNSL, including the ongoing Alliance A51901 trial.

Abstract Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network blast phase registry on 240 pts reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we undertook this study through the H Jean Khoury Cure CML Consortium (HJKC3) to describe the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2025 were included. Categorical variables were compared using Chi-square test. Overall survival (OS) was calculated from time of diagnosis of CML BP to death from any cause. Event free survival (EFS) was calculated from date of best response to event (death or relapse). Results: Of the 283 pts with CML-BP, 96 (33.9%) were female and 187 (66.1%) were males. At the time of diagnosis, 183 (64.6%) had CML-CP, 21 (7.4%) pts had CML-AP and 79 (27.9%) pts had de-novo CML-BP. For the 204 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 22.5 months (1-207 months). Median age at diagnosis of CML-BP was 50 years (range 16-86 years). EM disease was present in 78 (27.6%) pts (38 myeloid sarcoma, 30 central nervous system and 10 skin). Blasts were of myeloid phenotype in 168 (59.4%), lymphoid in 103 (36.4%) and mixed in 9 (3.2%) pts. The bcr-abl protein was p210 in 229 (80.9%), p190 in 8 (2.8%) and p230 in 2 (0.7%) pts. ABL kinase domain mutation was seen in 42.1% (80/190) pts, with T315I being the most common (n=32), followed by E255K (n=16). Next generation sequencing was performed in 117 pts. The most common mutations were ASXL1 (n=27), RUNX1 (n=14), BCOR (n=4), DNMT3A (n=4) and BCORL1 (n=3). Of the 283 pts, 269 underwent CML-BP directed therapy. 63 (23.4%) pts were treated with TKI monotherapy, 184 (68.4%) pts were treated with a combination of chemotherapy (chemo) and TKI and 22 (8.2%) pts were treated with chemo alone. Response rate after CML-BP directed therapy was 75.3% (n=213). Best response was return to CML-CP in 49 pts, CHR with PCyR in 18 pts, CCyR in 31 pts, MMR in 31 pts, MR4 in 18 pts, MR4.5 in 19 pts and MR5 in 47 pts. Rate of response with 2G and ponatinib was significantly better than imatinib (85.3% and 77.3% vs 63.6%; p=0.04). 149 (55.4%) pts proceeded to alloSCT. Of the 213 pts that responded, 59 (27.7%) relapsed. At a median follow-up of 47 months, the median OS for all pts was 19.7 months (95% CI: 16.3-40.2 months), with 5-year OS rate of 38% (95% CI: 32-45%). Pts with myeloid phenotype had a significantly lower OS compared to lymphoid and mixed phenotype (Median OS 14.9 vs 45.9 and 31.1 months respectively; p=0.02). OS of pts that were treated with a combination of TKI and chemo was significantly longer compared to pts treated with TKI or chemo alone (52.9 vs 16.1 or 7.5 months; p<0.0001). Dasatinib (n=99; 34.9%) and ponatinib (n=97; 34.3%) were the most used TKIs followed by imatinib (n=23; 8.1%), nilotinib (n=21; 7.4%), bosutinib (n=8; 2.8%) and asciminib (n=3; 1.1%). Pts treated with ponatinib had a numerically longer OS compared to 2G-TKI and imatinib, however this was not statistically significant (40.1 vs 30.6 and 20.3 months; p=0.52). EFS for pts treated with ponatinib was significantly longer compared to 2G-TKI or imatinib (25.9 vs 17.6 and 15.9 months; p=0.03). In a landmark analysis, pts that underwent alloSCT within 6 months of diagnosis had a significantly longer OS compared to those who did not (69.3 vs 16.0 months; p=0.006). Conclusion: CML-BP continues to have poor prognosis. Treatment is heterogenous involving various combinations of TKI and chemo. In our analysis, treatment with 2G-TKI or ponatinib led to better responses. CML-BP with myeloid phenotype had worse OS. Treatment with ponatinib was associated with a numerically longer OS and significantly longer EFS compared to 2G-TKI and imatinib. In addition, treatment with chemo in combination with TKI and alloSCT led to improved OS.

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs <1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC <2000/uL, 13.6% (n=43) had ANC <1500/uL, and 2.5% (n=8) had <1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC <3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC <2000/uL, 38.7% (n=198) had ANC <1500/uL, and 14.4% (n=74) had ANC <1000/uL. For those <1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p<0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.