Call, Timothy G.

7522 Background: Ibrutinib therapy is associated with an increased risk (~15%) of AF. An accurate risk assessment model for the development of AF in pts starting ibrutinib is not established, and outcomes after AF are not well described. Methods: An IRB approved retrospective review of CLL pts treated with ibrutinib at Mayo Clinic between Oct 2012 and Nov 2018 was conducted. Results: 299 pts were identified with a total of 565 years of ibrutinib exposure (Table). After a median follow-up of 24 months (range 0–70 months), 51 pts developed treatment-emergent AF (13 [25%] CTCAE 3 or higher). Our study assessed 3 clinical prediction models, the Framingham (Schanbel:Lancet 2009), Italian (Visentin:Blood 2018;132:3118), and Shanafelt (Shanafelt:Leuk Lymp; 2017) risk scores. Based on a lower Akaike information criteria, the Italian score was best able to predict risk of treatment emergent AF (2-year risk of AF with score 0 6%; 1-2 8%; 3-4 26%; 5+ 47%). Thirty (61%) pts were treated with medical therapy for AF (27 rate control; 2 rhythm control; 1 both). 16 (31%) pts underwent interventional therapy (3 AV node ablation; 11 cardioversion; and 2 pacemaker). Twelve (23%) pts temporarily held ibrutinib and resumed their original dose, 22 (43%) pts continued reduced dose ibrutinib and 11 (22%) continued their initial ibrutinib dose. Six (12%) pts permanently discontinued ibrutinib. Of 51 pts with treatment-emergent AF, 41 (80%) had a CHA2DS2-VASc score of ≥2 (41% received anticoagulation alone; 12% received antiplatelet therapy alone; 10% received both). No pt developed a thrombotic stroke after treatment-emergent AF. Two major bleeds, (1 GI and 1 intracranial) occurred, one in a pt on concomitant antiplatelet and anticoagulation therapy, and one in a pt receiving neither. The development of AF was associated with shorter event-free survival (HR 2.5, 95%CI 1.5-4.2, p<.001) and shorter overall survival (HR 3.5, 95%CI 2.0-6.3, p<.001). Conclusions: The Italian score was the best predictor of AF development in this cohort of ibrutinib treated pts. Although the vast majority of pts who develop AF after ibrutinib are able to continue therapy, the occurrence of AF appears to be associated with shorter EFS and OS. [Table: see text]

Background The CLL international prognostic index (CLL-IPI) is a validated staging system for newly diagnosed CLL patients that combines age, clinical stage, serum Beta-2 microglobulin, TP53, and IGHV mutation status into a single score and stratifies CLL patients into four prognostic risk groups with a c-statistic=0.72. Next-generation sequencing identified ~60 putative driver genes recurrently mutated in CLL, and genome-wide association studies (GWAS) identified 41 single nucleotide polymorphisms (SNPs) associated with CLL risk. We previously showed that a polygenic risk score (PRS) of the weighted average of the number of risk alleles among these 41 SNPs is associated with risk of both CLL and MBL. We and others have also shown that the tumor mutational load (TML), i.e., the total number of somatically mutated driver genes, is associated with time to first treatment (TTT). Herein, we examine whether TML and PRS add prognostic value beyond CLL-IPI for disease progression in a cohort of CLL and high-count MBLs. Methods We used the Mayo Clinic CLL resource to identify newly diagnosed (&lt;2 years) previously untreated CLL and high-count MBL patients based on the 2008 International Workshop CLL (IWCLL) criteria . We extracted DNA from CD5+/CD19+ clonal B-cells and sequenced the coding regions of 59 recurrently mutated CLL driver genes using a custom SureSelect panel and Illumina HiSeq 4000. The median coverage depth per sample was 2737X. Somatic mutations were called using MuTect2 in tumor-only mode. Germline variants were eliminated based on minor allele frequencies &gt;0.01%, and by those identified in 1000 Genomes Project, ExAC and/or ESP6500 databases, unless present in known mutation hotspots or COSMIC. After filtering high/moderate impact mutations, we calculated the TML. Peripheral blood DNA was genotyped on Illumina Omni Express array; after extensive quality control metrics, we calculated the germline PRS as the weighted average of the number of risk alleles among the CLL susceptibility SNPs. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) to test for associations with TTT. We analyzed the low/intermediate risk groups and the high/very high risk groups in stratified analyses and tested for interactions between CLL-IPI and TML or PRS. Survival curves are displayed using the Kaplan-Meier method using P-values from the log-rank test; the PRS is displayed by tertile categories. Results Of 166 patients (120 CLL, 46 MBL), 67% were male and the median age at diagnosis was 62 years (range: 28-85). The median follow-up was 5.3 years, and 73 were treated for progressive disease as defined by the 2018 IWCLL criteria. Low risk CLL-IPI comprised 51%, intermediate risk 27%, high risk 18%, and very-high risk 4%. The most commonly somatically mutated genes were TP53 (8%), CHD2 (8%), BIRC3 (8%), SF3B1 (7%), and NOTCH1 (7%). We found that 42%, 32%, and 26% of patients had 0, 1, or 2+ genes with somatic mutations, respectively. The median PRS was 8.3 (range: 6.1-11.3) which is consistent with our prior PRS study on CLL/MBL and higher than 7.53 found in 7983 controls from our prior work. When we modeled TML, PRS, sex, CLL/MBL status and CLL-IPI together with the joint effects of CLL-IPI with TML and PRS, both interactions were significant in the model (P=0.008 for TML*CLL-IPI and P=0.014 for PRS*CLL-IPI), with c-statistic=0.81 (CI:0.77-0.85). When we stratified by CLL-IPI, TML was associated with shorter TTT in the low/intermediate risk (N=129, continuous HR=2.36 per TML category, CI: 1.61-3.47, P=1.3x10-5, Figure 1.A), but there was no evidence of an association in the high/very-high risk (N=37, continuous HR=1.12 per TML category, CI: 0.70-1. 78, P=0.64, Figure 1.B), after adjusting for PRS, sex, and CLL/MBL status. However, the PRS was associated with a shorter TTT in the high/very-high risk (continuous HR=1.77 per SD, CI: 1.00-3.12, P=0.048, Figure 1.D), with no evidence of an association in the low/intermediate risk (continuous HR=0.95 per SD, CI: 0.95-1.29, P=0.74, Figure 1.C), after adjusting for TML, sex, and CLL/MBL status. Conclusions In our study, TML was prognostic among the low/intermediate CLL-IPI risk groups while the PRS was prognostic among the high/very-high CLL-IPI risk groups. Sequencing CLL driver genes and genotyping relevant germline SNPs at time of diagnosis may provide incremental value over the CLL-IPI in predicting TTT among patients with CLL/MBL. Disclosures Parikh: MorphoSys: Research Funding; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Research Funding; Ascentage Pharma: Research Funding; Acerta Pharma: Research Funding. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB.

Abstract Introduction. CLL primarily affects elderly individuals who frequently have comorbid health conditions. It is typically assumed non-CLL-related etiologies will be the ultimate cause of death for most CLL patients, particularly those with comorbid conditions at diagnosis. Methods. Between 9/2002 and 11/2014, 1174 patients with newly diagnosed CLL were enrolled in a prospective cohort study evaluating the natural history of CLL. Comorbidities were prospectively recorded at the time of diagnosis. Comorbidities arising during the course of disease were not considered for this analysis. Standardized longitudinal follow-up was performed in all patients every 6 months for the first 3 years after diagnosis and annually thereafter through 04/2015. Internal and external medical records, death certificates, and information from next of kin were centrally reviewed to determine cause of death, using a standardized protocol. Categorical and continuous variables were evaluated using the c2 or Fisher exact tests and the Mann-Whitney test, as appropriate. Results. Baseline characteristics at time of CLL diagnosis are shown in the Table. Over 80% of patients had 2 or more comorbidities at diagnosis (median 3, range 0-11). After a median follow up of 5 years, 224 (19%) patients have died. The cause of death could be accurately determined in 183 (82%) of these patients. The cause of death was due to CLL in 135 (74%), including 84 (46%) CLL progressions, 14 (8%) infections, and 37 (20%) other cancers. Death was due to non-CLL-related causes (such as congestive heart failure, stroke or chronic obstructive pulmonary disease) in the remaining 48 (26%) patients. On univariable analysis, age and number of comorbid health conditions were not related to whether or not the cause of death was related/unrelated to CLL. The only specific co-morbid condition at diagnosis that predicted for non-CLL related death was stroke (8% vs 1%, p=0.04). Unmutated IGHV was the only prognostic factor thatpredicted greater likelihood of CLL-related death (70% vs 50%, p=0.03). Conclusions. The majority of patients with CLL have multiple comorbidities at time of diagnosis. Despite this fact, CLL progression and/or CLL-related complications are the primary cause of death. The number and type of comorbidities at diagnosis have minimal relationship to whether or not the ultimate cause of death was CLL-related. In contrast, the CLL-specific characteristic IGHV status (but interestingly not FISH defects) correlates with cause of death. Collectively, these findings illustrate the need for more effective CLL therapy, particularly treatments that can be tolerated by patients with comorbid health conditions. It is hoped the signaling inhibitors may help address this unmet need. Table. Number (%), median [range] N=1174 Age (years) 63 [23-89] Males Females 791 (67) 383 (33) Creatinine-Clearance > (mL/min) 86 [10-252] B2M (mg/dL) 2.3 [1.1-13.2] Rai stage 0 I-II III-IV 604 (52) 512 (38) 54 (10) CD49d positive negative 277 (30) 638 (70) CD38 positive negative 332 (30) 780 (70) ZAP70 positive negative 380 (37) 650 (63) IGHV unmutated mutated 394 (44) 506 (56) FISH del13q negative +12 del11q del17p 395 (40) 175 (18) 276 (28) 90 (9) 50 (5) Comorbid health conditions Other cancers 237 (20) Stroke 38 (3) Cardiac disease 326 (28) Hypertension 472 (40) Respiratory 210 (18) Endocrinologic 165 (14) Diabetes 118 (10) Hyperlipidemia 485 (41) Rheumatologic 489 (42) Gastrointestinal 384 (33) Genitourinary 412 (35) Psychiatric 197 (17) DVT/PE 33 (3) Substance abuse 58 (5) Sexually transmitted disease 35 (3) Obesity 376 (32) # of Comorbidities 0 1 2 3 4 > 4 66 (6) 148 (13) 203 (17) 220 (19) 206 (17) 331 (28) Disclosures Kay: Hospira: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Tolero Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding.

Abstract Background : Effective therapy for classical hairy cell leukemia (c-HCL) refractory to purine nucleoside analog (PNA) treatment is limited, and there are no accepted treatment standards for variant hairy cell leukemia (v-HCL). Ibrutinib, an oral small molecule inhibitor of Bruton tyrosine kinase (BTK), has shown single-agent efficacy and acceptable tolerability in patients with various B-cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's. While BTK is expressed in HCL cells, the clinical activity of ibrutinib in this disease has not been previously assessed. We conducted a single-arm, multi-center phase 2 study (NCI #9268) of single-agent ibrutinib to characterize the overall response rate (complete + partial response) and safety of single-agent ibrutinib treatment for HCL. Methods : Patients with c-HCL (unfit for or relapsed after PNA) and v-HCL (relapsed or treatment-naïve) were eligible. Enrolled patients required treatment, had ECOG ≤ 2, no active infection, and preserved end-organ function. Patients received continuous once daily ibrutinib in 28-day cycles. Using a Simon 2-stage design, the first 13 patients were treated at 420 mg daily, and a second cohort of 13 patients was accrued at the 840 mg dose-level. Ultimately, the pre-specified number of objective responses was reached at the 420 mg dose-level, and accrual to the second stage of the design continues at that dose. Response, including bone marrow biopsy with immunohistochemistry for minimal residual disease (MRD), was assessed after 8 and 12 cycles. Patients experiencing clinical benefit may continue ibrutinib until unacceptable toxicity or progressive disease. Results: As of 15 May 2016, 28 patients had been enrolled and were evaluable for response: 420 mg/day (n=15) and 840 mg/day (n=13). Enrolled patients (1 treatment-naïve v-HCL, 10 relapsed v-HCL, 17 relapsed c-HCL) included 22 male and 6 female patients with median age 65 years (range: 43-78). Relapsed patients received median 4 prior therapies (range: 1-11); all had prior PNA, 81% had prior rituximab, and 3 c-HCL patients had prior vemurafenib. Response data are summarized by dose and histology in the table. To date, the ORR is 46% [4 CR (all c-HCL) and 9 PR (6 c-HCL)], with objective responses more commonly observed in patients with c-HCL. Eight additional patients (29%) with stable disease have experienced clinical benefit (resolution of symptoms, improvement in peripheral blood cell counts) not meeting criteria for PR, most commonly attributable to persistent thrombocytopenia, and continue on treatment. At median follow-up of 22 months, 20 patients (71%) remain on treatment, 3 patients (1 v-HCL, 2 c-HCL) have progressed, 2 patients (c-HCL) with severe neutropenia at baseline (c-HCL) had early deaths from pneumonia, 1 (c-HCL) discontinued during cycle 8 for failure to resolve baseline neutropenia, and 2 other patients (v-HCL) have discontinued for adverse events. Estimated 24-month progression-free survival (PFS) was 79% (95% CI: 57-91%) and the median PFS has not been reached. Redistribution lymphocytosis was observed in patients with circulating disease at baseline. Soluble interleukin-2 receptor (sIL2R) level was increased at baseline in all c-HCL patients for whom data were available and correlated with response. In general, toxicity did not differ by dose level or disease histology. The most frequent (>10%) grade ≥3 adverse events (AEs) were lymphopenia (21%), neutropenia (18%), lung infection (18%), thrombocytopenia (14%), hypophosphatemia (11%), and hypertension (11%). Common grade 1/2 non-hematologic toxicities included myalgia (57%), diarrhea (54%), fatigue (50%), nausea/vomiting (46%), bruising (46%), and rash (46%); grade 1/2 atrial fibrillation (no grade ≥3) was observed in 5 patients. Grade ≥3 infection was observed in 25%, but no grade ≥3 bleeding AEs were reported. Conclusions: Ibrutinib can induce remission in both c-HCL and v-HCL patients, including heavily pre-treated patients, but complete remissions have only been observed in c-HCL to date. The drug is generally well-tolerated during long-term administration, and durable clinical benefit is observed in the majority of treated patients even when objective response criteria are not met. Table 1. Table 1. Figure 1. Figure 1. Disclosures Jones: Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding.

Abstract Background: Monoclonal B-cell lymphocytosis (MBL) is characterized by the presence of a circulating population of clonal B-cells where the total B-cell count is <5 × 109/L and criteria for the diagnosis of other lymphoproliferative disorders are not present. In most patients the immunophenotype is similar to that of chronic lymphocytic leukemia with co-expression of CD19 and CD5. The natural history of MBL is unclear. We used the Mayo Clinic hematopathology database to identify patients with MBL and abstracted clinical information on natural history and prognostic parameters from clinical and research records. Methods: After IRB review and approval, we reviewed the hematopathology records of 2292 patients seen at Mayo Clinic between August 1998 and May 2006 who had a clonal B-cell population on flow cytometry phenotypically consistent with CLL and fewer than <5 × 109/L B-cells. Clinical records were then reviewed to identify patients who fulfilled the criteria for MBL (no evidence of other lymphoproliferative disorders, no adenopathy on exam). Patient characteristics, prognostic parameters, and clinical outcomes were abstracted from the clinical and research records of these patients. Cox regression analysis was used to evaluate association between prognostic markers and time to treatment. Results: A total of 118 patients meeting the criteria for MBL were identified. Median age at the time of MBL diagnosis was 69.4 years (range 39.0 – 91.4). A slight male preponderance was observed (54% male). CD38 status was available for 106 (90%) patients of whom 20% were CD38 positive using the 30% threshold to classify CD38. Cytogenetic analysis by fluorescent in situ hybridization (FISH) was available in 58 (49%) patients. Using the hierarchical classification system of Dohner and colleagues, 26 (44.8%) were 13q-, 10 (17.2%) were trisomy 12, 2 (3.4%) were 11q-, 1 (1.7%) was 17p-, and 19 were (32.8%) no defect was detected. ZAP-70 status was available for 32 patients of whom 22% were ZAP-70+ positive. IgVH gene mutation status was only available for 15 (12.7%) patients of whom 40% were unmutated. Time from MBL diagnosis to treatment is shown in Figure 1. Survival free of treatment was 92.7% (95%CI: 86.8–99.1%) at 1 year, 90.9% (95%CI: 84.2–98.2%) at 2 years, and 87.5% (95% CI: 78.7–97.4%) at 5 years. While age (p=0.68) and gender (p=0.14) were not found to be associated with time to treatment (TTT), CD38 status showed a strong relationship with TTT (p<0.001, HR: 22.7, 95% CI: 3.4–239.6). Conclusion: The distribution of prognostic parameters (e.g. CD38, FISH) in patients with MBL appears similar to that of patients with early stage CLL. We observed a low rate of progression, with 5 year survival free of treatment greater than 87%. TTT among newly diagnosed MBL patients was associated with the CD38 status of clonal B-cells. Figure Figure

Background: The 2018 iwCLL guidelines recommend close observation of early stage CLL pts who do not meet indications for therapy ("watch and wait" strategy). Prior attempts at early therapeutic intervention in unselected early-stage CLL pts using alkylating agents such as chlorambucil and chemoimmunotherapy failed to show a significant benefit; and these therapies were associated with substantial toxicities. The introduction of Bruton tyrosine kinase (BTK) inhibitors has revolutionized the treatment landscape of CLL. The German CLL Study group recently presented results of the CLL12 study which demonstrated a significant improvement in event-free survival (EFS) among untreated early stage high risk CLL pts who received ibrutinib compared to placebo (median EFS not reached vs. 47.8 months, respectively; Langerbeins, EHA, 2019). Acalabrutinib is a more selective second-generation BTK inhibitor that has fewer adverse events in pts with CLL, and has shown equally impressive clinical activity for CLL pts. We are conducting an investigator initiated randomized phase 2 study to compare acalabrutinib with or without obinutuzumab (a glycoengineered anti-CD20 monoclonal antibody approved in the treatment of CLL) among high risk early stage CLL pts. Study Design: All pts with newly diagnosed (<2 years from registration) previously untreated early stage CLL who do not meet the 2018 iwCLL guidelines for initiation of therapy are eligible for enrollment in this study. Pts undergo risk stratification according to the CLL-International prognostic index (CLL-IPI) which consists of the following 5 variables: age >65 years (1 point), Rai stage I-IV (1 point), del17p and/or TP53 mutation (4 points), unmutated immunoglobulin heavy chain (IGHV) genes (2 points), and serum β2-microglobulin >3.5 g/dL (2 points). Pts with high (4-6) and very high (7-10) risk CLL-IPI are randomly (1:1) assigned to acalabrutinib 100 mg orally twice daily (Arm A) or acalabrutinib with obinutuzumab at a standard approved schedule (Arm B). Treatment with acalabrutinib is continued for a minimum of 2 years unless the patient has unacceptable side effects or withdraws consent. Pts with low (0-1) and intermediate (2-3) risk CLL-IPI score are assigned to an observation arm with follow-up once every 6 months for 2 years, and then according to routine clinical practice (Arm C). Endpoints: The primary endpoint of the intervention arms (Arms A and B) is the achievement of minimal residual disease (MRD)-negative complete remission in the bone marrow after 2 years of therapy. MRD is assessed using an 8-color flow cytometry with a detection limit of 0.01%. The primary endpoint of the observation arm (Arm C) is time to first therapy. Secondary endpoints for all arms are: progression-free survival, overall survival, and safety. Statistical design: A randomized trial comparing the experimental arm (acalabrutinib plus obinutuzumab) against the control arm (acalabrutinib alone) will be conducted as described by Rubinstein. A sample size of 36 pts per arm provides 80% power to detect an improvement in MRD-negative complete response rate from 10% to 30%, using a one-sided test at a significance level of 0.10 (EAST 6.4). We anticipate accruing an additional 8 high/very high risk pts (4 in each arm) to account for ineligibility, cancellation, or major treatment violation. The total enrollment for Arms A and B will be 80 pts. We will enroll 40 pts to Arm C; for a total enrollment of 120 pts. Key correlatives: Comprehensive profiling to assess the innate and adaptive immune system in paired peripheral blood and bone marrow will be conducted in all pts registered to Arms A and B at baseline, 12 and 24 months after enrollment. In addition, bone marrow hematopoietic function will be assessed in all pts at these time points. We will employ a CLL focused custom 61-gene panel to estimate tumor mutational burden as well as mutational profiles for each patient at baseline, 12, and 24 month time points, as well at the time of disease progression. Preliminary results: The trial is registered at clinicaltrials.gov NCT03516617. The trial opened to accrual at all three Mayo Clinic sites (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ) in September 2018. Twenty-eight pts have been registered; the baseline characteristics are shown in Table 1. The trial is expected to complete enrollment in September 2020; and the primary analysis will be available in September 2022. Disclosures Parikh: Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria. Ding:DTRM Biopharma: Research Funding; Merck: Research Funding. Ailawadhi:Pharmacyclics: Research Funding; Cellectar: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Chanan-Khan:Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Jansen: Research Funding; AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding. Kay:Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board. OffLabel Disclosure: Drug: Acalabrutinib Purpose: treatment of CLL

INTRODUCTION Mutations in BTK and PLCG2 have been reported to occur in ~80% of CLL patients (pts) who have progression of disease on ibrutinib therapy (Woyach, JCO 2017; Ahn, Blood 2017). These mutations are described as appearing months before actual relapse and thus considered as a potential predictive biomarker for future relapse (Quinquenel, Blood 2019). However, the outcomes of these pts after disease progression are not well described. In this study, we seek to investigate time to next therapy and overall survival (OS) following progression among CLL pts on ibrutinib therapy with and without these resistance mutations. METHODS Between 10/2012 and 6/2019, we identified 34 pts in the Mayo Clinic clinical CLL resource who progressed while receiving ibrutinib therapy and also had testing for BTK and PLCG2 mutation performed as part of routine clinical practice at either NeoGenomics Laboratories or The Ohio State University. OS was calculated from time of ibrutinib progression to last known alive or death date; OS was plotted using Kaplan Meier methods and was compared using the log-rank test between various groups (e.g., mutation positive vs negative; CLL progression vs Richter's). Cumulative incidence of time to next treatment in those who had a treatment after progression was adjusted for the competing risk of death. RESULTS Of 34 pts who progressed while receiving ibrutinib, 26 pts experienced CLL progression and 8 pts had Richter's transformation; baseline characteristics in Table 1A. The presence of a BTK or PLCG2 mutation was found in 20/34 (59%) pts (specific mutations in Table 1B). BTK mutation alone was present in 9 pts, 7 pts had PLCG2 mutation alone, and 4 pts had both mutations. Median time between a positive test and start of next therapy was 4 months (range 1-19 months) and did not vary between BTK vs PLCG2 mutations. Among the 26 pts with CLL progression, 18 (69%) pts had a mutation present: BTK alone (n=8), PLCG2 alone (n=6), both (n=4). Therapy following progression on ibrutinib in these pts was as follows: venetoclax (n=16; 11 pts who continued ibrutinib in combination), idelalisib (n=4), investigational treatments (n=2), continued ibrutinib alone (n=2), dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; n=1), and unknown (n=1). Twelve of the 26 pts with CLL progression on ibrutinib, including 8 pts with a prior resistance mutation detected, had subsequent progression of disease on the aforementioned next line therapy. Treatment of these patients consisted of the following: restarted ibrutinib in addition to current treatment of venetoclax (n=5), venetoclax (n=2), pembrolizumab (n=2; 1 pt with continued ibrutinib), obinutuzumab with continued ibrutinib (n=1), gemcitabine and vinorelbine with continued ibrutinib (n=1), and no further treatment (n=1). Among the 8 pts with Richter's transformation as the initial progression event on ibrutinib after mutation testing, 1 pt had a BTK mutation and 1 pt had a PLCG2 mutation. Treatments following progression on ibrutinib included multi-agent chemoimmunotherapy (n=3; 2 pts received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP] with continued ibrutinib and 1 pt received doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD] alone), pembrolizumab (n=3; 1 pt in combination with continued ibrutinib), venetoclax in combination with continued ibrutinib (n=1), and venetoclax and obinutuzumab (n=1). The median time to next treatment (second line of treatment beyond ibrutinib) for the 31 pts who started another therapy following progression on ibrutinib was 16.7 months (95% CI 9.6-NE; Figure 1A) and was not significantly different for pts with or without a resistance mutation (p=0.57). Median OS for all 26 pts with CLL progression was 28.7 month and there was no difference according to presence or absence of a resistance mutation (median 28.7 months vs 18.2 months, p=0.53; Figure 1B). The 8 pts with Richter's transformation had a median OS of 7.1 months (95% CI 2.0-NE). CONCLUSION Approximately 60% of pts tested in this progression cohort had a BTK or PLCG2 mutation at time of or preceding progression on ibrutinib therapy. OS and time to next therapy did not differ statistically between pts with mutated vs non-mutated clones; however, caution should be applied with the conclusions given the limited sample size. Disclosures Ding: DTRM Biopharma: Research Funding; Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Parikh:Ascentage Pharma: Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding.

Background: The 2008 International Working Group for CLL (IWCLL) criteria define MBL as a clonal B-cell disorder with a peripheral blood B-cell count of <5 x 109/L, in the absence of cytopenias(s), lymphadenopathy and/or organomegaly on physical examination, and no other concomitant lymphoproliferative disorder. In the presence of palpable lymphadenopathy and/or organomegaly, and a B-cell count of < 5 x 109/L, a diagnosis of small lymphocytic lymphoma (SLL) is established. A study by Gentile et al (Am J Hematol. 2013) reported that 29 out of 62 individuals with clinically identified MBL (42%) had lymphadenopathy identified on CT imaging. Notably, however, after a median follow-up of 35 months, the rate of progression among cases of MBL with lymphadenopathy identified on CT imaging was only 6.9% (2/29 patients), which was no different than in cases of MBL without lymphadenopathy on CT imaging (rate of progression, 9%; 3/33 patients). Our study sought to 1) determine if lymphadenopathy and/or organomegaly detected by imaging studies performed for unrelated reasons in individuals with MBL can identify a subset with shorter time to first CLL therapy (TFT) and overall survival (OS); and 2) compare outcomes of individuals with MBL who have incidentally detected lymphadenopathy/splenomegaly and SLL patients. Methods: We used the Mayo Clinic CLL Database to identify individuals with high-count MBL (absolute B-cell count: 0.5 - 4.9 x 109/L) and divided them into the following three cohorts: a) Cohort A: no imaging studies available at MBL diagnosis; b) Cohort B: imaging studies done within one year of MBL with no evidence of lymphadenopathy and/or organomegaly; and c) Cohort C: imaging studies done within one year of MBL with lymphadenopathy and/or organomegaly, attributable to MBL. All individuals with MBL were first seen at Mayo Clinic after 1/1/2002; those with a concomitant lymphoproliferative disorder within 3 months of diagnosis were excluded. Patients with SLL seen during the same time interval were identified as a comparison cohort. We compared the baseline characteristics (Kruskal Wallis for continuous and Chi-square for categorical variables) and TFT and OS across the three MBL cohorts, and patients with SLL. Cumulative incidence of TFT was adjusted for the competing risk of death. Age- and sex-adjusted OS was analyzed using inverse weights methods. Results: 657 individuals with high-count MBL with a median follow-up of 6.7 years were identified: 415 (63%) individuals were in Cohort A, 142 (22%) in Cohort B, and 100 in (15%) Cohort C. Compared to Cohort B, individuals in Cohort C were more likely to have unmutated IGHV, high expression of CD38, and higher beta-2 microglobulin level (Table 1). SLL patients were younger, had higher rate of unmutated IGHV, and had high expression of CD49d compared to MBL individuals in Cohort C (Table 1). There was suggestive evidence of a difference in TFT between Cohorts B and C (estimated 10-year treatment rate 28.3% vs. 41.6%; p=0.16; HR 1.62 95% CI 0.84-3.15). TFT was significantly shorter in SLL patients compared to those with Cohort C (estimated 10-year treatment rate 71% vs. 41.6%, respectively, P<0.001; Figure 1A). There was a trend toward shorter OS in Cohort C compared to Cohort B (estimated 10-year OS rate 53.7% vs. 64.2%, respectively, P=0.09; Figure 1B). In contrast, there was no difference in OS among MBL individuals in Cohort C compared to those with SLL (estimated 10-year OS rate 56.9% vs. 62.6%, P=0.72). Summary/Conclusion: Our findings demonstrate that individuals with MBL who have incidentally identified lymphadenopathy/splenomegaly at diagnosis are more likely to have an unfavorable risk profile, shorter TFT and OS compared to patients who did not have lymphadenopathy/splenomegaly at MBL diagnosis. Additionally, these individuals have a longer TFT but similar OS compared to SLL patients seen during the same time interval. If externally validated, these findings have significant implications for individuals with newly diagnosed MBL. Disclosures Ding: Merck: Research Funding; DTRM Biopharma: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Parikh:AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding.