A Review of Selected Presentations From ASH 2023
December 9-12, 2023 • San Diego, California
Acalabrutinib ± Obinutuzumab vs Obinutuzumab + Chlorambucil in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-up of ELEVATE-TN
Inhibition of Bruton tyrosine kinase (BTK) in patients with chronic lymphocytic leukemia (CLL) has revolutionized the treatment of this disease, yielding significant improvements in efficacy outcomes vs traditional therapy.1,2 Acalabrutinib is a BTK inhibitor that is approved for the treatment of adult patients with CLL/small lymphocytic lymphoma (SLL).3 The international, open-label, phase 3 ELEVATE-TN trial evaluated acalabrutinib, with or without obinutuzumab, vs chlorambucil plus obinutuzumab in patients with treatment-naive CLL.4-7 The study included patients aged 65 years or older, and patients between 18 and 65 years of age were eligible if they had a creatinine clearance rate of 30 to 69 mL/min and a Cumulative Illness Rating Score-Geriatric (CIRS-G) above 6. Patients with significant cardiovascular disease were excluded. Stratification factors included chromosome 17p deletion (del[17p]), Eastern Cooperative Oncology Group performance status, and geographic region. Patients were evenly randomized into the 3 treatment arms. Acalabrutinib (100 mg, daily) was administered until disease progression or unacceptable toxicity; obinutuzumab and chlorambucil were administered for 6 cycles. The primary endpoint was progression-free survival (PFS) with acalabrutinib plus obinutuzumab vs PFS with chlorambucil plus obinutuzumab, assessed by independent review. Patients in the chlorambucil-plus-obinutuzumab arm with disease progression were allowed to cross over into the acalabrutinib monotherapy arm.
The ELEVATE-TN study included 535 patients with a median age of 70 years (range, 41-91). Across the 3 arms, the proportions of patients with bulky disease ranged from 26% to 38%, the proportions with del(17p) ranged from 8.9% to 9.6%, and the proportions with an unmutated immunoglobulin heavy chain variable region (IGHV) ranged from 10.6% to 11.9%. TP53 mutation was observed in 10.6% to 11.9% of patients. After a median follow-up of 73.3 to 74.6 months, approximately half of patients continued to receive acalabrutinib therapy. The relative dose intensity was 93.9%±11.8% in the acalabrutinib-plus-obinutuzumab arm and 95.7%±10.0% in the acalabrutinib monotherapy arm. At 72 months, the median PFS was 78% with acalabrutinib plus obinutuzumab, 62% with acalabrutinib monotherapy, and 17% with chlorambucil plus obinutuzumab (Figure 1). The trial continued to show a significant improvement in median PFS with acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab (HR, 0.14; 95% CI, 0.10-0.20; P<.0001). In a post hoc analysis, acalabrutinib plus obinutuzumab was also superior to acalabrutinib monotherapy in terms of PFS (HR, 0.58; 95% CI, 0.39-0.86; P=.0229), objective response rate (ORR; P=.022), and complete response (CR) rate (P=.022). Among all patients treated with acalabrutinib, achievement of a CR was associated with a longer PFS (P<.0001). Among patients with unmutated IGHV, acalabrutinib plus obinutuzumab yielded a superior median PFS vs chlorambucil plus obinutuzumab (HR, 0.08; 95% CI, 0.05-0.12; P<.0001), and acalabrutinib monotherapy was superior to chlorambucil plus obinutuzumab (HR, 0.12; 95% CI, 0.08-0.18; P<.0001); however, the difference between acalabrutinib with or without obinutuzumab was not significant (P=.2586). Among patients with del(17p) or TP53 mutation, no differences in outcome were observed with the 3 treatment regimens. However, among patients lacking del(17p) or mutated TP53, a benefit was observed with obinutuzumab plus acalabrutinib vs acalabrutinib monotherapy. At 72 months, the median overall survival (OS) was 87% with acalabrutinib plus obinutuzumab, 80% with chlorambucil plus obinutuzumab (P=.0349), and 79% with acalabrutinib monotherapy.
Rates of adverse events (AEs) of clinical interest were similar to those previously reported and were similar in the 2 acalabrutinib-containing arms. Rates of cardiac-related AEs remained low. Atrial fibrillation of any grade was reported in 7% to 9% of patients, major bleeding of any grade was observed in 6% to 9% of patients, and hypertension was observed in 11% of patients.
References
1. Desikan SP, Venugopal S, Ferrajoli A. BTK inhibitor selection for chronic lymphocytic leukemia: which drug for which patient? Expert Rev Hematol. 2022;15(5):403-409.
2. Wolska-Washer A, Robak T. Acalabrutinib: a bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia. Expert Rev Hematol. 2022;15(3):183-194.
3. Acalabrutinib (Calquence) prescribing information. AstraZeneca; August 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216387Orig2s000Correctedlbl.pdf. Accessed January 29, 2024.
4. Sharman J, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of elevate-TN [ASH abstract 636]. Blood. 2023;142(suppl 1).
5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN four-year follow up [ASCO abstract 7509]. J Clin Oncol. 2021;39(15)(suppl):7509.
6. 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.
7. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
Relapse After First-Line Fixed Duration Ibrutinib + Venetoclax: High Response Rates to Ibrutinib Retreatment and Absence of BTK Mutations in Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) With Up to 5 Years of Follow-up in the Phase 2 CAPTIVATE Study
Ibrutinib is a BTK inhibitor that is approved for the treatment of adult patients with CLL/SLL.1 Venetoclax is an oral inhibitor of B-cell leukemia/lymphoma 2 (BCL2) that is also approved for the treatment of CLL/SLL.2 The international phase 2 CAPTIVATE study evaluated ibrutinib plus venetoclax as first-line therapy in patients with CLL/SLL.3-5 All patients received initial therapy consisting of 3 cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. Patients enrolled in the fixed-dose (FD) cohort received no further therapy. After the initial 15 cycles of study therapy, patients in the measurable residual disease (MRD) cohort were randomized into 4 arms. Those with confirmed undetectable MRD were randomized to receive placebo vs ibrutinib monotherapy, while patients without confirmed undetectable MRD were randomized to receive ibrutinib vs ibrutinib plus venetoclax. A 5-year efficacy and safety analysis included 159 patients from the FD cohort and 43 patients from the MRD placebo arm. Among these 202 patients, 53 had experienced disease progression, which occurred more than 2 years after the completion of study therapy in 33 patients (62%). Of the 53 patients, 49 had progressive CLL and 4 had Richter transformation. A comparison of baseline characteristics in the 49 patients with CLL relapse vs baseline characteristics in the 149 patients without disease progression suggested that patients whose disease progressed were more likely to have del(17p)/mutated TP53 (22% vs 11%), del(11q) (27% vs 15%), or unmutated IGHV (76% vs 52%).
Bone marrow and/or peripheral blood samples were available at disease progression from 40 patients who received FD therapy. None of these patients had mutations in the BTK or PLCG2 gene, which can confer resistance to ibrutinib. One patient had an unusual A113G mutation in BCL2, which did not appear to attenuate the response to venetoclax. Among the 202 patients in the FD cohort, the median time to next treatment was not reached. The estimated 4.5-year rate of freedom from next line of treatment was 82% (95% CI, 76%-87%). In the 28 patients who experienced disease progression, ibrutinib therapy was reinitiated (22 with ibrutinib alone and 6 with ibrutinib plus venetoclax), and in these 28 patients, the median time from the end of treatment to disease progression was 2.1 years (range, 0.2-4.3). After a median 17 months (range, 0-45) on retreatment with ibrutinib monotherapy, the ORR was 86%, including 5% CRs. After a median 14 months (range, 5-15) of retreatment with ibrutinib plus venetoclax, the ORR was 83%, including 33% CRs.
In the FD cohort, after 5 years of follow-up, the median PFS was not reached. The 54-month PFS rate was 70% (95% CI, 62%-77%). On the basis of genetic or chromosomal abnormalities, the median PFS rate at 54 months was lowest among the subgroup of patients with del(17p)/TP53 mutation (45%; 95% CI, 25%-64%) and highest among the subgroup of patients with unmutated IGHV (68%; 95% CI, 50%-80%) (Figure 2). The median OS rate was 97% (95% CI, 93%-99%), the ORR was 96%, and the rate of CR/incomplete CR (CRi) was 58%. The combination of ibrutinib plus venetoclax continued to show a manageable safety profile after up to 5 years of follow-up in this population of patients with CLL.
References
1. Ibrutinib (Imbruvica) prescribing information. Pharmacyclics, LLC; August 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/217003s000lbl.pdf. Accessed January 29, 2024.
2. Venetoclax (Venclexta) prescribing information. AbbVie Inc. North Chicago, IL. April 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf. Accessed January 29, 2024.
3. Ghia P, Wierda W, Barr PM, et al. Relapse after first-line fixed duration ibrutinib + venetoclax: high response rates to ibrutinib retreatment and absence of BTK mutations in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with up to 5 years of follow-up in the phase 2 CAPTIVATE study [ASH abstract 633]. Blood. 2023;142(suppl 1).
4. 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.
5. 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.
Ibrutinib Plus Venetoclax With MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study
Key studies in CLL over the last decade have compared the safety and efficacy of BTK inhibitors, alone or combined with other agents, with the safety and efficacy of the combination of fludarabine, cyclophosphamide, and rituximab (FCR). The multicenter, open-label, parallel group, phase 3 FLAIR trial investigated ibrutinib monotherapy, ibrutinib plus rituximab, and ibrutinib plus venetoclax vs FCR in patients with CLL. Results from a preplanned interim analysis have been published.1 For the third comparison of the FLAIR study, 523 patients were enrolled at 96 treatment centers in the United Kingdom from July 2017 to March 2021.2,3 Patients were required to have previously untreated CLL requiring therapy according to criteria from the International Workshop on CLL (iwCLL) and to be no older than 75 years.4 Patients with any prior Richter transformation or more than 20% TP53 deletion by fluorescence in situ hybridization were excluded, as were patients with symptomatic cardiac failure or angina. Enrolled patients were evenly randomized to receive ibrutinib (420 mg, daily) plus venetoclax (escalated to 400 mg, daily) vs FCR. The primary endpoint was PFS.
In the FLAIR trial, the administration of FCR was limited to 6 cycles, which is the accepted limit because of cumulative toxicity with the regimen. Critically in this trial, in an effort to optimize response rates with the ibrutinib combination, the total number of cycles of ibrutinib plus venetoclax was variable, depending on patient response. Patients were regularly monitored for MRD after the initiation of ibrutinib plus venetoclax. Once they achieved undetectable MRD, they continued the combination for twice as long as it took for them to achieve undetectable MRD. Therefore, patients who had undetectable MRD sooner received a shorter overall duration of therapy with ibrutinib plus venetoclax. Duration of therapy was guided by undetectable MRD assessed by flow cytometry analysis of peripheral blood and bone marrow samples.
The 523 patients included in the analysis had a median age of 62 years, and 42% had Binet stage C disease. The median duration of CLL disease before randomization was 36 months, and 48% of patients had B symptoms. Half of the patients had unmutated IGHV, and the most common genetic abnormality was del(13q) (36%), followed by del(11q) (18%). At 9 months, the ORR was 87% with ibrutinib plus venetoclax vs 76% with FCR (P<.05), with CR rates of 59% vs 49% (P<.05), respectively. Per the prespecified algorithm, 50% of patients stopped ibrutinib-plus-venetoclax therapy at 27 months, 63% stopped at 39 months, and 73% stopped at 51 months. After a median follow-up of 43.7 months, the trial met its primary endpoint, demonstrating a median 3-year PFS of 97.2% with ibrutinib plus venetoclax vs 76.8% with FCR (HR, 0.13; 95% CI, 0.07-0.24; P<.0001) (Figure 3). The trial also demonstrated an OS benefit with the ibrutinib combination vs FCR (HR, 0.31; 95% CI, 0.15-0.67; P<.005). Notably, the improvement in survival endpoints was evident in the subpopulation of patients with unmutated IGHV per median PFS (HR, 0.07; 95% CI, 0.02-0.29; P<.001) and median OS (HR, 0.23; 95% CI, 0.06-0.81; P=.022). However, the 2 treatments yielded similar rates of PFS and OS in patients with mutated IGHV (P>.05). Treatment with ibrutinib plus venetoclax was generally well tolerated, with no new safety signals.
References
1. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535-552.
2. Hillmen P, Cairns DA, Clifton Bloor AJ, et al. Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: report of the phase III UK NCRI FLAIR study [ASH abstract 631]. Blood. 2023;142(suppl 1).
3. Munir T, Cairns DA, Bloor A, et al; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337.
4. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
First-Line Venetoclax Combinations in Fit Patients With CLL: 4-Year Follow-up and NGS-Based MRD Analysis From the Phase 3 GAIA/CLL13 Trial
The open-label, phase 3 GAIA/CLL13 trial evaluated 3 different venetoclax-based regimens vs chemoimmunotherapy in fit patients with previously untreated CLL.1,2 Patients with TP53 mutation were not allowed. Eligible patients were evenly randomized into the 4 treatment arms. Patients in the experimental arms received either rituximab plus venetoclax (RV) for 12 months, obinutuzumab plus venetoclax (OV) for 12 months, or OV plus ibrutinib (OVI) for 12 to 36 months. In the control arm, patients aged 65 years or younger received FCR, and older patients received bendamustine plus rituximab (BR). Treatment in the OVI arm was guided by MRD; patients who failed to achieve undetectable MRD by month 15 were allowed to continue ibrutinib monotherapy for up to a total of 36 cycles. The trial had 2 coprimary endpoints: the rate of undetectable MRD at month 15 and the PFS.
The GAIA/CLL13 study enrolled 926 patients with a median age of 61 years (range, 27-84). The median CIRS-G score was 2 (range, 0-7). Of the 926 patients, 56% had unmutated IGHV and 17% had complex karyotype. The median observation time was 50.7 months, and the median observation time after the end of treatment was 40.7 months. The highest rate of early discontinuation of study therapy was in the chemoimmunotherapy arm (14.8%), followed by the OVI arm (11.7%), the RV arm (4.6%), and the OV arm (3.9%). The median 4-year PFS rate was significantly higher with OVI than with chemoimmunotherapy (85.5% vs 62.0%; HR, 0.30; 97.5% CI, 0.19-0.47; P<.001) (Figure 4). Per the median 4-year PFS, the OVI regimen was superior to RV (P<.001), OV was superior to chemoimmunotherapy (P<.001), and OV was superior to RV (P=.001). All of the venetoclax regimens were superior to chemoimmunotherapy in terms of median PFS in patients with unmutated IGHV (P<.05). Among patients with mutated IGHV, the median PFS rate was significantly higher with OVI vs chemoimmunotherapy, with OVI vs RV, and with OV vs RV (P<.05). Analysis of OS did not reveal any significant differences among the treatment arms.
At month 15, the rate of undetectable MRD was highest in the OVI arm (66.2%), followed by the OV arm (60.3%), the RV arm (23.6%), and the control arm (22.7%). PFS curves were generated according to the MRD level at month 15 in each arm. This analysis showed a positive correlation between increasing depth of MRD at month 15 and prolonged PFS. Another analysis that investigated the relationship between the depth of MRD at 15 months and iwCLL response in patients pooled from the OV and OVI arms suggested that achievement of MRD of less than 10-6 closely resembles a CR.3 The rate of grade 3 to 5 infection was highest with chemoimmunotherapy (33 events per 1000 patient-months [E1000]), followed by OVI (20 E1000), OV (14 E1000), and RV (10 E1000). The rate of cardiac AEs was highest with OVI (15 E1000), followed by chemoimmunotherapy (12 E1000), OV (7 E1000), and RV (7 E1000).
References
1. Eichhorst B, Niemann CU, Kater AP, et al; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754.
2. Fürstenau M, Ritgen M, Robrecht S, et al. First-line venetoclax combinations in fit patients with CLL: 4-year follow-up and NGS-based MRD analysis from the phase 3 GAIA/CLL13 trial [ASH abstract 635]. Blood. 2023;142(suppl 1).
3. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL)
Zanubrutinib is a highly selective BTK inhibitor.1,2 Whereas ibrutinib and acalabrutinib have active metabolites, as well as off-target activity, zanubrutinib has reduced off-target activity, no active metabolite, and favorable pharmacokinetics.3 The international phase 3 ALPINE trial evaluated zanubrutinib vs ibrutinib in patients with relapsed or refractory CLL/SLL.4,5 Eligible patients had received at least 1 prior therapy for the CLL/SLL, had measurable lymphadenopathy, and required treatment according to the iwCLL criteria.6 Patients who had received prior BTK inhibitor therapy were excluded. Stratification factors included age, refractory status, del(17p)/TP53 mutation, and geographic region. Patients were evenly randomized to receive zanubrutinib (160 mg, twice daily) or ibrutinib (420 mg, once daily).
The ALPINE trial enrolled 652 patients with a median age of 67.5 years (range, 35-90). Patients had received a median 1 prior line of systemic therapy (range, 1-12). Genetic and chromosomal characteristics included del(17p)/TP53 mutation (23%), unmutated IGHV (74%), and complex karyotype (19%). Bulky disease was noted in 45% of patients. After a median follow-up of 39 months, treatment was ongoing in 59% of patients in the zanubrutinib arm vs 47% in the ibrutinib arm. Zanubrutinib continued to show a superior PFS benefit compared with ibrutinib (3-year median PFS, 64.9% vs 54.8%; HR, 0.68; 95% CI, 0.53-0.86; P=.0011) (Figure 5). Zanubrutinib showed a favorable PFS benefit vs ibrutinib in most of the subgroups examined, which were based on age, prior lines of therapy, disease stage, and other factors. Notably, zanubrutinib yielded a superior median 3-year PFS among patients with del(17p)/TP53 mutation (58.6% vs 41.3%; HR, 0.52; 95% CI, 0.33-0.83; P=.0047), and the zanubrutinib PFS benefit was observed across multiple sensitivity analyses. The ORR and rate of CR/CRi improved over time. With longer follow-up, the median 3-year OS was 82.5% with zanubrutinib vs 79.6% with ibrutinib, but the difference was not significant (P=.098).
The median duration of treatment was slightly longer in the zanubrutinib arm (38.3 vs 35.0 months). Grade 5 AEs occurred in 12% to 13% of patients in each arm. The rate of serious AEs was numerically higher in the ibrutinib arm (50.9% vs 59.0%), as were the rates of dose reduction (14.5% vs 18.2%), study treatment discontinuation (19.8% vs 26.2%), and hospitalization (46.3% vs 55.6%). The rate of dose interruption was 60.5% with zanubrutinib vs 62.0% with ibrutinib. In the zanubrutinib arm vs the ibrutinib arm, rates of any-grade AEs of special interest included hypertension (26.5% vs 24.7%), atrial fibrillation or flutter (6.8% vs 16.4%), and neutropenia (30.9% vs 29.0%), respectively. Zanubrutinib continued to show a more favorable cardiac safety profile in comparison with ibrutinib, with cardiac AEs reported in 24.7% vs 34.6% of patients, respectively.
References
1. Ou YC, Liu L, Tariq B, et al. Population pharmacokinetic analysis of the BTK inhibitor zanubrutinib in healthy volunteers and patients with B-cell malignancies. Clin Transl Sci. 2021;14(2):764-772.
2. Tam CS, Muñoz JL, Seymour JF, Opat S. Zanubrutinib: past, present, and future. Blood Cancer J. 2023;13(1):141.
3. Marostica E, Sukbuntherng J, Loury D, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother Pharmacol. 2015;75(1):111-121.
4. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332.
5. Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL) [ASH abstract 202]. Blood. 2023;142(suppl 1).
6. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
Pirtobrutinib in Post-cBTKi CLL/SLL: ~30 Months Follow-up and Subgroup Analysis With/Without Prior BCL2i From the Phase 1/2 BRUIN Study
Pirtobrutinib is a selective, noncovalent BTK inhibitor that has shown promising efficacy and safety in early-stage clinical trials.1-3 The drug inhibits both wild-type and C481-mutated BTK at a low concentration. Pharmacokinetic data suggest 96% BTK target inhibition and a half-life of approximately 20 hours. The noncovalent binding of pirtobrutinib appears to stabilize BTK in an inactive conformation, blocking both kinase-dependent and kinase-independent signaling. The multicenter phase 1/2 BRUIN study used dose escalation and a 3 + 3 expansion trial design to evaluate pirtobrutinib in patients with CLL/SLL and other B-cell malignancies.4 Patients received pirtobrutinib at daily doses ranging from 25 to 300 mg. Intra-patient dose escalation was allowed, with cohort expansion permitted at dose levels that were considered safe. A key endpoint of the study was to determine the recommended phase 2 dose of pirtobrutinib in this patient setting, with additional safety, efficacy, and pharmacokinetic endpoints.
The BRUIN trial included 282 patients who had received prior covalent BTK inhibitor therapy, including 154 with prior BCL2 inhibitor exposure and 128 without. The 282 patients had a median age of 69 years (range, 36-88), 43% had Rai stage III/IV disease, and 31% had bulky lymphadenopathy of at least 5 cm. BTK C481 mutation was noted in 39% of patients. High-risk molecular characteristics included unmutated IGHV (86%), del(17p)/TP53 mutation (48%), complex karyotype (45%), and del(11q) (23%). Among the 282 patients with prior exposure to a covalent BTK inhibitor, the ORR was 81.6% (95% CI, 76.5%-85.9%) (Figure 6). Among patients without prior BCL2 inhibitor exposure, the ORR was 83.1% (95% CI, 76.2%-88.7%), and among those with prior BCL2 inhibitor exposure, the ORR was 79.7% (95% CI, 71.7%-86.3%). Pirtobrutinib therapy generally yielded consistent ORRs in subgroups based on age, Rai disease stage, performance status, and other factors.
Among the 282 patients with CLL/SLL in this analysis, the median PFS was 19.4 months (95% CI, 16.6-22.1) after a median follow-up of 27.5 months, and the 2-year PFS rate was 38.6%. Among patients without prior exposure to a BCL2 inhibitor, the median PFS was 23.0 months (95% CI, 19.6-28.4), and among those with prior exposure, the median PFS was 15.9 months (95% CI, 13.6-17.5). Among the 282 patients with prior exposure to covalent BTK inhibitor therapy, the 24-month OS was 73.2%, with the median OS not reached. Pirtobrutinib monotherapy was associated with a manageable safety profile. The most common treatment-emergent AEs of any grade were fatigue (36.9%), neutropenia (34.4%), and diarrhea (28.4%). The most common treatment-related AEs of grade 3 or higher were neutropenia (15.2%), followed by 2 AEs of special interest: infection (4.3%) and hemorrhage (1.1%). On December 1, 2023, the US Food and Drug Administration granted accelerated approval to pirtobrutinib for adult patients with CLL/SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.
References
1. Gomez EB, Ebata K, Randeria HS, et al. Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood. 2023;142(1):62-72.
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. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44.
4. Woyach J, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the phase 1/2 BRUIN study [ASH abstract 235]. Blood. 2023;142(suppl 1).
Lisocabtagene Maraleucel (liso-cel) in R/R CLL/SLL: 24-Month Median Follow-up of TRANSCEND CLL 004
Chimeric antigen receptor (CAR) T-cell therapy represents a groundbreaking advance in the treatment of cancers of the blood and is being investigated in CLL/SLL.1 Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed CAR T-cell therapy that was investigated in patients with CLL/SLL in the multicenter, single-arm, phase 1/2 TRANSCEND CLL 004 trial.2-4 Eligible patients had relapsed or refractory disease and had previously failed or were ineligible for therapy with a BTK inhibitor. Depending on their CLL risk category, patients were required to have failed 2 or 3 prior lines of therapy. Bridging therapy was allowed. Lymphodepletion was accomplished with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) for 3 days. Liso-cel was administered within 2 to 7 days after lymphodepletion. The study investigated 2 dose levels of liso-cel: 50 × 106 CAR T cells (DL1) and 100 × 106 CAR T cells (DL2). The primary endpoint was the CR/CRi rate at DL2 by independent review in a prespecified subset of patients who had failed prior therapy with a BTK inhibitor and venetoclax.5
The entire study population consisted of 118 patients with a median age of 65 years (range, 49-82). Patients had received a median 5 prior lines of therapy (range, 2-14). Bulky lymph nodes were noted in 45% of the patients, and 83% had high-risk cytogenetics. Prior BTK inhibitor and venetoclax therapy had been given to 81% of the patients, and 76% of them received bridging therapy. In the primary efficacy population of 50 patients, the CR/CRi rate was 20% (95% CI, 10%-34%) on the basis of iwCLL 2018 criteria, so that the primary endpoint was met (Table). The ORR was 44% (95% CI, 30%-59%), and the rate of undetectable MRD in the blood was 64% (95% CI, 49%-77%). The median duration of response was 35.3 months (95% CI, 12.4 months to not reached). The median PFS was 11.9 months (95% CI, 5.7-26.2), and among the 22 patients who exhibited a response, the median PFS was 38.1 months (95% CI, 13.4 months to not reached). The median OS for the 50 primary efficacy patients was 30.3 months (95% CI, 15.0 months to not reached).
No new safety signals arose. In the entire study population of 118 patients, the most common treatment-emergent AEs of any grade were cytokine release syndrome (85%, with no grade 4 or 5 events), anemia (67%), and neutropenia (62%). The most common treatment-emergent AEs of grade 3 or higher were cytopenias, including neutropenia (60%), thrombocytopenia (42%), and leukopenia (26%). Neurologic events were observed at grade 3 in 18% and grade 4 in 1% of patients. Death owing to treatment-emergent AEs that were considered unrelated to study treatment occurred in 4 patients (3%). One patient (1%) died of macrophage-activation syndrome; this death was considered to be related to liso-cel treatment.
References
1. Vitale C, Griggio V, Perutelli F, Coscia M. CAR-modified cellular therapies in chronic lymphocytic leukemia: is the uphill road getting less steep? HemaSphere. 2023;7(12):e988.
2. Siddiqi T, Maloney DG, Kenderian SS. Lisocabtagene maraleucel (liso-cel) in R/R CLL/SLL: 24-month median follow-up of TRANSCEND CLL 004 [ASH abstract 330]. Blood. 2023;142(suppl 1).
3. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654.
4. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2022;139(12):1794-1806.
5. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
Highlights in Chronic Lymphocytic Leukemia From the 2023 ASH Annual Meeting and Exposition: Commentary
Matthew S. Davids, MD, MMSc • Associate Professor of Medicine, Harvard Medical School • Boston, Massachusetts
The 65th American Society of Hematology (ASH) Annual Meeting and Exposition took place in early December 2023 in San Diego, California. The event featured several presentations offering insight into the management of chronic lymphocytic leukemia (CLL), with data presented on a variety of drug combinations involving acalabrutinib, obinutuzumab, ibrutinib, venetoclax, zanubrutinib, pirtobrutinib, and lisocabtagene maraleucel.
Acalabrutinib/Obinutuzumab
The ELEVATE-TN trial compared frontline acalabrutinib with or without obinutuzumab vs chlorambucil plus obinutuzumab in patients with treatment-naive CLL.1 This data set has been previously reported with shorter follow-up, but it is reassuring now to have the 6-year data presented at the 2023 ASH, which gives us more confidence in the durability of responses for both acalabrutinib-containing regimens.2 One interesting aspect of this update is the continued improvement in progression-free survival (PFS) with the acalabrutinib/obinutuzumab combination vs acalabrutinib monotherapy in a post hoc analysis. This benefit appears to be absent for patients with high-risk disease, specifically those with TP53 aberrations. For patients with non–high-risk disease, it is worth considering offering the combination, although no overall survival (OS) advantage was found over acalabrutinib monotherapy. Therefore, it is not mandatory to choose the combination. In my practice, I have observed that most patients are still opting for Bruton tyrosine kinase (BTK) inhibitor monotherapy, as excellent results can be achieved without the inconvenience and additional toxicities associated with obinutuzumab.
Ibrutinib
Several studies at ASH evaluated the combination of ibrutinib plus venetoclax in patients with CLL. The CAPTIVATE trial is a multicenter, phase 2 study of ibrutinib plus venetoclax as first-line treatment for CLL/small lymphocytic lymphoma (SLL) in 2 cohorts: one guided by fixed duration and the other by minimal residual disease (MRD).3 This most recent update focuses on the fixed duration cohort, now with 5 years of follow-up.4 A notable aspect of the update is the thorough description of retreatment data with ibrutinib-based regimens in patients who previously received the ibrutinib-plus-venetoclax regimen and then went into remission, were off treatment, and later relapsed. The data presented in this abstract suggest that most patients respond well to retreatment. Although the durability of retreatment is still not fully understood, the initial results appear promising. This regimen is not approved by the US Food and Drug Administration (FDA) in the United States; however, it is listed in the National Comprehensive Cancer Network Guidelines, so that it is an option to consider for patients seeking an all-oral, time-limited regimen.5 It is important to note that the patients in CAPTIVATE are younger, fitter patients with CLL, in whom the safety profile of this regimen looks better than it does in older patients and those with significant comorbidities.
The FLAIR trial is a large, phase 3 study running in the United Kingdom that features multiple different arms. What was presented at this year’s ASH meeting and simultaneously published in The New England Journal of Medicine was the comparison of ibrutinib plus venetoclax vs fludarabine, cyclophosphamide, and rituximab (FCR).6,7 This trial focused on a younger, fitter CLL population, and both regimens were anticipated to be effective. The data revealed an improvement in PFS with ibrutinib/venetoclax vs FCR, which was not surprising, especially because the patients could be on ibrutinib/venetoclax for several years, whereas FCR is only a 6-month therapy. What was interesting and surprising was the OS advantage of ibrutinib plus venetoclax over FCR, even though many patients whose disease progressed after FCR went on to receive targeted therapies. This speaks to the benefits of using targeted therapies for most patients with CLL, even those who are younger and fit. In other words, it matters what you start with. Another interesting aspect of the study was the use of MRD-guided duration of therapy with ibrutinib plus venetoclax. Patients received therapy for twice as long as it took to achieve undetectable MRD. This is a way to individualize the length of therapy to optimize outcomes. However, it is worth noting that this MRD-guided approach has not yet been directly compared with a fixed duration approach, and the superiority of one over the other in terms of outcomes is yet to be established. This study represents an encouraging first step in exploring the potential use of MRD-guided therapy to improve outcomes for patients.
Zanubrutinib
ALPINE provides another update on data that we saw published last year. This phase 3 trial compares ibrutinib with the more-selective BTK inhibitor zanubrutinib in relapsed/refractory (R/R) CLL.8 With longer follow-up, a couple of interesting points have emerged. First, the PFS advantage of zanubrutinib over ibrutinib has been maintained with longer follow-up, suggesting that zanubrutinib may be a more efficacious BTK inhibitor than ibrutinib. Second, the safety profile of zanubrutinib continues to look promising with longer-term follow-up. No signal of late toxicities is associated with the drug, instilling confidence that patients can be treated with zanubrutinib and experience long-term remissions with good tolerability. Overall, it appears to be a helpful drug in clinical practice.
Venetoclax
CLL13 is a frontline study focusing on younger, fit patients with CLL who were treated with 1 of 4 different regimens: chemoimmunotherapy; venetoclax with rituximab; venetoclax with obinutuzumab; or a triplet therapy of ibrutinib, venetoclax, and obinutuzumab. Last year, data with 3 years of follow-up, including a report in The New England Journal of Medicine, were published.9 At the 2023 ASH, 4 years of follow-up and detailed MRD-based analyses were shared.10 The key takeaways from the update include that the obinutuzumab-containing arms continue to appear superior to the other arms of the study, in terms of both depth of MRD and PFS. The triplet therapy shows a slightly better performance than the doublet of venetoclax/obinutuzumab, but the difference is not dramatic. With 4 years of follow-up, my main conclusion is that venetoclax plus obinutuzumab remains the regimen to beat. So far, none of these other regimens has displaced it, and this study provides additional confidence that very durable responses can be achieved for younger, fit patients with CLL treated with venetoclax/obinutuzumab in the frontline setting.
Pirtobrutinib
Pirtobrutinib, a noncovalent BTK inhibitor, was the focus of this presentation, and its timing was particularly noteworthy because it had received FDA approval for R/R CLL in early December, just before the presentation.11 The data presented were from the BRUIN study and included a longer-term follow-up analysis with a median of 30 months of follow-up.12 The patients were a very heavily pretreated group, with most having undergone several prior lines of therapy. A notable theme that has emerged with pirtobrutinib is its high level of activity even in patients with previous progression on a covalent BTK inhibitor and those with progression on both a covalent BTK inhibitor and the BCL2 inhibitor venetoclax. The response rate is quite high, and the durability is reasonably good in this population. It will be interesting to see how the use of this drug evolves over time. The presentation highlighted the promising future of pirtobrutinib, and additional studies exploring combinations of pirtobrutinib with venetoclax are now underway. Moreover, studies are investigating moving pirtobrutinib into earlier lines of therapy, including frontline therapy for CLL. This update was particularly timely, given that pirtobrutinib is now approved for patients with CLL and available to use in clinical practice.
Lisocabtagene Maraleucel
Lisocabtagene maraleucel (liso-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, and we had previously seen data published this past year.13 Dr Siddiqi presented longer-term follow-up from that study of liso-cel monotherapy.14 This involved a heavily pretreated group of patients with CLL, many of whom had disease refractory to both BTK inhibitors and venetoclax. Nonetheless, some durable responses were achieved. The complete response (CR) rate of 20% is modest, but among those patients who did achieve a CR, very few recurrences have been noted with 24 months of follow-up. This is encouraging, indicating that a subset of patients can derive very durable benefits from this product. It is important to note the risks of cytokine-release syndrome and neurologic side effects, especially in older patients with CLL. With this product currently under consideration for possible accelerated approval by the FDA, the TRANSCEND data set is valuable. If this product does become available, it will help guide us in understanding the likely outcomes for patients treated with an exciting new therapy.
Disclosures
Davids reports receiving grant support, paid to his institution, and consulting fees from Ascentage Pharma, AbbVie, AstraZeneca, Genentech, MEI Pharma, Novartis, and TG Therapeutics. He has received consulting fees from Adaptive Biotechnologies, BeiGene, BMS, Celgene, Eli Lilly, Genmab, Janssen, Merck, Nuvalent, Research To Practice, Secura Bio, and TG Therapeutics.
References
1. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
2. Sharman J, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of elevate-TN. [ASH abstract 636]. Blood. 2023;142(suppl 1).
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. Ghia P, Wierda WG, Barr PM, et al. Relapse after first-line fixed duration ibrutinib + venetoclax: high response rates to ibrutinib retreatment and absence of BTK mutations in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with up to 5 years of follow-up in the phase 2 CAPTIVATE study [ASH abstract 633]. Blood. 2023;142(suppl 1).
5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Chronic lymphocytic leukemia/small lymphocytic leukemia. Version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated November 3, 2023. Accessed January 22, 2024.
6. Hillmen P, Cairns DA, Clifton Bloor AJ, et al. Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: report of the phase III UK NCRI FLAIR study [ASH abstract 631]. Blood. 2023;142(suppl 1).
7. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332.
8. Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL) [ASH abstract 202]. Blood. 2023;142(suppl 1).
9. Eichhorst B, Niemann CU, Kater AP, et al; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754.
10. Fürstenau M, Ritgen M, Robrecht S, et al. First-line venetoclax combinations in fit patients with CLL: 4-year follow-up and NGS-based MRD analysis from the phase 3 GAIA/CLL13 trial [ASH abstract 635]. Blood. 2023;142(suppl 1).
11. FDA. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. Published December 1, 2023. Accessed January 22, 2024.
12. Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the phase 1/2 BRUIN study [ASH abstract 235]. Blood. 2023;142(suppl 1).
13. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2022;139(12):1794-1806.
14. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel (liso-cel) in R/R CLL/SLL: 24-month median follow-up of TRANSCEND CLL 004 [ASH abstract 330]. Blood. 2023;142(suppl 1).