Roeker, Lindsey E.

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

Abstract Early-phase clinical trials of BTK degraders in relapsed/refractory CLL have shown response rates of over 80%, including in patients with BTK mutations that confer resistance to conventional BTK inhibitors (BTKi). The molecular basis of resistance to BTK degraders is unknown and, given the promise of this class of drugs, would hold implications for therapy sequencing and the design of next-generation BTK degraders. To this end we identified five patients at Memorial Sloan Kettering who developed progressive disease while being treated on the phase 1 trials of zelebrudomide (NCT04830137, 4 patients) or bexobrutideg (NCT05131022, 1 patient). In two patients, one treated with zelebrudomide and the other with bexobrutideg, a pre-existing BTK A428D mutation had expanded at progression, rising from <1.5% at the start of treatment to >25%. In both cases, the increase in frequency of BTK A428D coincided with the loss of BTK degradation in peripheral blood B cells. No mutation in cereblon, the ligase utilized by these BTK degraders, was detected. To validate these clinical findings we generated wild-type and BTK A428D knock-in single-cell clones in TMD8 and HBL1 cells. BTK A428D conferred resistance to BTKi, including ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, as well as the clinical-stage BTK degraders zelebrudomide, bexobrutideg, BGB-16673, and AbbVie-1 (Compound 1, WO 2023183811). BTK A428D’s pan-resistance is unique compared to previously studied BTKi resistance mutations which remain susceptible to at least one BTKi and all clinical-stage BTK degraders tested. To understand how BTK A428D confers pan-resistance to BTKi and BTK degraders we conducted surface plasmon resonance studies which demonstrated that BTKi and all four clinical-stage BTK degraders tested are unable to bind BTK A428D. We next solved the crystal structure of apo BTK A428D to 1.8Å, which revealed that the mutant aspartate, which is larger and negatively charged compared to the wild-type alanine, sterically blocks BTKi and degraders from accessing residues in the hinge region of the kinase that are required for drug binding. We next asked why BTK A428D, despite conferring pan-resistance, has only been detected in 1.1% of patients treated with BTK inhibitors. Intriguingly, we noted that in one of our index patients, the frequency of BTK A428D declined and became undetectable after the withdrawal of zelebrudomide, suggesting a fitness defect. To assess this hypothesis, we compared the proliferation rates of five TMD8 wild-type and five BTK A428D single-cell clones; the BTK A428D clones grew more slowly and were consistently outcompeted in mixing studies. In summary, low-frequency BTK A428D mutations can expand under the selection pressure of BTK degraders and confer clinical resistance by preventing drug binding. The mutation, however, is outcompeted in the absence of BTK-targeted therapies. These findings provide rationale for the investigation of combination therapies and the development of next-generation BTK degraders capable of circumventing BTK A428D. Citation Format: Quinlan Sievers, Hao Lu, Allison Cool, Stefan Grajewski, Tim Kong, Mark Noviski, Xiaoli Mi, Emel Ficici, Ratul Mukerji, James Iuliano, Jordan Ye, Mateo Sanchez Garcia de los Rios, Hugo Bousquet, Sarah Whelan, May Tan, Christopher Phelps, Jahan Raman, Ryan Notti, Lizbeth Mendoza Navarrete, Samantha Sekeres, Eria Lamkin, Eduardo Bravo, Mark Ewalt, Prioty Islam, Anthony Mato, Lindsey Roeker, Justin Taylor, Meghan Thompson, Gwenn Hansen, Omar Abdel-Wahab. BTK A428D is a recurrent pan-resistance mutation to BTK degraders in clinical trials [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr PR004.

Abstract Prognostic indices such as the CLL International Prognostic Index (CLL-IPI) and the International Prognostic Score for Early-stage CLL (IPS-E) can predict time to first treatment (TTFT) in patients with early-stage CLL. Their ability to predict risk of infection - a leading contributor to morbidity and mortality in CLL - remains uncertain. The CLL-TIM is a machine-learning model developed in Europe that integrates clinical, laboratory, and infection-related data to predict TTFT or infection risk within 2-years of diagnosis, Receiver Operating Characteristic - Area Under the Curve (ROC-AUC) 0.74; Agius et al., Nat Comm 11, 363 2020. We conducted the first validation of CLL-TIM in a US cohort of newly diagnosed CLL patients and compared its performance with the CLL-IPI and IPS-E indices. Adults with newly diagnosed CLL (2000-2020) were identified through the Rochester Epidemiology Project using International Classification of Disease (ICD) codes; all diagnoses were confirmed. We replicated the variable selection from the original CLL-TIM model and applied it to our cohort. The primary endpoint was a 2-year composite of either TTFT or incident infection (defined as having blood cultures drawn). Model performance was evaluated using ROC-AUC consistent with the original CLL-TIM methods. CLL-IPI and IPS-E performance was assessed using time-dependent ROC-AUC; pairwise differences in discrimination were tested using DeLong. We identified 454 CLL patients with a median age of 72 years [range, 30-97], 166 (37%) were female, Rai Stage was 0-II in 399 (92%) patients. IGHV genes were unmutated in 130/305 (42%) patients and TP53 disruption (either del17p by FISH or TP53 mutation) was present in 24/329 (8%) patients. At 2-years, 55 (12%) patients received CLL therapy, and 56 (12%) patients had an infection. The 2-year composite endpoint was observed in 94 (21%) patients. The ROC-AUC was 0.74 (95% CI 0.68-0.80) for CLL-TIM, 0.69 for CLL-IPI (95% CI 0.63-0.75, p=0.11 compared to CLL-TIM) , and 0.68 for IPS-E (95% CI 0.62-0.74, p=0.02 compared to CLL-TIM). We also evaluated the ROC-AUC using all the prognostic models for each individual endpoints. The corresponding ROC-AUC for TTFT at 2 years were 0.79, 0.74, and 0.76 for CLL-TIM, CLL-IPI, and IPS-E, respectively; and for infection at 2 years were 0.68, 0.57, and 0.52, respectively. This is the first validation of the CLL-TIM in a US-based cohort of newly diagnosed CLL patients. Although the CLL-TIM model exceeded the minimally meaningful discrimination threshold (AUC >0.7) for individual patient-level risk prediction, there was no statistical difference in AUC between CLL-TIM and CLL-IPI, suggesting either model can predict the composite endpoint at 2 years. Most of the observed discrimination was driven by prediction of TTFT rather than infection, underscoring the need to develop more infection-specific risk models for newly diagnosed CLL. Citation Format: Raphael Mwangi, Tait D. Shanafelt, Soren Basnet, Emily L. West, Owen Keegan, Timothy G. Call, Yao Yuan, Bryan Alexis Vallejo, Paul J. Hampel, Lindsey E. Roeker, Yucai Wang, Saad J. Kenderian, Sara J. Achenbach, Aaron D. Norman, Kari G. Rabe, Neil E. Kay, James R. Cerhan, Curtis A. Hanson, Susan L. Slager, Sameer A. Parikh. Validation of the CLL treatment infection model (CLL-TIM) in patients with newly diagnosed chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4228.

Abstract Background: Hypogammaglobulinemia at the time of CLL diagnosis predicts shorter time to first therapy (TTFT). However, the depth of immunoparesis and its impact on TTFT in newly diagnosed MBL/CLL remains unexplored. Methods: We identified previously untreated MBL/CLL patients from Mayo Clinic CLL Database (2000-2024) who had serum immunoglobulin (Ig; IgG, IgM and IgA) and monoclonal protein assessed within 1 year of diagnosis. Immunoparesis was evaluated: a) qualitatively by classifying patients into preserved, partial and full Ig suppression, based on the number of suppressed Igs; and b) quantitatively by calculating the average relative difference (ARD), defined as the mean percentage below normal for all Igs. For both methods, only uninvolved Igs were considered for those with monoclonal protein. TTFT was estimated by Kaplan-Meier with competing risk of death. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 1420 patients, median age at diagnosis was 65 (range 28-96); 954 (67%) were male; 493 (44.8%) had unmutated IGHV, and 86 (6.8%) had TP53 disruption. The median [range, mg/dL] serum IgG, IgA, and IgM were 889 [111-5290], 132 [1-4880], and 49 [4-9480]. Low IgG was present in 472 (33.2%), low IgA in 223 (16.4%), and low IgM in 530 (37.3%) patients. An M-spike was detected in 122 (8.6%) patients; distribution was: IgG (73), IgM (30), IgA (6), or multiple (13). By qualitative assessment, preserved Ig were seen in 664 (46.8%), partial Ig suppression in 604 (42.5%), and full suppression in 152 (10.7%) patients. By quantitative assessment, median ARD was 0.6 (-0.8 to 11.3); 280 (19.7%) patients had negative ARD, and 1140 (80.3%) had positive ARD. In those with negative ARD, 128 (9%) had partial Ig suppression and 152 (10.7%) had full Ig suppression; in those with positive ARD, 664 (46.8%) had preserved Ig and 476 (33.5%) had partial Ig suppression. Median follow-up was 14.7 years; 510 patients progressed requiring therapy. Median TTFT was 9.6 years. Median TTFT for patients with preserved Ig was 12.6 years, 8.0 years for partial Ig suppression (HR 1.4, 95%CI 1.1-1.7), and 1.8 years for full Ig suppression (HR 3.1, 95%CI 2.4-4.0). The median TTFT was 2.3 and 12.1 years for patients with negative vs positive ARD; negative ARD was associated with shorter TTFT (HR 2.4, 95%CI 2.0-2.9). After adjusting for sex and CLL-International Prognostic Index (CLL-IPI) score, full Ig suppression (HR 2.9, 95%CI 2.2-3.9) and partial Ig suppression (HR 1.6, 95% CI 1.3-2.0) were associated with shorter TTFT (model 1, c-stat 0.77); and negative ARD (HR 2.4, 95%CI 2.0-2.9) was associated with shorter TTFT (model 2, c-stat 0.76). Negative ARD identified an additional 9% of patients at higher risk for shorter TTFT beyond full Ig suppression. Conclusions: The depth of immunoparesis at diagnosis predicts TTFT and enhances risk stratification in newly diagnosed MBL/CLL. Citation Format: Yuan Yao, Kari G. Rabe, Eli Muchtar, Paul Hampel, Yucai Wang, Lindsey Roeker, Saad Kenderian, Amber Koehler, Catherine Wagner, Amy Behnken, Jose F. Leis, Mazie Tsang, Talal Hilal, Ricardo Daniel Parrondo, Susan M. Schwager, Min Shi, Curtis A. Hanson, Celine M. Vachon, Shaji Kunnathu Kumar, Esteban Braggio, Neil E. Kay, Susan Slager, Sameer A. Parikh. Depth of immunoparesis predicts time to first therapy in newly diagnosed monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1191.

Abstract Advancements in the understanding of chronic lymphocytic leukemia (CLL) have transformed patient care, leading to the development of novel targeted therapies. Traditionally, patient fitness for treatment was based on the tolerability of chemoimmunotherapy such as fludarabine–cyclophosphamide–rituximab. As the CLL patient population is predominantly older, age has historically been a major factor in how a physician selects a patient's treatment. However, as a patient's fitness goes beyond age, the definition of patient fitness should also evolve. Here, we provide suggestions for the current best practice on assessing fitness for treating CLL. Considerations for treatment include assessment of polypharmacy, history of infections, cardiovascular and renal comorbidities, functional status, cognitive and psychological status, nutritional status, and social support. The flow of assessments can start with a typical clinical evaluation followed by geriatric, cardiovascular, and renal reviews, if needed, and include collecting a patient's full history to evaluate their risk of complications with specific CLL treatments. The severity of a patient's cardiovascular profile can range from low to high risk; for those at high risk, collaboration with a cardiologist is recommended. Geriatric assessment is advised to determine baseline frailty and resilience to tolerate treatments, to avoid inappropriate treatment or undertreating patients based on chronological age, and to align the patient's fitness status with the most optimal treatment. Continuous monitoring and assessment, regardless of therapy, are recommended. Patient preferences are also integral to this decision‐making process. Looking beyond a patient's age and basing treatment selection on their fitness is key in the new era of treatment in CLL.

Abstract BACKGROUND Early disease progression within 24 months following chemoimmunotherapy (CIT) is an established adverse prognostic factor for overall survival (OS) in patients (pts) with indolent non-Hodgkin lymphomas. Initially reported in pts with follicular lymphoma, progression of disease (PD) within 24 months in pts with CLL treated with CIT (occurring in ~1-out-of-4 pts) is also associated with inferior OS. The prognostic utility of early event status in pts with CLL treated with targeted therapies is unknown. Recently, we reported worse than expected outcomes with BCL2 inhibitor (BCL2i) treatments in an international cohort of pts with covalent BTK inhibitor (BTKi)-resistant, CIT-naïve CLL. We hypothesize that early disease progression on first-line (1L) targeted agent treatment will identify additional pts with high-risk disease beyond conventional prognostics in the current era. METHODS We identified pts in the Mayo Clinic CLL Database with the following 1L treatments a) BTKi (+/- anti-CD20 monoclonal antibody [CD20mAb]); b) BCL2i + CD20mAb; c) BTKi + BCL2i +/- CD20mAb. PD was defined by a) new or progressive lymphadenopathy or splenomegaly; and/or b) ≥ 50% increase from nadir absolute lymphocyte count (ALC) with persistent (>2 months), and otherwise unexplained ALC ≥ 10x109/L; and/or c) Richter transformation. Logistic regression model evaluated association between clinical factors and POD36 status. OS in pts with PD within 36 months of 1L start (POD36) was evaluated and compared to those without early PD (non-POD36) with analyses: a) starting from time of PD (POD36) and starting from 3 years after 1L initiation (non-POD36); and b) Kaplan-Meier landmark analysis amongst pts alive 3 years post 1L initiation. Cox regression analyses compared a) OS from POD36 by groups and b) OS from 1L treatment with POD36 as a time-dependent covariate. RESULTS A total of 787 pts with CLL initiated 1L targeted therapy (n=538 [68%] BTKi +/- CD20mAb; n=151 [19%] BCL2i + CD20mAb; n=98 [13%] BTKi + BCL2i +/- CD20mAb. The median age at 1L start was 67 years (range 26-92 years), and 67% of pts were male. Among pts with complete CLL-IPI data (n=519), 44% and 15% had high- and very high-risk CLL-IPI risk scores, respectively. Specific pre-1L treatment disease characteristics included TP53 disruption (del17p or TP53 mutation) in 120/639 (19%), del11q in 103/634 (16%), unmutated IGHV in 406/591 (69%), complex karyotype (≥3 clonal structural or numerical abnormalities on karyotype) in 70/273 (26%), and positive CD49d expression in 229/449 (46%). The median pre-treatment beta-2-microglobulin level was 3.3 mcg/mL (range 1.2-24.4 mcg/mL). The median follow-up from 1L start was 50 months (95% CI 46-54 months). 496 pts met criteria for defining POD36 status; 72 (15%) had PD, and 424 did not. TP53 disruption (OR 2.9; 95% CI 1.5-5.7, P=0.001) was associated with POD36 on univariate analysis; complex karyotype, unmutated IGHV status, elevated serum lactate dehydrogenase level, age, sex, and inclusion of CD20mAb were not associated with POD36 status. Median OS from the time of determination of POD36 status was not reached. OS was significantly shorter after POD36 compared to non-POD36 pts (HR 3.5; 95%CI 2.1-6.0, P<0.0001), with 4-year OS estimates of 65% and 88%, respectively. When assessed by landmark analysis at the 3-year timepoint following 1L start (n=50 POD36), OS was also shorter in pts with POD36 compared to non-POD36 pts (HR 3.5; 95%CI 1.8-6.8, P=0.0002). In the overall cohort (n=787), when evaluating OS from 1L treatment with POD36 as a time-dependent covariate, POD36 status was associated with an increased risk of death (HR 4.3; 95% CI 2.6-7.1, P<0.0001) on univariable analysis; and remained an independent marker of shorter OS in multivariable analyses after adjusting for age, sex, TP53 disruption status, and IGHV status (HR 4.2; 95% CI 2.1-8.4, P<0.0001). CONCLUSIONMost pts achieved durable CLL disease control with 1L targeted treatments, and early PD occurs much less frequently than previously reported with CIT. However, among pts who receive 1L targeted therapies for CLL, PD within 36 months is associated with a ~4-fold higher risk of death. These results, if validated in larger data sets, will provide a practical measure for identifying a high-risk subgroup of pts in need of novel treatment strategies in future trials.

Abstract Introduction: Pirtobrutinib, a highly selective non-covalent BTK inhibitor, demonstrated encouraging efficacy in Richter transformation (RT) of chronic lymphocytic leukemia (CLL) in the BRUIN trial (Wierda et al, Lancet Haematology, 2024). However, a control arm was not included in this phase 1/2 trial, and how pirtobrutinib compares to usual care is unknown. To address this gap of knowledge, we sought to compare efficacy outcomes in BRUIN to that in a control cohort consisting of RT patients treated with usual care at Mayo Clinic. Methods: The study was approved by the Mayo Clinic IRB. Patient-level data from BRUIN (n=79; investigator-assessed) were obtained from the study sponsor. Patients with histologically confirmed RT (large B-cell lymphoma) who received at least one line of therapy (n=230) were identified from the Mayo Clinic CLL Database. Multivariable logistic regression was employed to calculate propensity scores for baseline covariates (ie, age at RT treatment line, number of prior lines of CLL treatment [truncated at 3], number of prior lines of RT treatment [truncated at 3], and LDH). For each Mayo patient, propensity scores for each line of RT therapy were calculated, and the line with the highest propensity score was chosen as the index RT treatment line. Using the inverse probability treatment weighting (IPTW) methodology, individual weights were computed, and standardized mean differences (SMDs) were examined for each of the unadjusted and weighted baseline covariates to ensure that balance was obtained between BRUIN cases and Mayo controls. Overall survival (OS; the primary endpoint) and progression-free survival (PFS) were analyzed using unweighted and weighted Cox proportional hazards models. Unweighted and weighted overall response rates (ORRs) and complete response (CR) rates were analyzed using logistic regression. Results: The final analysis dataset contained 79 BRUIN cases (median age 67 [range 26-95], 66% male) and 204 Mayo controls (median age 69 [range 30-89], 74% male). The BRUIN cohort had more patients with ECOG PS ≥1 (61% vs 40%, p=0.001) and elevated LDH (81% vs 63%, p=0.003) than the Mayo cohort. The proportion of patients with TP53 aberration was not statistically different in both cohorts (57% vs. 44%, p=0.15). The index line of RT treatment in the Mayo cohort included chemoimmunotherapy (n=167, 80%) and novel agent-based therapy (eg, cBTKi, venetoclax, PI3Ki, immune checkpoint inhibitor, etc; n=42, 20%). Median lines of prior CLL therapy were 2 (IQR 1-4) vs 1 (IQR 0-3) in the BRUIN and Mayo cohorts, respectively; median lines of prior RT therapy were 2 (IQR 1-2) vs 0 (IQR 0-2). The SMDs of the weighted baseline factors met pre-determined criteria (-0.25≤SMD≤0.25), indicating that balance between the two cohorts was achieved. The median follow-up was 18.3 months (range 0.7-32.9) in the BRUIN cohort and 122.8 months (range 0-280.2) in the Mayo cohort. The unweighted median OS was 12.5 months (95% CI 7.0-20.6) in the BRUIN cohort and 5.7 months (95% CI 3.9-10.7) in the Mayo cohort. The unweighted HR was 0.76 (95% CI 0.54-1.07, p=0.12). After IPTW, the weighted HR was 0.63 (95% CI 0.50-0.78, p<0.001), significantly favoring the BRUIN cohort. The unweighted median PFS was 3.6 months (95% CI 2.8-5.1) in the BRUIN cohort and 3.1 months (95% CI 2.5-4.3) in the Mayo cohort. The unweighted HR was 0.98 (95%CI 0.72-1.34, p=0.92). After IPTW, the weighted HR was 0.78 (95% CI 0.64-0.95, p=0.01), again favoring the BRUIN cohort. Response was evaluable/available in 69 patients in BRUIN and 182 patients in Mayo cohort. The unweighted ORR was 58% vs 53% in BRUIN and Mayo cohorts, respectively (OR=0.83, 95% CI 0.47-1.45, p=0.51), and the CR rate was 16% vs 36% (OR=2.94, 95% CI 1.43-5.88, p=0.003). After IPTW, the weighted OR was 0.65 (95% CI 0.45-0.93, p=0.02) for ORR, favoring the BRUIN cohort, and 1.89 (95%CI 1.23-2.86, p=0.02) for CR rate, favoring the Mayo cohort. Conclusions: This individual patient-level IPTW-based analysis demonstrated that single agent pirtobrutinib is associated with improved OS, PFS, and ORR compared to usual care in patients with RT. These results support the choice of pirtobrutinib over traditional therapies for RT. Although these results are encouraging, the durability of response to pirtobrutinib remains suboptimal. Ongoing trials and other future research will evaluate the efficacy of pirtobrutinib in combination with other treatments in this setting.

Abstract Background: Monoclonal B-cell lymphocytosis (MBL), a precursor to chronic lymphocytic leukemia (CLL), is an understudied yet common premalignant condition present in ~8 million adults in the United States. Based on flow cytometry, MBL can be classified into two immunophenotypes: CLL-type (CD5, CD23, and CD20 co-expression) and non-CLL-type (CD5-negative). While the majority of the data to date pertains to CLL-type MBL, the available evidence indicates non-CLL-type MBL is also associated with an increased risk of hematologic malignancies. Clonal hematopoiesis of indeterminate potential (CHIP) is another precursor condition associated with hematologic malignancies. The relationship between non-CLL-type MBL and CHIP and their combined effect remains unknown. Herein, we report findings on these two precursor conditions in the largest screening cohort to date. Methods: Using flow cytometry, we screened for MBL in the Mayo Clinic Biobank participants who were 40 years or older with no prior history of hematologic cancers. Using whole-exome sequencing of whole-blood DNA, CHIP was screened on 291 genes related to myeloid (56 genes) or lymphoid malignancies (235 genes). Incident hematologic malignancies were detected during follow-up using International Classification of Diseases (ICD) codes in the medical record. All diagnoses were manually reviewed for confirmation. Multivariable logistic regression was used to evaluate the association between non-CLL-type MBL and CHIP. Time to incident hematologic malignancy was calculated from date of MBL screening to the earliest date of incident malignancy, withdrawal, death, last medical visit, or study end. Overall survival (OS) was calculated from date of MBL screening to date of death or last known alive. Multivariable Cox regression, adjusted for age, sex and residency, was used to investigate associations between non-CLL-type MBL and CHIP with clinical outcomes; with results reported using hazard ratios (HR) and 95% confidence intervals (CI). Results: In total, 8,802 individuals with MBL screening and CHIP data were analyzed. Non-CLL-type MBL was detected in 249 (2.8%) individuals; 121 (49%) were male, and median age was 78 years (range, 47-95). We identified 757 (8.6%) individuals with CHIP in at least one of the 291 genes tested. The most frequently mutated CHIP genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. A total of 47 (0.5%) individuals had both non-CLL-type MBL and CHIP; the four genes with the highest number of CHIP variants in these individuals were DNMT3A (n=16), TET2 (n=10), ASXL1 (n=3), and ATM (n=3). An association between non-CLL-type MBL and any CHIP (OR=1.6, 95%CI:1.2-2.3, P=0.006) was observed. When analyzing CHIP in genes related to myeloid malignancies, the association with non-CLL-type MBL was also significant (OR=1.6, 95%CI:1.1-2.3, P=0.012); however, the association was not statistically significant for genes related to lymphoid malignancies (OR=1.6, 95%CI:0.8-3.3, P=0.165). With a median follow-up of 5.4 years, 104 individuals developed incident hematologic malignancies (66 lymphoid and 38 myeloid malignancies). Non-CLL-type MBL (HR=3.5, 95%CI:1.9-6.5, P<0.001) and CHIP (HR=3.2, 95%CI:2.1-5.1, P<0.001) were each associated with increased risk of incident hematologic malignancies. Co-existence of both precursor conditions was associated with a substantially higher risk of incident hematologic malignancies (HR=10.3, 95%CI:4.0-26.2, P<0.001) compared to individuals with neither precursor condition. Among individuals with non-CLL-like MBL, any CHIP was a borderline significant predictor for incident hematologic malignancy (HR=3.6, 95%CI:1.0-12.9, P=0.049). Compared to individuals with no precursor conditions, OS was not significantly different in those with non-CLL-type MBL-only (HR=1.1, 95%CI:0.8-1.5, P=0.40), those with CHIP-only (HR=1.2, 95%CI:0.99-1.4, P=0.06), or those with both CHIP and non-CLL-type MBL (HR=1.3, 95%CI:0.8-2.1, P=0.39). Conclusions: In the largest screening cohort to date evaluating the relationship of CHIP and non-CLL-type MBL, we found that non-CLL-type MBL and CHIP are associated with each other. Individuals with non-CLL-type MBL were more likely to have CHIP variants in DNMT3A, TET2, ASXL1, and ATM. Among individuals with non-CLL-type MBL, the presence of any CHIP was associated with increased risk of developing hematologic malignancy.