A Review of Selected Presentations from ASH 2022
December 10-13, 2022 • New Orleans, Louisiana
Combination of Ibrutinib Plus Venetoclax with MRD-Driven Duration of Treatment Results in a Higher Rate of MRD Negativity in IGHV Unmutated Than Mutated CLL: Updated Interim Analysis of the FLAIR Study
The ongoing phase 3 FLAIR study was developed with an adaptive trial design to compare different ibrutinib-based regimens with standard frontline treatment for chronic lymphocytic leukemia (CLL).1 Initially, the study included 2 arms comparing fludarabine, cyclophosphamide, and rituximab (FCR) vs ibrutinib plus rituximab.2 The trial design was subsequently adapted in 2017 to add 2 arms: ibrutinib monotherapy as well as ibrutinib in combination with venetoclax. The primary endpoint for the comparison between these 2 newer arms—achievement of minimal residual disease (MRD) negativity—was evaluated during the interim analysis, when 50% of patients reached 2 years postrandomization, and presented at ASH 2022.3
The duration of therapy in both arms was determined by MRD status. MRD was assessed in the peripheral blood and bone marrow at 9 months postrandomization; MRD in the peripheral blood was subsequently assessed at 12 months postrandomization and every 6 months thereafter. The first MRD-negative result prompted a repeat analysis 3 months later; if again negative, MRD was assessed in both the peripheral blood and bone marrow 3 months after that. An MRD-negative status in both the peripheral blood and bone marrow rendered the initial MRD-negative status the time to MRD negativity. The planned duration of therapy was calculated as twice the time to MRD negativity. A patient could stop therapy as early as 2 years postrandomization, and patients could restart ibrutinib if they became MRD-positive.
Patients who were 75 years of age or less and with previously untreated CLL requiring therapy by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria were eligible for enrollment. At this interim analysis, the median patient age was 63 years (range, 33-75 years), with 34.3% of patients over the age of 65. A total of 45.3% of patients had unmutated IGHV, and 9.1% had subset 2 IGHV status (defined by the IGHV3-21/IGLV3-21 combination with a short variable heavy complementarity-determining region 3 of 9 amino acids4).
The combination of ibrutinib plus venetoclax resulted in 65.4% MRD-negative remissions in the bone marrow and 71.3% in the peripheral blood, within 2 years postrandomization. The median time to achieving MRD negativity in the ibrutinib plus venetoclax arm was 19 months in the bone marrow and 12 months in the peripheral blood. A total of 58 of the 136 patients (42.6%) in this arm stopped treatment at month 24 because of MRD negativity.
When assessed by subgroup in an exploratory analysis, the incidence of MRD negativity within 2 years of ibrutinib plus venetoclax treatment was higher in patients with IGHV-unmutated than -mutated CLL (79.7% vs 56.4%, respectively). A logistical regression model was used to assess achievement of MRD negativity within 2 years in bone marrow by IGHV status for patients treated with ibrutinib plus venetoclax. Patients with IGHV-unmutated CLL had a 3.6-fold higher likelihood of achieving MRD negativity in the bone marrow compared with patients with IGHV-mutated CLL (95% CI, 1.59-8.15; P=.0022). The median time to MRD negativity was also shorter in patients with IGHV-mutated disease.
References
1. Collett L, Howard DR, Munir T, et al. Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial. Trials. 2017;18(1):387.
2. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib plus rituximab is superior to FCR in previously untreated CLL: results of the phase III NCRI FLAIR trial. Blood. 2021;138(Suppl 1):642.
3. Munir T, Pitchford A, Bloor A, et al. Combination of ibrutinib plus venetoclax with MRD-driven duration of treatment results in a higher rate of MRD negativity in IGHV unmutated than mutated CLL: updated interim analysis of FLAIR study [ASH abstract 94]. Blood. 2022;140(Suppl 1).
4. Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119(19):4467-4475.
Residual Disease Kinetics Among Patients with High-Risk Factors Treated with First-Line Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O): the GLOW Study
The phase 3 GLOW study evaluated a fixed-duration combination regimen of ibrutinib plus venetoclax in older patients and/or patients with comorbidities with previously untreated CLL.1 In GLOW, compared to chlorambucil plus obinutuzumab, this fixed-duration combination was associated with superior PFS, deeper and more durable undetectable MRD responses, and a reduced requirement for subsequent anticancer treatment. At ASH 2022, a further evaluation of patients in the GLOW study was reported, with a focus on patients with risk factors associated with worse outcomes for both chemoimmunotherapy and venetoclax plus anti-CD20 therapies—namely, unmutated IGHV.2 This current analysis occurred with a median study follow-up of 46 months.
In the overall population, progression-free survival (PFS) by independent review committee remained superior for the combination of ibrutinib plus venetoclax compared with chlorambucil plus obinutuzumab (3.5-year PFS: 74.6% vs 24.8%, respectively; HR 0.214; 95% CI, 0.138-0.334; P <.0001). Undetectable MRD was achieved early during the course of treatment with ibrutinib plus venetoclax. Nearly half of patients (46.2%) treated with this combination achieved undetectable MRD after 6 cycles of combined ibrutinib plus venetoclax, reaching up to 54.7% at 3 months after the end of treatment. From there, the rate of undetectable MRD declined by <10% annually, with a 17% decrease over 2 years. At 27 months after the end of treatment, nearly 40% of patients had undetectable MRD. The ibrutinib plus venetoclax combination was associated with superior PFS regardless of MRD status at 3 months after the end of treatment. The PFS rate at 2 years post-treatment remained ≥80% regardless of MRD status.
The 3.5-year PFS rate was also higher for the ibrutinib plus venetoclax combination compared to the chlorambucil plus obinutuzumab combination in patients with either mutated or unmutated IGHV. However, patients with mutated IGHV achieved prolonged PFS compared to patients with unmutated IGHV. Among patients with mutated IGHV, the 3.5-year PFS rate was over 90% regardless of MRD status at three months after the end of treatment. In patients with unmutated IGHV, the 3.5-year PFS rate was 90% in patients with undetectable MRD, and 67% in patients with detectable MRD at three months after the end of treatment.
Finally, 3.5-year overall survival (OS) was reported, and was higher with ibrutinib plus venetoclax compared with chlorambucil plus obinutuzumab (87.5% vs 77.6%, respectively; HR 0.487; 95% CI, 0.262-0.907; nominal P =.0205. Most deaths in the chlorambucil plus obinutuzumab arm occurred while off treatment, and more infection-related deaths were seen with chlorambucil plus obinutuzumab.
References
1. Kater AP, Owen C, Moreno C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1(7):1-13.
2. Niemann CU, Munir T, Moreno C, et al. Residual disease kinetics among patients with high-risk factors treated with first-line fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O): the Glow study [ASH abstract 93]. Blood. 2022;140(Suppl 1).
Treatment Outcomes after Undetectable MRD with First-Line Ibrutinib (Ibr) Plus Venetoclax (Ven): Fixed Duration (Placebo) Treatment Versus Continued Ibr with up to 5 Years Median Follow-up in the CAPTIVATE Study
CAPTIVATE was an international, multicenter phase 2 study designed to evaluate the combination of ibrutinib plus venetoclax as frontline therapy in 2 cohorts of patients: a fixed-duration cohort and an MRD cohort.1,2 In the MRD cohort, patients with confirmed undetectable MRD following completion of ibrutinib plus venetoclax were randomized in a double-blind manner to receive placebo (ie, a fixed-duration regimen) or continued ibrutinib. At a primary analysis, the 1-year disease-free survival (DFS) rates were similar between these 2 arms (95% vs 100%, respectively; difference, 4.7%; 95% CI, -1.6-10.9; P=.15).3 Results from a longer-term follow-up (median 56 months) were presented at ASH 2022.4
In this longer-term follow-up of the MRD cohort, the 3-year DFS rates continued to be similar between the placebo and ibrutinib arms (85% vs 93%, respectively; difference, 8.3%; 95% CI, -5.5-22.1; P=.1621). The responses achieved with the ibrutinib plus venetoclax combination proved durable, with no significant difference in duration of complete response (CR) between the placebo and ibrutinib arms (Figure 1A).
The 4-year-free PFS rate was 88% (95% CI, 73.6-94.8) in the placebo arm, compared with 95% (95% CI, 82.3-98.8) with continued ibrutinib. The 4-year OS rates were also similar between the 2 arms (100% vs 98%, respectively). Further, these efficacy outcomes were analyzed across patient subgroups, including those with del(17p), TP53 mutation, or a complex karyotype (Figure 1B). Overall, the outcomes among these subgroups were consistent with those observed in the overall MRD cohort.
During the randomized portion of this trial, the incidence of adverse events was small. One new atrial fibrillation event occurred in the ibrutinib arm, and there were no new grade 3 or higher hemorrhage events. The study investigators concluded that these results continued to support a fixed-duration regimen and the potential for durable treatment-free remissions.
References
1. Clinicaltrials.gov. Ibrutinib plus venetoclax in subjects with treatment-naive chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL). Last updated February 18, 2022. Accessed January 17, 2023. https://clinicaltrials.gov/ct2/show/NCT02910583
2. Tam CS, Allan JN, Siddiqi T, et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood. 2022;139(22):3278-3289.
3. Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865.
4. Allan JN, Siddiqi T, Kipps TJ, et al. Treatment outcomes after undetectable MRD with first-line ibrutinib (Ibr) plus venetoclax (Ven): fixed duration treatment (placebo) versus continued Ibr with up to 5 years median follow-up in the CAPTIVATE study [ASH abstract 92]. Blood. 2022;140(Suppl 1).
Final Analysis of the Prospective Multicenter CLL2-GIVe Trial of Obinutuzumab (GA101, G), Ibrutinib (I), and Venetoclax (Ve) in Untreated Patients with CLL with 17p Deletion/TP53 Mutation
CLL2-GIVe was an open-label, multicenter phase 2 trial that enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. This study was designed to evaluate time-limited, response-adapted, fixed-duration combination treatment composed of obinutuzumab, ibrutinib, and venetoclax in these high-risk patients. The GIVe regimen consisted of induction therapy (6 cycles of obinutuzumab, ibrutinib, and venetoclax), with venetoclax and ibrutinib continued for up to 6 additional cycles as consolidation therapy. Ibrutinib monotherapy was then administered for cycles 13 to 36 in patients not achieving a CR and with undetectable MRD at cycles 9 and 12. The primary endpoint was CR rate at cycle 15 (final restaging). Initial results from the CLL2-GIVe trial were previously published, showing that the primary endpoint was met with a CR rate of 58.5% at cycle 15 (95% CI, 42.1-73.7; P<.001).1 Final results were presented at ASH 2022.2
The median age of patients in the CLL2-GIVe trial was 62 years (range, 35-85 years), and 78.0% had IGHV-unmutated disease. Nearly two-thirds of patients (61.6%) had a complex karyotype (3 or more chromosomal aberrations). A total of 58.5% had del(17p) and TP53 mutation, and 4.9% had del(17p) without TP53 mutation. One-third of patients (36.6%) had TP53 mutation with no del(17p).
In this final analysis, the overall response rate (ORR) at cycle 15 was 100%, composed of 58.5% CR/incomplete CR (CRi) (95% CI, 42.1-73.7; P<.001) and 41.5% partial responses (PR). MRD results are shown in Figure 2; 87.8% of patients achieved undetectable MRD at cycles 9 and 12. After a median follow-up of 38.4 months, the 3-year PFS rate was 79.9% and the 3-year OS rate was 92.6%. PFS outcomes were impacted by the CLL genetics. For example, the 3-year PFS rate was 100% in patients with no del(17p) and was 67.6% in patients with del(17p) (log-rank P=.012). In patients with a complex karyotype, the 3-year PFS was 70.4%, compared with 93.3% in patients without a complex karyotype (log-rank P=.215). Finally, the 3-year PFS rate was 74.0% in patients with unmutated IGHV compared with 100% in patients with mutated IGHV (P=.147). However, these analyses were limited to a small patient number.
The incidence of adverse events was highest during the first 6 cycles, then decreased during the course of treatment. Neutropenia (48.8% grade ≥3) and thrombocytopenia (17.1% grade ≥3) were the most common hematologic adverse events reported. The most frequently reported nonhematologic adverse events were infections/infestation, diarrhea, infusion-related reactions, headache, and nausea. The most common infections included respiratory tract infections (33%), gastrointestinal infections (9%), and viral infections (9%), as well as infections with an unspecified pathogen (24%). Atrial fibrillation was reported in 14.6% of patients (2.4% were grade ≥3).
References
1. Huber H, Edenhofer S, von Tresckow J, et al. Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia. Blood. 2022;139(9):1318-1329.
2. Huber H, Tausch E, Schneider C, et al. Final analysis of the prospective multicenter CLL2-GIVe trial of obinutuzumab (GA101, G), ibrutinib (I), and venetoclax (Ve) in untreated patients with CLL with 17p deletion/TP53 mutation [ASH abstract 343]. Blood. 2022;140(Suppl 1).
Updated Results from a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease
The CLL14 trial demonstrated that venetoclax plus obinutuzumab administered in a time-limited regimen was highly effective as a frontline regimen for CLL.1 However, this study also showed that responses with this combination were not as durable for patients with TP53-mutated disease.2 The addition of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib to this combination, creating a triplet regimen, has shown efficacy in both all-comer and patients with high-risk disease; however cardiac and infectious adverse events were common.3-5 Because of its lower incidence of these toxicities, the second-generation BTK inhibitor acalabrutinib has also been explored in this triplet regimen (acalabrutinib plus venetoclax and obinutuzumab [AVO]). Results from an initial cohort unrestricted by genetic risk who were treated with this triplet regimen have been previously published.6 At ASH 2022, results from a different cohort with enrollment restricted to high-risk patients were presented.7 In addition, results from the initial unrestricted cohort were updated.
The primary endpoint, the rate of CR with undetectable MRD in the bone marrow at cycle 16, was achieved in 43% of the unrestricted cohort and in 45% of the TP53-mutated cohort (Figure 3A). An additional 50% and 52% of patients in each cohort, respectively, achieved a PR. Further, in patients in the unrestricted cohort, the AVO triplet regimen was associated with high rates of undetectable MRD at cycle 16 (Figure 3B) both in the peripheral blood (86%) and bone marrow (86%). Similar rates of undetectable MRD at cycle 16 were also reported in the peripheral blood (86%) and bone marrow (83%) of patients with TP53-mutated disease. An exploratory analysis showed that these results were durable through cycle 25. At a median follow-up of 35 months, 92.6% of patients remained progression free, and the overall OS rate was 98.5%.
Headache (78%), fatigue (76%), bruising (66%), and nausea (49%) were the most common nonhematologic adverse events reported; neutropenia and thrombocytopenia each occurred in more than 70% of patients. Atrial fibrillation occurred at a rate of 3.0%. There were no major bleeding events and no occurrences of opportunistic infections. Grade 3 non-COVID-19 infections occurred in 5.8% of patients; COVID-19 infections occurred in 9.0% of patients.
The AVO combination is currently under further investigation in the phase 3 ACE-CL-311/AMPLIFY trial in patients with non-high-risk CLL.8
References
1. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.
2. Tausch E, Schneider C, Robrecht S, et al. Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax. Blood. 2020;135(26):2402-2412.
3. Rogers KA, Huang Y, Ruppert AS, et al. Phase II study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naïve and relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(31):3626-3637.
4. Huber H, Edenhofer S, von Tresckow J, et al. Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia. Blood. 2022;139(9):1318-1329.
5. Huber H, Tausch E, Schneider C, et al. Final analysis of the prospective multicenter CLL2-GIVe trial of obinutuzumab (GA101, G), ibrutinib (I), and venetoclax (Ve) in untreated patients with CLL with 17p deletion/TP53 mutation [ASH abstract 343]. Blood. 2022;140(Suppl 1).
6. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402.
7. Ryan CE, Lampson BL, Tyekucheva S, et al. Updated results from a multicenter, phase 2 study of acalabrutinib, venetoclax, obinutuzumab (AVO) in a population of previously untreated patients with CLL enriched for high-risk disease [ASH abstract 344]. Blood. 2022;140(Suppl 1).
8. Clinicaltrials.gov. Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL. Last updated December 16, 2022. Accessed January 17, 2023. https://clinicaltrials.gov/ct2/show/NCT03836261
Contribution of Obinutuzumab to Acalabrutinib Therapy in Patients with Treatment-Naive CLL: Analysis of Survival Outcomes By Genomic Features
The ELEVATE-TN trial evaluated acalabrutinib, administered as monotherapy or in combination with the anti-CD20 antibody obinutuzumab, as frontline treatment for CLL.1,2 Significantly improved PFS was observed with the acalabrutinib plus obinutuzumab combination, but a post hoc analysis showed no significant difference in OS between the 2 groups.3 This combination has also been evaluated in the CL-003 study.4 In a poster presented at ASH 2022, a post hoc analysis was performed from patients with previously untreated CLL who received either acalabrutinib alone or in combination with obinutuzumab.5
A total of 376 patients were included, of whom 260 were considered to have high-risk disease (comprised of 20% with del(17p) and/or TP53 mutation, 88% with unmutated IGHV, and 25% with a complex karyotype).
Among patients with non-high-risk disease, differences in PFS and OS outcomes were not significantly different between the acalabrutinib monotherapy and acalabrutinib plus obinutuzumab groups. In patients with del(17p) and/or TP53 mutation, or with a complex karyotype, the addition of obinutuzumab to acalabrutinib also did not significantly improve PFS or OS. In contrast, PFS (HR, 0.44; 95% CI, 0.21-0.86; P=.02) and OS (HR, 0.34; 95% CI, 0.11-0.89; P=.03) were significantly prolonged with the addition of obinutuzumab to acalabrutinib in patients with unmutated IGHV (Figure 4).
References
1. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
2. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175.
3. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: five-year follow-up of ELEVATE-TN. J Clin Oncol. 2022;40(suppl 16):7539.
4. Woyach JA, Blachly JS, Rogers KA, et al. Acalabrutinib plus obinutuzumab in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia. Cancer Discov. 2020;10(3):394-405.
5. Davids MS, Sharman JP, Eyre TA, et al. Contribution of obinutuzumab to acalabrutinib therapy in patients with treatment-naive chronic lymphocytic leukemia: analysis of survival outcomes by genomic features [ASH abstract 1815]. Blood. 2022;140(Suppl 1).
Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of the ALPINE Randomized Phase 3 Study
The second generation BTK inhibitor zanubrutinib was designed to have greater BTK specificity than ibrutinib. As a result, zanubrutinib is hypothesized to have an improved toxicity profile compared with the first-generation agent ibrutinib. In previously untreated patients with CLL without del(17p), treatment with zanubrutinib resulted in superior PFS compared with bendamustine plus rituximab in the phase 3 SEQUOIA study.1 In a late-breaking abstract presented at ASH 2022, final results from the phase 3 ALPINE study were presented and simultaneously published.2,3 ALPINE was a head-to-head study comparing zanubrutinib with ibrutinib in patients with relapsed/refractory CLL/SLL.
The ALPINE study randomized 652 patients with relapsed/refractory CLL to treatment with zanubrutinib or ibrutinib. Patients were eligible for enrollment if they had measurable disease and had received at least 1 prior therapy (no prior BTK inhibitor therapy was allowed). The primary endpoint, ORR, was previously reported to have achieved statistical significance (78.3% with zanubrutinib vs 62.5% with ibrutinib; superiority 2-sided P=.0006).4
At the final analysis, at a median follow-up of 29.6 months, the median PFS was not reached with zanubrutinib vs 34.2 months with ibrutinib (HR, 0.65; 95% CI, 0.49-0.86; P=.002). PFS favored zanubrutinib across several patient subgroups, including in patients with del(17p)/TP53 mutation (Figure 5). Fewer deaths were reported with zanubrutinib than with ibrutinib, and the median OS was not reached in either arm (HR, 0.76; 95% CI, 0.51-1.11).
Differences were also observed in the tolerability profiles of zanubrutinib and ibrutinib. The rate of grade 3 or higher adverse events was slightly higher with ibrutinib (67.3% with zanubrutinib vs 70.4% with ibrutinib). The incidence of any-grade atrial fibrillation and flutter, a key secondary endpoint, was 5.2% with zanubrutinib compared with 13.3% with ibrutinib (nominal 2-sided P=.0004). The incidence of grade 3 or greater atrial fibrillation and flutter events was also lower with zanubrutinib vs ibrutinib (2.5% vs 4.0%, respectively). Any-grade cardiac disorders were more common in ibrutinib-treated patients than in zanubrutinib-treated patients (21.3% with zanubrutinib vs 29.6% with ibrutinib). The incidence of any-grade and grade 3 or greater neutropenia was higher with zanubrutinib than with ibrutinib (any grade, 29.3% vs 24.4%; grade ≥3, 16.0% vs 13.9%, respectively). However, the rate of infections was not higher with zanubrutinib. Hypertension was reported in 23.5% of patients in the zanubrutinib arm and 22.8% of patients in the ibrutinib arm. Grade 3 hypertension was reported in 15.1% and 13.6% of the treatment arms, respectively. The incidence of hemorrhagic events, including major hemorrhagic events, were similar in both arms.
The study investigators concluded by noting that ALPINE was the first study to demonstrate both PFS and ORR superiority in a head-to-head comparison of BTK inhibitors in patients with relapsed/refractory CLL.
References
1. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043.
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): results from final analysis of ALPINE randomized phase 3 study [ASH abstract LBA-6]. Blood. 2022;140(Suppl 1).
3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2022 Dec 13. doi: 10.1056/NEJMoa2211582. Epub ahead of print. PMID: 36511784.
4. Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: interim analysis of a randomized phase III trial. J Clin Oncol. 2022 Nov 17:JCO2200510. doi: 10.1200/JCO.22.00510. Epub ahead of print. PMID: 36395435.
MRD4 Eradication at 6 Months and Early Clearance of MRD with Combination of Ibrutinib Plus Venetoclax Results in Sustained Clinical and MRD Responses: Exploratory Analysis of the Blood Cancer UK TAP CLARITY Study
The CLARITY study evaluated the combination of ibrutinib and venetoclax in patients with relapsed/refractory CLL, with the intention of stopping treatment, depending on MRD response.1 A 5-year follow-up of the CLARITY study was presented at ASH 2022, including an updated exploratory analysis of MRD eradication at 6 months and early clearance of MRD.2
A total of 54 patients were enrolled (50 patients were treated with the combination regimen). The treatment regimen began with a 2-month ibrutinib run-in followed by venetoclax introduction. The primary endpoint, undetectable MRD in the bone marrow, was assessed at 12 months of treatment with the combination therapy. The overall duration of therapy was determined by MRD analysis.
The primary endpoint, undetectable MRD in the bone marrow, was achieved by 40% of patients. The MRD negativity rate in the bone marrow was 45% among the 20 patients previously treated with FCR or bendamustine plus rituximab (BR) chemoimmunotherapy, and was 56% among the 9 patients who received prior idelalisib. In the peripheral blood, 58% of patients achieved an undetectable MRD (70% of patients previously treated with FCR or BR chemoimmunotherapy and 67% of patients previously treated with idelalisib).
The CR/CRi rate at month 38 was 78%, and the ORR was 92%. Most patients retained the response at the latest data cutoff. Neither median PFS nor median OS was reached by 60 months of follow-up. The estimated 5-year PFS was 78%; the estimated 5-year OS was 91%. No significant difference was observed in PFS or OS outcomes between IGHV-mutated and -unmutated patients, suggesting that both groups may benefit from the combination of ibrutinib plus venetoclax.
MRD rates at various time points of the trial in both peripheral blood and bone marrow are shown in Figure 6. The sensitivity of combination was assessed according to leukocyte depletion in the peripheral blood at month 4 (after 2 months of combination treatment). A greater than 2-log leukocyte depletion in the first 2 months of treatment with the ibrutinib and venetoclax combination was associated with an improved MRD and clinical responses at later time points. This suggests that the initial rate of disease depletion is highly predictive of longer-term response to ibrutinib plus venetoclax.
References
1. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol. 2019;37(30):2722-2729.
2. Munir T, Cherrill L-R, Webster N, et al. MRD4 eradication at 6 months and early clearance of MRD with combination of ibrutinib plus venetoclax results in sustained clinical and MRD responses: exploratory analysis of the Blood Cancer UK TAP CLARITY study [ASH abstract 91]. Blood. 2022;140(Suppl 1).
Phase 1/2 Study of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Results with >4 Years of Follow-up
A final analysis of the phase 1/2 ACE-CL-001 study of acalabrutinib monotherapy in patients with relapsed/refractory CLL/SLL was reported at ASH 2022.1 Earlier interim analyses have previously been reported.2,3
At a median follow-up of 52.6 months, 31% of the 134 patients initially enrolled remained on treatment. The ORR among patients in this study was 90%; of these, 4% were CRs. The median duration of response was 60.1 months, and the 66-month duration of response rate was 45%. The 72-month PFS rate was 45% in the overall population. The PFS rate was impacted by CLL genetics (Figure 7). For example, patients with unmutated IGHV had a 72-month PFS rate of 37%. For patients with a complex karyotype, the 72-month PFS rate was 20%. Among patients with del(17p), the 72-month PFS rate was 5%. At this long-term follow-up, no new safety signals were reported with acalabrutinib. The toxicity profile at 72 months was consistent with those reported at the earlier interim analyses.
References
1. Furman RR, Wierda WG, Schuh A, et al. Phase 1/2 study of acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: final results with >4 years of follow-up. [ASH abstract 4434]. Blood. 2022;140(Suppl 1).
2. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.
3. Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020;135(15):1204-1213.
Efficacy of Pirtobrutinib in Relapsed/Refractory CLL and Richter Transformation: Additional Results From the Phase 1/2 BRUIN Study
Two studies presented at ASH 2022 examined pirtobrutinib, a novel, investigational, highly selective, noncovalent (reversible) BTK inhibitor. Pirtobrutinib has been shown to inhibit both wild-type and the BTK inhibitor-resistant C481-mutant version of BTK with equally high potency.1 Both studies were analyses of the phase 1/2 BRUIN study, which evaluated pirtobrutinib in patients with relapsed or refractory B-cell malignancies, including CLL/SLL.2
The first study presented data from additional patients and an extended follow-up of the BRUIN study.3 After more than 2 years of additional data, these updated results continued to demonstrate the efficacy of pirtobrutinib in patients with CLL/SLL who were previously treated with BTK inhibitors. The ORR was 82.2% among 247 patients; in 100 patients who had prior treatment with both a BTK inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor, the ORR was 79.0%. PFS was not significantly impacted by BTK C481 mutation status, age, TP53 mutation and/or del(17p) status, or additional prior lines of therapy. Discontinuations owing to treatment-related adverse events were reported in 2.6% of patients.
The second study focused on the efficacy of pirtobrutinib in the cohort of 57 heavily pretreated patients with Richter transformation in the BRUIN study.4 Historically, these patients have an extremely poor prognosis. The ORR among 50 evaluable patients was 54%, including 5 CRs and 22 PRs. After a median follow-up of 5.5 months, the median duration of response was 8.6 months (95% CI, 1.9 to not estimable). At a median follow-up of 9.7 months, the median OS was 13.1 months (95% CI, 7.1 to not estimable).
References
1. Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735-743.
2. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901.
3. Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed/refractory CLL/SLL: additional patients and extended follow-up from the phase 1/2 BRUIN study [ASH abstract 961]. Blood. 2022;140(Suppl 1).
4. Wierda WG, Lewis DJ, Ghia P, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in richter transformation: results from the phase 1/2 BRUIN study [ASH abstract 347]. Blood. 2022;140(Suppl 1).
Initial Results from a Phase 1/2 Dose Escalation and Expansion Study Evaluating MS-553, a Novel and Selective PKCβ Inhibitor, in Patients with CLL/SLL
The B-cell receptor (BCR) signaling complex signals via a pathway composed sequentially of BTK, phospholipase C γ 2 (PLCγ2), and protein kinase C β (PKCβ).1 Treatment with a BTK inhibitor can lead to the development of resistance mutations in BTK and PLCγ2.2,3 As a result, downstream signaling can persist even in the presence of a BTK inhibitor. Because these mutations are in proteins that lie upstream of PKCβ, inhibition of this protein has the potential to overcome these resistance mutations.
MS-553 is a novel, investigational, selective PKCβ inhibitor. After preclinical studies demonstrated that MS-553 could reduce activation of primary CLL cells with both wild-type and C481-mutated BTK, a phase 1/2 dose escalation and expansion study was developed.4,5 The initial results from this study were reported at ASH 2022.6
Key populations of patients enrolled in this study include those with relapsed/refractory disease; patients with relapsed/refractory disease and BTK or PLCγ2 mutations; previously untreated patients; and previously untreated patients with TP53-mutated CLL. A total of 43 patients were included in the initial analysis.
At this interim analysis, the ORR in patients with CLL was 48%. Further analysis also showed activity with MS-553 in combination with either acalabrutinib or venetoclax plus an anti-CD20 antibody, though the patient numbers were very small in the frontline setting. MS-553 was primarily associated with gastrointestinal-related toxicities, including nausea (60%), diarrhea (44%), decreased appetite (23%), vomiting (21%), abdominal pain (19%), and dysgeusia (12%). In contrast, side effects normally associated with BTK inhibitors (arthralgia, hemorrhage, atrial fibrillation, and others) were uncommon. A recommended phase 2 dosage was identified as 250 mg twice daily.
References
1. Gu D, Tang H, Wu J, Li J, Miao Y. Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021;14(1):40.
2. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294.
3. Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735-743.
4. Muhowski EM, Lehman AM, S, MA, et al. The protein kinase C inhibitor MS-553 for the treatment of chronic lymphocytic leukemia. Blood. 2019;134 (Suppl 1):2077.
5. Clinicaltrials.gov. A Study of the selective PKC-β inhibitor MS- 553. Last updated November 21, 2022. Accessed January 17, 2023. https://clinicaltrials.gov/ct2/show/NCT03492125
6. Blachly JS, Stephens DM, Ye JC, et al. Initial results from a phase 1/2 dose escalation and expansion study evaluating MS-553, a novel and selective PKCβ inhibitor, in patients with CLL/SLL [ASH abstract 963]. Blood. 2022;140(Suppl 1).
Highlights in Chronic Lymphocytic Leukemia from the 2022 ASH Annual Meeting and Exposition: Commentary
The 64th American Society of Hematology (ASH) Annual Meeting and Exposition took place in early December 2022 in New Orleans, Louisiana. It was good to see many colleagues at this in-person and virtual meeting, and a number of impactful studies were presented in CLL.
One of the main highlights in CLL was a presentation of the final results of the ALPINE study, which was a randomized phase 3 trial of zanubrutinib versus ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL.1 These results were simultaneously published.2 The study enrollment was open to all patients with R/R CLL/SLL, including those with either high-risk genetic features or standard risk features. The investigators reported that PFS in patients treated with zanubrutinib was significantly improved compared with patients who received ibrutinib. The 2-year PFS was 79.5% in the zanubrutinib arm, and 67.3% in the ibrutinib arm. Importantly, 2-year PFS was also better with zanubrutinib in those patients with high-risk disease (i.e, TP53 aberration): 77.6% vs 55.7% with ibrutinib. The safety data from this trial were previously described and demonstrated that zanubrutinib was associated with fewer cardiac events, particularly atrial fibrillation, as well as other adverse events.4 The results were particularly important as they contributed to the recent US Food and Drug Administration (FDA) approval of zanubrutinib in patients with CLL.3 This new indication allows use of zanubrutinib in both frontline and relapsed/refractory settings.
The final results from the ALPINE trial clearly indicate that zanubrutinib is superior to ibrutinib, both in terms of efficacy and safety, in R/R CLL/SLL. The fact that zanubrutinib also demonstrates improved efficacy in a high-risk patient population is particularly encouraging, further suggesting that this drug acts differently than ibrutinib.
One interesting feature from this study was that the rate of hypertension was similar between zanubrutinib (21.9%) and ibrutinib (19.8%) arm. This was somewhat in contrast to previous reports with zanubrutinib, for example in patients with Waldenström macroglobulinemia in the ASPEN study, where the rate of hypertension was higher with ibrutinib (16% versus 11% with zanubrutinib).5 It is not yet clear if this difference in incidences is due to the study population or some other feature, but nevertheless it remains an important observation and patients with CLL who are treated with zanubrutinib should be monitored for hypertension.
Another point from ALPINE was that there was a fairly high discontinuation rate for both zanubrutinib (27.2%) and ibrutinib (41.5%). These discontinuation rates were a bit higher than we typically expect based on clinical trials of these agents in the past. However, it is notable that the ALPINE study enrolled patients in many countries, and also was conducted in recent years where patients may now have better access to novel agents and clinical trials. Thus, this study may in fact represent the current real world situation in terms of how frequently BTK inhibitors get discontinued for adverse events.
It may be that ibrutinib underperformed in terms of PFS in this study. For example, patients in the RESONATE study who had received 1 prior line of therapy—similar to the ALPINE study—had a higher PFS at 2 years than in this study.6 Again, it is important to consider that the RESONATE study was conducted several years ago, and the treatment landscape for CLL has evolved since then.
A final note is that some publications now suggest that zanubrutinib may be associated with a distinct BTK mutational profile compared to ibrutinib when resistance occurs.7 This may suggest a somewhat different biological effect of zanubrutinib compared with ibrutinib.
Several studies were presented which evaluated the combination of ibrutinib and venetoclax in patients with CLL. The GLOW study randomized patients with previously untreated CLL who did not have a TP53 abnormality to either a combination of ibrutinib and venetoclax or chlorambucil and obinutuzumab.8 This study led to approval of the ibrutinib plus venetoclax combination regimen in Europe; this regimen is not approved in the United States. The GLOW study revealed superior PFS for this combination over the control arm. The recently presented results also included some granular data. We know, for example, that the combination of venetoclax plus obinutuzumab (the CLL14 regimen) demonstrates high efficacy in all patients with previously untreated CLL.9 However, patients with unmutated IGHV demonstrate an inferior PFS with the combination of venetoclax plus obinutuzumab. We now begin to see a similar result in the GLOW study. After a median follow-up of 46 months, the curves begin to separate for PFS for patients with mutated vs unmutated IGHV. For patients with unmutated IGHV treated with the ibrutinib plus venetoclax combination, the PFS curve has dropped by about 20 percentage points at the 3-year follow-up mark, compared with mutated IGHV. This suggests what we have already suspected – this regimen will not be curative, and may not result in long-term remissions in patients with unmutated IGHV. Additionally, it remains to be seen if patients with previously untreated CLL will benefit from this regimen to the same degree as venetoclax plus obinutuzumab – CLL17 aims to answer that exact question.
An important feature of the ibrutinib-venetoclax combination is that it is an all-oral regimen and does not require intravenous administrations of an anti-CD20 antibody. However, a drawback of this all-oral regimen is that even though the GLOW regimen has an ibrutinib lead-in that can partially mitigate the risk for tumor lysis syndrome (TLS), it does not fully circumvent the need for TLS monitoring, and patients still need to come to the clinic for blood draws .
Another ibrutinib-based combination study presented was CAPTIVATE, which focused on the MRD cohort in this study.10 After receiving an ibrutinib plus venetoclax combination, patients with confirmed undetectable MRD were randomized to continued treatment with either ibrutinib or placebo. The 4-year PFS rate was very high in both the ibrutinib and placebo arms (95% and 88%, respectively), suggesting that those patients who reach undetectable MRD with this combination are able to maintain the undetectable MRD state for several years, even after treatment stops. Interestingly, contrary to GLOW, patients with mutated and unmutated IGHV in the CAPTIVATE study showed statistically similar rates of PFS. However, the follow-up on the study may still be too short to see a difference here.
Both the GLOW and CAPTIVATE studies showed high efficacy with the oral combination regimen of ibrutinib and venetoclax. Whether this combination targeting dual pathways simultaneously is better than sequential therapy targeting BTK and BCL-2 separately remains to be seen.
An important caveat from these studies is that both use ibrutinib, a drug that was demonstrated to be less efficacious and associated with greater toxicities than zanubrutinib in the ALPINE study described above, and that also had inferior toxicity profile (albeit similar efficacy) to acalabrutinib in patients with high risk R/R CLL in the ELEVATE-R/R study.1,2,11 This prompts the question of whether ibrutinib is the right partner in this oral combination. Studies investigating zanubrutinib and acalabrutinib in combination with venetoclax are ongoing.
Updated data from triplet regimens were also presented at ASH 2022. Data from a phase 2 study of acalabrutinib plus venetoclax and obinutuzumab in patients with previously treated CLL enriched for high-risk disease were presented.12 These data demonstrated promising safety and efficacy with this triplet combination, but a longer follow-up is required.
The CLL2-GIVe trial, examining the triplet regimen of ibrutinib plus venetoclax and obinutuzumab in patients with previously untreated del(17p) or TP53-mutated CLL, were also presented.13 This study demonstrated impressive PFS and OS (3-year PFS 79.9%; 3-year OS 92.6%) and high responses rates, but the median follow-up of 38.4 months is relatively short.
Patients who progress on BTK inhibitors, and in particular those who are refractory to both BTK and BCL-2 inhibitors (“double-refractory”) remain a high unmet medical need for whom there is no accepted standard of care. Pirtobrutinib, a noncovalent BTK inhibitor, may help address this gap. Pirtobrutinib has been studied in the phase 1/2 BRUIN study with additional updates presented at ASH. These updated results showed high response rates with pirtobrutinib in patients who received a prior BTK inhibitor and also in “double-refractory” patients.14 It is also now known that resistance to this noncovalent BTK inhibitor can emerge via a set of novel resistance mutations.15
Efficacy of pirtobrutinib in patients with Richter transformation was also reported.16 Among these patients who have no good treatment options, pirtobrutinib resulted in a response rate of 54%, with about 10% of patients achieving a CR. Importantly, several patients in this small study achieved long-term PFS and remained on the drug for longer than 6 months, which is remarkable for a single oral agent in this disease.
An innovative approach to circumvent BTK inhibitor resistance was highlighted in a first-in-human trial of NX-2127-001, a BTK protein degrader.17 Instead of inhibiting the enzymatic activity of BTK, this agent utilizes the ubiquitin proteasome pathway to ubiquitinate BTK, leading to a decrease in BTK levels. This study included 23 patients with CLL, many of whom were refractory to both BTK and BCL-2 inhibitors. Eight patients had progressed on pirtobrutinib as well, and most patients had a BTK mutation present. NX-2127-001 was well tolerated, with side effects including fatigue, neutropenia, contusion, thrombocytopenia, hypertension, and atrial fibrillation which were overall characteristic of those seen with covalent BTK inhibitors. The very preliminary efficacy results show an ORR of 33% among the evaluable patients. Response assessments are ongoing. We certainly look forward to more data with this novel class of drug.
Finally, epcoritamab, a bispecific antibody, was evaluated in the EPCORE CLL-1 trial.18 Even though only a small number of patients with Richter transformation were treated, 6 out of 10 achieved a response, with 5 patients showing a complete metabolic response. These data, coupled with other reports of various investigational bispecific antibodies, are very encouraging and suggest that bispecific antibodies may be a future option for these patients with a high unmet need.
Overall, several important and some practice-changing abstracts were presented at the ASH 2022 Annual Meeting. We look forward to further follow-up from the studies discussed here.
References
1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): results from final analysis of ALPINE randomized phase 3 study [ASH abstract LBA-6]. Blood. 2022;140(Suppl 1).
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2022 Dec 13. doi: 10.1056/NEJMoa2211582. Epub ahead of print. PMID: 36511784.
3. Zanubrutinib [prescribing information]. San Mateo, CA; BeiGene USA, Inc. Revised January 2023.
4. Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: interim analysis of a randomized phase III trial. J Clin Oncol. 2022 Nov 17:JCO2200510. doi: 10.1200/JCO.22.00510. Epub ahead of print. PMID: 36395435.
5. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050.
6. Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353-1363.
7. Blombery P, Thompson ER, Lew TE, et al. Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance. Blood Adv. 2022;6(20):5589-5592.
8. Niemann CU, Munir T, Moreno C, et al. Residual disease kinetics among patients with high-risk factors treated with first-line fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O): the GLOW study [ASH abstract 93]. Blood. 2022;140(Suppl 1).
9. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.
10. Allan JN, Siddiqi T, Kipps TJ, et al. Treatment outcomes after undetectable MRD with first-line ibrutinib (Ibr) plus venetoclax (Ven): fixed duration treatment (placebo) versus continued Ibr with up to 5 years median follow-up in the CAPTIVATE study [ASH abstract 92]. Blood. 2022;140(Suppl 1).
11. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.
12. Ryan CE, Lampson BL, Tyekucheva S, et al. Updated results from a multicenter, phase 2 study of acalabrutinib, venetoclax, obinutuzumab (AVO) in a population of previously untreated patients with CLL enriched for high-risk disease [ASH abstract 344]. Blood. 2022;140(Suppl 1).
13. Huber H, Tausch E, Schneider C, et al. Final analysis of the prospective multicenter CLL2-GIVe trial of obinutuzumab (GA101, G), ibrutinib (I), and venetoclax (Ve) in untreated patients with CLL with 17p deletion/TP53 mutation [ASH abstract 343]. Blood. 2022;140(Suppl 1).
14. Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed/refractory CLL/SLL: additional patients and extended follow-up from the phase 1/2 BRUIN study [ASH abstract 961]. Blood. 2022;140(Suppl 1).
15. Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735-743.
16. Wierda WG, Lewis DJ, Ghia P, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: results from the phase 1/2 BRUIN study [ASH abstract 347]. Blood. 2022;140(Suppl 1).
17. Mato AR, Wierda WG, Ai WZ, et al. NX-2127-001, a first-in-human trial of NX-2127, a Bruton’s tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies [ASH abstract 965]. Blood. 2022;140(Suppl 1)
18. Kater AP, Ye JC, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with Richter’s syndrome: early results from phase 1b/2 trial (EPCORE CLL-1) [ASH abstract 348]. Blood. 2022;140(Suppl 1).