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Purpose: Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an “add on” approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO). Patients and Methods: Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, Results: Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7–67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%. Conclusions: This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti–SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20–directed therapies, and anti-CD38/B-cell maturation antigen–directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not.Significance:Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577.This article is highlighted in the In This Issue feature, p. 549

Supplemental Table 1 and Supplemental Figure Legends

Supplementary Data from Adding Umbralisib and Ublituximab (U2) to Ibrutinib in Patients with CLL: A Phase II Study of an MRD-Driven Approach

Purpose:Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.Experimental Design:This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.Results:The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.Conclusions:These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Purpose:Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.Experimental Design:To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].Results:We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.Conclusions:For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501

Supplemental Figure 2: Progression free survival of patients without prior BTKi exposure who had progressed on venetoclax and were then treated with BTKi.

Purpose:Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an “add on” approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO).Patients and Methods:Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, –4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation.Results:Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7–67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%.Conclusions:This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

Supplemental Figure 1: Overall survival of entire cohort from initiation of venetoclax.

The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti–SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20–directed therapies, and anti-CD38/B-cell maturation antigen–directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not.Significance:Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577.This article is highlighted in the In This Issue feature, p. 549

Background: Richter transformation (RT) is an aggressive diffuse large B-cell lymphoma that can occur in 10% of patients with chronic lymphocytic leukemia (CLL). RT has no approved therapies, poor prognosis, and an estimated median overall survival (OS) of 3-11 months. Pirtobrutinib is a well-tolerated highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi) with favorable oral pharmacology and promising efficacy in patients with poor-prognosis B-cell malignancies following prior covalent BTKi therapy. We now report on RT patients from BRUIN. Methods: Patients previously treated for B-cell malignancies were eligible for pirtobrutinib monotherapy in dose escalation/expansion within the phase 1/2 BRUIN study. Key endpoints: investigator-assessed overall response rate (ORR) and duration of response (DoR) per Lugano 2014 criteria, and safety. The response-evaluable cohort consisted of patients with RT who completed either first response assessment or discontinued therapy. The safety cohort consisted of patients who received ≥1 dose of pirtobrutinib monotherapy (n=725). Data cut was 31 January 2022. Results: Of 57 RT patients (median age: 67 years), 91% (n=52) received at least 1 prior RT-directed therapy. Median lines of prior RT therapy were 2: (anti-CD20 antibody [86%, n=49], chemotherapy [79%, n=45], BCL-2 inhibitor [35%, n=20], BTKi [28%, n=16], PI3K inhibitor [12%, n=7], CAR-T [9%, n=5], immunomodulator [5%, n=3], stem cell transplant [4%, n=2], other systemic therapy [33%, n=19]) and median lines of prior CLL were 2: (BTKi [60%, n=34], anti-CD20 antibody [60%, n=34], chemotherapy [47%, n=27], BCL-2 inhibitor [42%, n=24], immunomodulator [9%, n=5], PI3K inhibitor [7%, n=4], stem cell transplant [7%, n=4], CAR-T [2%, n=1], other systemic therapy [11%, n=6]). ORR for patients within phase 2 (n=56, 200mg once/day starting dose) was 54% (95% CI, 39-68): 5 complete responses, 22 partial responses. Median DoR was 8.6 months (95% CI, 1.9-NE, 63% censored) and median OS was 13.1 months (95% CI, 7.1-NE) at a median follow up time of 5.5 months and 9.7 months respectively. Six patients electively discontinued pirtobrutinib to pursue curative-intent therapy (allogeneic transplant, n=6, 3.8 months median time-on-therapy). The most frequent TEAEs were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). Of Grade≥3 TEAEs, neutropenia (20%, n=143) was the most frequent and hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were of low grade. Fifteen (2%) patients discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib demonstrated promising preliminary efficacy and was well tolerated for patients who received prior RT-directed chemoimmunotherapy and covalent BTKi. Presented:ASH2022. Citation Format: Joanna Rhodes, David Lewis, Paolo Ghia, Nirav N. Shah, Catherine C. Coombs, Chan Y. Cheah, Jennifer Woyach, Nicole Lamanna, Marc S. Hoffmann, Shuo Ma, Toby A. Eyre, Talha Munir, Manish R. Patel, Alvaro J. Alencar, Constantine S. Tam, John F. Seymour, Wojciech Jurczak, Ewa Lech-Maranda, Lindsey E. Roeker, Philip A. Thompson, Paolo B. Abada, Chunxiao Wang, Binoj Nair, Hui Liu, Donald E. Tsai, Anthony R. Mato, William G. Wierda. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: Results from the phase 1/2 BRUIN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT167.

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice. Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected. Results: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose. Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL), but patients (pts) discontinue these agents due to resistance or intolerance. Pirtobrutinib is an oral, highly selective, non-covalent (reversible) BTKi with promising efficacy and safety in heavily pretreated relapsed/refractory (R/R) CLL pts, regardless of BTK C481 mutation status. Recent clinical studies reported on the safety and efficacy of time-limited venetoclax and covalent BTKi combination regimens. We evaluated the safety and efficacy of pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: BRUIN is a phase 1/2 global, multicenter study (NCT03740529) of pirtobrutinib in pts with advanced B-cell malignancies. The phase 1b portion evaluated the safety of pirtobrutinib at a continuous dose of 200 mg QD from Cycle 1, Day 1 plus venetoclax starting on Cycle 2, Day 1 with a standard 5-week dose ramp to 400 mg QD (PV) and PV plus rituximab at 375 mg/m2 on Cycle 1, Day 1, then 500 mg/m2 on Day 1 of Cycles 2-6 (PVR). Prior BTKi was allowed; prior venetoclax was not permitted. Objectives included safety and overall response rate (ORR) of each combination. Results: As of 27 SEP 2021, 15 pts received PV and 10 pts received PVR. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4). The majority of pts in both cohorts had received prior chemotherapy (56%, n=14), CD20 monoclonal antibody (72%, n=18), and/or covalent BTKi (68%, n=17). No dose-limiting toxicities were reported. Safety profiles were generally similar across both cohorts. The most common treatment-emergent adverse events (TEAE) of any grade, regardless of attribution, were neutrophil count decrease (36%), nausea (32%), fatigue (32%), diarrhea (28%), and constipation (24%). The only Grade ≥3 TEAE to occur in more than 2 pts was neutrophil count decrease (36%, n=9). One pt experienced Grade 4 clinical tumor lysis syndrome with resultant acute kidney injury during venetoclax dose escalation, which resolved with supportive measures. No pts discontinued treatment due to AEs. For the 22 pts with efficacy data available as of 03 NOV 2021, median duration of follow-up was 9 months (range, 3.9-15) and the ORR was 95.5% (95% CI, 77-100). All responding pts except 1 remain on therapy (PVR responder discontinued due to death unrelated to study treatment). As all responses were ongoing and early, and MRD analysis was not yet performed. Conclusions: Pirtobrutinib combined with venetoclax ± rituximab was well tolerated and had a safety profile consistent with known drug class findings and no clear additive toxicities in pts with R/R CLL. Early results demonstrate promising efficacy with combination therapy. Citation Format: Lindsey E. Roeker, Anthony R. Mato, Jennifer R. Brown, Catherine C. Coombs, Nirav N. Shah, William G. Wierda, Manish R. Patel, Katharine L. Lewis, Minna Balbas, Junjie Zhao, Nora C. Ku, Jennifer F. Kherani, Donald E. Tsai, Binoj Nair, Chan Y. Cheah. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in combination with venetoclax ± rituximab in relapsed/refractory chronic lymphocytic leukemia: Results from the BRUIN phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT138.