Shanafelt, Tait D.

Abstract Monoclonal B-cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1% to 5% per year. Improved prediction of progression would greatly benefit individuals with MBL. Patients with CLL separate into 3 distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk immunoglobulin lambda variable (IGLV) 3-21 rearrangements, impacting outcomes for these patients. Here, we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for individuals with MBL compared with other established prognostic indicators, including the CLL international prognostic index (c-statistic, 0.767 vs 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL vs a cohort of 226 patients with CLL revealed ELCLV3-21 high-risk individuals with MBL had significantly shorter time to therapy (P = .003) and reduced overall survival (P = .03) compared with ELCLV3-21 low-risk individuals with CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.

Background: Monoclonal B-cell lymphocytosis (MBL) is a precursor condition to chronic lymphocytic leukemia (CLL) characterized by the presence of circulating monoclonal B-cell populations in the peripheral blood of otherwise healthy individuals. MBL increases risk of several adverse clinical outcomes, including development of hematological malignancies. Mosaic chromosomal alterations (mCAs) are a form of clonal hematopoiesis which affect large segments of DNA and include gains, losses, and copy number neutral loss of heterozygosity events. mCAs can be detected from SNP-array genotyping. Prior work has suggested mCAs as a potent risk factor for hematological malignancies. However, the nature of the relationship between mCAs and MBL is unknown. We sought to determine 1) the association between mCAs and MBL and 2) their combined effect on risk of hematological malignancies, in a large, prospectively collected, and well-annotated cohort of individuals with known MBL, mCA, and clinical outcomes. Methods: We examined the prevalence of mCA in a cohort of individuals from the Mayo Clinic Biobank who were screened for MBL using a sensitive eight-color flow cytometry assay. We classified MBL by the size of the clone relative to total B-cells, with high count (HC) defined as those individuals who had a percent clonal B-cell count ≥85% out of total B-cell count and low-count (LC) otherwise. Autosomal mCAs were detected from whole blood DNA collected at the time of MBL screening using a SNP-array-based assay. The MoChA pipeline was used to identify mCA events. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). To examine incident hematological cancers, we identified and validated all hematological cancers through medical record abstraction using the International Statistical Classification of Diseases codes. Cox regression was used to calculate hazard ratios (HR) and 95% CIs, stratified by MBL status or autosomal mCA status. All models were adjusted for age and sex. Results: We evaluated the prevalence of autosomal mCA in 3,764 individuals (792 individuals with MBL of whom 64 had HC-MBL and 2,972 without MBL). The prevalence of autosomal mCA was 7.7% ( n=288) with a median mCA cell fraction of 0.09 (range 0.01-1). Among those with and without MBL overall, the prevalence of mCA was 15.5% ( n=123) and 5.6% ( n=165), respectively (Figure 1). Compared to those without an autosomal mCA, individuals with an autosomal mCA were 2.4-fold more likely to have MBL (95% CI 1.9-3.2; P =2.0x10 -11; Figure 1). CLL-associated mCA (i.e., those commonly altered in CLL including trisomy 12 and deletion of 6q, 11q, 13q, and 17p) were present in 42 individuals, of whom 38 (90.5%) had MBL overall and 30 (71.4%) individuals had HC-MBL. Compared to those without a CLL-associated mCA, individuals with a CLL-associated mCA were 539.39-fold more likely to have HC-MBL (95% CI 190.3-1975.9; P <2.0x10 -16) and 6.7-fold more likely to have LC-MBL (95% CI 2.0-26.5; P =0.0031; Figure 1). Next, we evaluated the relationship between MBL and mCA with risk of developing a hematologic malignancy in 3,009 individuals with follow-up data (median 10 years). Forty-one individuals developed an incident hematological malignancy (68.3% lymphoid). When we evaluated the effect of autosomal mCA stratified by MBL status we observed elevated but non-significant risk of hematological malignancies (Figure 2). When we evaluated the effect of MBL stratified by autosomal mCA status we observed elevated and significant increased risk of developing a hematological malignancy (Figure 2). Conclusions: We found that the presence of an autosomal mCA is highly associated with having MBL. In particular, >90% of CLL-associated mCA carriers had MBL with ~7- and ~540-fold increased association for LC- and HC-MBL, respectively. These results suggest that almost all individuals in large biobanks with CLL-associated mCAs have undiagnosed MBL. However, not all individuals with MBL have an mCA. When evaluating risk of hematological malignancies, we found autosomal mCAs had >2-fold elevated but non-significant effects when stratified by MBL status while MBL remained a significant risk factor regardless of autosomal mCA status. Collectively these results support that MBL remains an important risk factor and suggests that mCAs hold potential to identify a subgroup of individuals at greater risk of developing a hematological malignancy.

Introduction: The treatment of chronic lymphocytic leukemia (CLL) has evolved over the past two decades, from finite duration chemoimmunotherapy (CIT) to an era of targeted agents such as Bruton Tyrosine Kinase (BTK) inhibitors, BCL2 inhibitors, and anti-CD20 monoclonal antibodies. Little is known about how initial management strategy (watch and wait [W&W] vs. treatment) at diagnosis impacts patient reported outcomes (PROs) in CLL survivors over time, particularly in light of therapeutic advances over the last decade. Methods: Newly diagnosed CLL patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER1) study between 9/1/02 and 6/30/15, and within 6 months of diagnosis in the MER Phase 2 (MER2) study between 7/1/15 and 5/1/20. PROs were measured using the Functional Assessment of Cancer Therapy-General scale (FACT-G), which generates Physical (PWB, range 0-28), Social/Family (SFWB, 0-28), Emotional (EWB, 0-24), and Functional Well-Being (FWB, 0-28) scores and a Total Score (0-108), with higher scores indicating better WB. In both cohorts, FACT-G was measured at enrollment and at years 1, 2, and 3 after diagnosis, while the timing of later assessments varied slightly by study (MER1: 6 yrs and 9 yrs; MER2: 5 years). We employed a generalized linear mixed model to evaluate change from baseline between groups with groups defined by each participant's initial management strategy (W&W vs. upfront systemic treatment). Initial management strategy was determined by the treating physician. The study was approved by the Mayo Clinic IRB. Results: A total of 722 patients were identified in MER1 and 256 patients in MER2. The median age at diagnosis was 63 years in MER1 and 66 years in MER2 (P<0.05); 66% were male in MER1 and 68% were male in MER2 (P>0.05). More patients initiated upfront systemic therapy in MER1 (n=380, 53%) than in MER2 (n=110, 43%). Other baseline clinical characteristics were similar between the cohorts ( Table 1). There was no statistical difference in the mean FACT-G total score at baseline between MER1 (85.0, SD 12.5) and MER2 (85.2, SD 12.7). In the MER1 cohort, statistically significant lower baseline QOL scores were observed in patients initiating upfront treatment compared to W&W on the FACT-G total score (P=0.002) as well as the PWB (P=0.01), EWB (P=0.03), and FWB (P=0.006) subscales. We also observed that over time, EWB and FWB scores were consistently lower amongst those treated upfront compared to W&W. Further, EWB scores steadily improved over time regardless of initial management ( Figure 1), whereas the FWB and PWB subscales were largely stable over time. Mean SFWB scores dropped amongst patients who received upfront therapy at 3 years, which then steadily improved through year 9 but did not recover back to baseline. SFWB scores were stable among W&W patients. In the MER2 cohort, no statistically significant differences in any of the baseline QOL scores were noted between the W&W vs. initial treatment groups. Despite this, we observed consistently lower mean EWB scores among patients who initiated upfront treatment compared to W&W pts over time. No other statistically significant differences in mean QOL scores over time were observed between groups. Similar to MER1, we did observe a drop in mean SFWB scores amongst patients initiating upfront therapy at 3 years of follow-up that remained decreased at year 5. Conclusion: This is the largest longitudinal study of CLL survivors that spanned over 18 years and two treatment eras. We demonstrated that in the novel treatment era, QOL metrics were similar between initial management strategies (W&W vs. treatment), suggesting that initial management had little to no impact on QOL at baseline or over time. In contrast, in the CIT era, we observed differences in QOL metrics at baseline between groups. In both treatment eras, patients with CLL who required upfront therapy demonstrated a decrease in SFWB from baseline at year 3 of follow-up, and the mean EWB scores were lowest at baseline regardless of initial management strategy (W&W vs. upfront treatment) or treatment era (CIT vs. novel agents), but steadily improved over time. These findings suggest opportunities for interventions to improve QOL in patients with CLL, and additional analyses are ongoing. Further follow-up in the era of novel agents is needed.

Introduction: Despite the improved clinical outcomes with novel therapies in patients with chronic lymphocytic leukemia (CLL), Richter transformation (RT) of CLL remains a major clinical challenge. Our group showed a selective response (~40%) with the PD-1 blocking antibody pembrolizumab in patients with RT, particularly after prior exposure to ibrutinib (Ding et al, Blood, 2017). It has been established that PD-1 inhibits cytotoxic T-cell functions via the interaction with its ligands, PD-L1 and PD-L2. However, the role of PD-1 in tumor B-cells is understudied. Here we show the expression and functional implications of the PD-1 signaling axis in B-cell pathobiology. Methods: CLL-involved lymph node (LN) (n=26) and RT (with diffuse large B-cell lymphoma [DLBCL] histology) -involved LN (n=20) samples were tested for PD-1 expression by immunohistochemistry (IHC) (mouse clone NAT105, Abcam). Then, PD-1 expression was examined in 10 lymphoma cell lines and 1 CLL-like cell line (MEC-1) by both flow cytometry (FC) and Western blot (WB) analysis. PD-1 overexpression using pLEX-lentiviral packaging system (Thermo Scientific) was evaluated for its impact on in vitro cell cycle regulation and in vivo tumor growth. CRISPR/CAS9 mediated PD-1 knockdown evaluated on cell growth in MEC-1 and Mino cells. Role of PD-1 was further examined on the regulation of cell signaling pathways using human phospho kinase array kit (R&D) and WB analysis. Additionally, gene expression signatures were evaluated by RNA-seq using pLEX-lentiviral-PD-1 transfected DLBCL cell lines OCI-LY7 and OCI-LY19. Results: PD-1 expression was significantly increased in RT-LN compared to CLL-LN (mean ± SEM in RT vs. CLL, 30.6% ± 4.7% vs. 11.5% ± 2.8%, p<0.001) as determined by IHC. PD-1 expression was highest in patients with RT where the last prior CLL therapy was ibrutinib. To test the role of PD-1 in tumor B-cells, its expression was assessed in lymphoma and CLL cell lines. The expression of PD-1 was found to be variable by both FC and WB analysis, but at very low-levels in DLBCL cell lines OCI-LY7 and OCI-LY19. Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in OCI-LY7 and OCI-LY19 cells led to increased cell growth (1.4 and 1.9 fold, respectively, compared to original lines after 4 days of culturing of equal number of cells), which was further confirmed by cell cycle analysis which showed an increase in S phase by 20.4% (p<0.05) and 24.5% (p<0.05) in OCI-LY7 and OCI-LY19 cells, respectively. When the luciferase+ PD-1 overexpressing OCI-LY7 cells (1X10 6) were injected intravenously into NSG mice, increased tumor growth (p<0.01) was observed by bioluminescence imaging after 22 days of follow-up. PD-1 knockdown in MEC-1 and Mino cells (high basal PD-1 expression) led to significant inhibition of cell growth (85% and 79.5%, respectively, p<0.05). Using phospho-kinase array, an overall decrease of phosphorylation was detected on multiple sites of p53 (S392, S15, S46) and Chk-2 (T68) in PD-1 overexpressing OCI-LY7 and OCI-LY19 cell lines. This finding was further confirmed by WB analyses. In addition, decreased total p53 and increased phosphorylation on both SHP-1 and SHP-2 were found in PD-1 overexpressing OCI-LY7 and OCI-LY19 cell lines. SHP-1 (TPI-1) and SHP-1+SHP-2 (TPI-1+TNO155) inhibitor treatment promoted OCI-LY19 cell death and led to recovery of phosphorylation on ATM, Chk-2 and p53 in these cells. RNA sequencing data in PD-1 overexpressing OCI-LY7 and OCI-LY19 cells revealed increased expression of genes that promote cell cycle progression and DNA replication. Conclusion: Our data showed robust PD-1 expression in patients with Richter transformation from CLL to DLBCL. PD-1 overexpression in DLBCL lymphoma cell lines enhanced cell proliferation in vitro and in vivo. Further investigation identified that PD-1 modified the phosphorylation/function of SHP phosphatases and thereby regulated p53 pathways ( Figure 1). These findings indicate that RT with DLBCL cells have the ability to “hijack” the PD-1 pathway which results in downregulation of p53 mediated DNA repair. This novel finding provides for new strategies to further evaluate the interaction of PD-1 signals with DNA repair pathways and suggest potential novel targets for RT.

Abstract Bruton tyrosine kinase inhibitors (BTKis) that target B-cell receptor signaling have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. BTKis have been shown to reduce abnormally high CLL-associated T-cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T-cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pretreatment and on-treatment (6 and 12 months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab with fludarabine, cyclophosphamide, and rituximab (FCR). Intriguingly, we report that despite reduced overall T-cell counts; higher numbers of T cells, including effector CD8+ subsets at baseline and at the 6-month time point, associated with no infections; and favorable progression-free survival in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T-cell killing function during ibrutinib-rituximab treatment, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T-cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T-cell cytotoxicity during ibrutinib-rituximab treatment, using the bispecific antibody glofitamab, supporting combination immunotherapy approaches.

AbstractBackgroundTobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer.MethodsA modified Cancer Patient Tobacco Use Questionnaire (C‐TUQ) was administered to patients enrolled in nine ECOG‐ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression.ResultsA total of 740 patients completing the C‐TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69–7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64–10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02–0.58; p = .0086) versus those in the least disadvantaged neighborhoods.ConclusionsGreater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Abstract Background: While cigarette smoking has declined among the U.S. general population, sale and use of non-cigarette alternative tobacco products (ATP; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among patients with cancer in national trials. Methods: Cancer survivors (N = 756) enrolled in 9 ECOG-ACRIN clinical trials (2017–2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30 days. Results: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30 days, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30 days. Males (vs. females; OR 4.33; P = 0 < 0.01) and individuals not living with another person who smokes (vs. living with; OR, 8.07; P = 0 < 0.01) were more likely to use ATPs only versus cigarettes only in the past 30 days. Conclusions: Among patients with cancer, cigarettes were the most prevalent tobacco product reported. Impact: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings.

7577 Background: Prior research has consistently shown that patients with chronic lymphocytic leukemia (CLL) have an ~2-fold increased risk of developing melanoma compared to controls. MBL is a common condition affecting 8-10 million adults over the age of 40 years in the United States and is a precursor to CLL. Little is known about the association between MBL and melanoma. Herein, we evaluated the risk of incident melanoma in a large cohort of individuals screened for MBL. Methods: Participants from the Mayo Clinic Biobank who had no prior history of hematologic malignancy, were 40 years or older, were residents of counties surrounding Mayo Clinic, and who provided blood samples between 7/2009 and 4/2022 were included in the study. Peripheral blood mononuclear cells were screened for MBL using highly sensitive eight-color flow cytometry. Individuals with MBL were classified as CLL-like MBL (CD5+, CD20dim) or atypical MBL (CD5+, CD20+) based on immunophenotypes, and also classified as low-count MBL (LCMBL) or high-count MBL (HCMBL) based on whether the percent clonal B-cell count was < 85% or ≥85%, respectively. Diagnosis of melanoma was ascertained using ICD codes and review of the electronic health records. All individuals were followed from date of sample upon which MBL screening was performed to the earliest of incident melanoma, loss to follow-up, withdrawal from the study, or September 30, 2022. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for age, sex, and history of melanoma in previous 5 years. Results: A total of 7,334 participants were screened for MBL, of which 1,151 (16%) individuals had MBL. Among those with MBL, 1,107 (96.2%) had CLL-like MBL and 1098 (95.4%) had LC MBL. The median age at entry into the MBL screening cohort was 67 years (range 40-101) and 37% were male; individuals with MBL were older (median age 72 vs 65 years) and male (49% vs 35%). After a median follow-up of 2.9 years (range 0-13.2), 121 of the 7,334 (1.6%) participants developed incident melanoma after the date of MBL screening. The 10-year cumulative incidence of melanoma among individuals with MBL was 7.8% (95% CI 4.5-13.5%) compared to 3.4% (2.7-4.4%) in those who screened negative for MBL. After adjusting for age, sex, and history of prior melanoma, we found a 1.81-fold increased risk of incident melanoma (95% CI 1.19-2.76) among individuals with MBL. The increased risk of melanoma persisted when the analysis was restricted to individuals with LCMBL (HR = 1.84; 95% CI 1.21-2.82). Conclusions: In the largest MBL screening cohort to date, we found that LCMBL, a common condition, was associated with an 84% elevated risk of melanoma, similar to the ~2-fold increased risk observed in patients with CLL. These data, together with our prior findings of a heightened risk of serious infections and lymphoid malignancies, suggest that individuals with LCMBL are at increased risk for adverse health outcomes.

Abstract As health care organizations in the United States move toward recovery from the COVID-19 pandemic, physicians and clinical faculty are experiencing occupational burnout and various manifestations of distress. To mitigate these challenges, health care organizations must optimize the work environment and provide support for individual clinicians using a variety of approaches, including mentoring, group-based peer support, individual peer support, coaching, and psychotherapy. While often conflated, each of these approaches offers distinct benefits. Mentoring is a longitudinal 1-on-1 relationship, typically focused on career development, usually with an experienced professional guiding a junior professional. Group-based peer support involves regular, longitudinal meetings of health professionals to discuss meaningful topics, provide mutual support to one another, and foster community. Individual peer support involves training peers to provide timely 1-on-1 support for a distressed colleague dealing with adverse clinical events or other professional challenges. Coaching involves a certified professional helping an individual identify their values and priorities and consider changes that would allow them to adhere to these more fully, and providing longitudinal support that fosters accountability for action. Individual psychotherapy is a longitudinal, short- or long-term professional relationship during which specific therapeutic interventions are delivered by a licensed mental health professional. When distress is severe, this is the best approach. Although some overlap exists, these approaches are distinct and complementary. Individuals may use different methods at different career stages and for different challenges. Organizations seeking to address a specific need should consider which approach is most suitable. Over time, a portfolio of offerings is typically needed to holistically address the diverse needs of clinicians. A stepped care model using a population health approach may be a cost-effective way to promote mental health and prevent occupational distress and general psychiatric symptoms.

Abstract Low count (LC) MBL is characterized by a circulating population of clonal B-cells and is a precursor state to CLL. Most individuals with LC MBL do not progress to CLL and never come to clinical attention. An active area of research is to identify factors that distinguish those individuals with MBL who progress from those who do not. Currently, 41 single nucleotide polymorphisms (SNPs) are known to be associated with CLL risk, and a portion of these SNPs have also been found to be associated with MBL risk. We hypothesize that these CLL-susceptibility SNPs associated with both MBL and CLL risk are SNPs associated with developing a B-cell clone; whereas the remaining SNPs found not to be associated with MBL risk are associated with progression of the B-cell clone (i.e., progression from MBL to CLL). To test this hypothesis, we evaluated the association of these 41 SNPs with risk of progression to CLL using a case-control study of 1,911 CLL cases and 1,579 individuals with MBL from Mayo Clinic. Individuals with MBL were identified through screening using 8-color flow cytometry assay. Individuals with LC MBL (defined by having a clonal B-cell population with the percent clonal B-cells out of total B-cell count &lt;85%) who had an immunophenotype consistent with CLL were included as controls. CLL cases were obtained through the Mayo Clinic hematology practice. DNA was genotyped from whole blood. We analyzed the 41 CLL susceptibility SNPs with risk of progression to CLL using logistic regression and estimated odds ratio (OR) and 95% confidence interval (CI), adjusting for sex and age. We evaluated the CLL polygenic risk score (CLL-PRS), comprised of a weighted average of the 41 SNPs, with risk of CLL. Out of the 41 established CLL susceptibility SNPs, 15 were associated with CLL progression from MBL to CLL (all P&lt;0.05). Nine of these 15 significant SNPs were not previously found to be associated with risk of MBL. The most significant SNPs were rs9880772 (OR=1.23, CI: 1.11-1.36, P=6.1 × 10−5), rs888096 (OR=1.25, CI: 1.12-1.38, P=3.0 × 10−5), and rs305065 (OR=1.28, CI: 1.14-1.43, P=1.5 × 10−5). One SNP (rs77551289) had a suggestive association (OR=1.21, P=0.069). The remaining 25 SNPs had no evidence of association with progression (ORs ranging between 0.9-1.1 and all P&gt;0.1). The CLL-PRS was also associated with CLL risk (continuous OR = 1.25, CI: 1.15 - 1.35, P = 6.7 × 10−8). In our study accounting for the presence of B-cell clonal population, we identified 15 out of 41 CLL-susceptibility SNPs to be significantly associated with progression from LC MBL to CLL. The remaining 25 non-significant CLL-SNPs were not associated with progression and may instead be associated with development or initiation of the B-cell clone. These findings suggest that the established CLL susceptibility SNPs may play differing role (i.e., development or progression of the clone) in the etiology of CLL. Citation Format: Raphael Mwangi, Geffen Kleinstern, Sara J. Achenbach, Dennis Robinson, Aaron D. Norman, Kari G. Rabe, Janet E. Olson, Neil E. Kay, Rosalie G. Waller, Nicholas J. Boddicker, James R. Cerhan, Esteban Braggio, Sameer A. Parikh, Curtis A. Hanson, Celine M. Vachon, Tait Shanafelt, Susan L. Slager. Genetic variants associated with progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5222.