BACKGROUND:

The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival, but without improvement to overall survival likely due to toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL.

METHODS:

Patients aged ≥65 years with previously untreated mantle cell lymphoma received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus 6 cycles of bendamustine (90 mg/m2; days 1 and 2) and rituximab (375 mg/m2; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. Primary endpoint was progression-free survival per independent review committee; overall response rate and overall survival were secondary endpoints.

RESULTS:

In total, 598 patients were randomized, with 299 in each arm. At a median follow-up of 44.9 months, median progression-free survival was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio, 0.73; 95% confidence interval, 0.57 to 0.94; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. Overall survival was not significantly different (hazard ratio, 0.86; 95% confidence interval, 0.65 to 1.13; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.

CONCLUSIONS:

Combination of acalabrutinib with bendamustine-rituximab significantly improved progression-free survival. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Introduction: Bruton tyrosine kinase inhibitors (BTKi) are a mainstay of treatment for B‐cell malignancies; however, their use can be limited by adverse events (AEs), many of which are potentially caused by off‐target inhibition of other tyrosine kinases. The next‐generation BTKi zanubrutinib was designed to maximize tolerability by minimizing off‐target binding. Previous results from this ongoing phase 2 study (BGB‐3111‐215; NCT04116437) showed that zanubrutinib was well tolerated in pts intolerant of ibrutinib and/or acalabrutinib (Shadman et al. Lancet Haematol. 2023;10[1]:e35‐e45). Here, we report updated results of the tolerability and efficacy of zanubrutinib in pts intolerant of acalabrutinib (cohort 2). Methods: Eligible pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL) who met protocol‐defined criteria for intolerance of acalabrutinib received zanubrutinib 160 mg twice daily or 320 mg once daily. Pts whose disease progressed with prior BTKi therapy were excluded. Safety and efficacy, including recurrence of acalabrutinib intolerance events, were evaluated. Investigators assessed responses every 3 cycles based on standard response criteria for each indication using parameters at study entry as baseline. Results: As of May 15, 2023, 27 pts received zanubrutinib in cohort 2 (CLL/SLL, 19; WM, 4; MCL, 2; MZL, 2). Median age was 73 y (range, 51‐87 y); median treatment duration was 11.4 mo (range, 0.5‐32.2 mo), with median follow‐up of 12.4 mo (range, 1.6‐32.2 mo). Median number of prior therapies was 2 (range, 1‐6); 13 pts (48%) received prior ibrutinib and acalabrutinib. Median cumulative exposure to acalabrutinib was 5.4 mo (range, 0.5‐33.7 mo). Seven pts discontinued zanubrutinib (AE, n=2; physician decision, n=2; withdrawal, n=2; progressive disease, n=1) and 20 pts remained on treatment. A total of 40 acalabrutinib intolerance events were reported in 27 pts, most commonly arthralgia (n=6 events), headache (n=5), myalgia (n=5), diarrhea (n=3), and rash (n=3). Twenty‐eight acalabrutinib intolerance events (70%) did not recur with zanubrutinib, corresponding to 17 pts (63%) not experiencing any recurrence of acalabrutinib intolerance events. Twelve events (30%) recurred (5 at a lower grade, 7 at the same grade, 0 at a higher grade; Figure 1) and 2 pts discontinued due to recurrence (myalgia and diarrhea; both recurred at the same grade); 1 pt discontinued due to investigator decision after the pt experienced a fall. Of 3 pts who experienced the same intolerance event with ibrutinib and acalabrutinib, 2 pts (1 experiencing atrial fibrillation and the other, pain in extremity) did not have a recurrence of these events with zanubrutinib, and 1 pt (experiencing diarrhea of grade 3 with ibrutinib and grade 2 with acalabrutinib) had a recurrence with zanubrutinib at a lower grade (grade 1). Although many pts entered the study with well‐controlled disease, 24 of 25 efficacy‐evaluable pts receiving zanubrutinib (96%) maintained or improved responses (at least stable disease) and 16 (64%) achieved a response better than stable disease compared with baseline. Conclusions: With a median zanubrutinib exposure that was 6 months longer than the reported cumulative acalabrutinib exposure before discontinuation (11.4 vs 5.4 mo, respectively), 17 pts (63%) did not experience any recurrence of their prior acalabrutinib intolerance events, and disease was controlled in 24 of 25 efficacy‐evaluable pts treated with zanubrutinib (96%). This suggests that pts who are intolerant of acalabrutinib can attain clinical benefit by switching to zanubrutinib. Enrollment and follow‐up are ongoing.

This phase II trial tests how well acalabrutinib works in treating patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and evaluates how treatment with acalabrutinib affects heart function. Acalabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers at abnormal levels. This may help keep cancer cells from growing and spreading. CLL/SLL patients treated with a different BTK inhibitor called ibrutinib often experience cardiac side effects, leading to discontinuation of life-saving therapy. Treatment with acalabrutinib after discontinuing, or even before starting, treatment with ibrutinib may reverse or prevent cardiac side effects and be an effective treatment option for patients with CLL/SLL.

Background: Bruton tyrosine kinase (BTK) inhibition has shown clinical benefit in FL. Acalabrutinib is a highly selective, potent, covalent inhibitor of BTK. We evaluated acalabrutinib ± R in a Phase 1b study of patients (pts) with treatment-naive (TN) or relapsed/refractory (R/R) FL. Methods: Pts with R/R FL (≥1 prior treatment) were randomized to acalabrutinib (mono) or acalabrutinib + R (combo); TN pts received the combo. In 28-day cycles, R (375 mg/m2 IV) was given weekly in Cycle 1 and on Day 1 of Cycles 2-6; acalabrutinib (100 mg PO bid [2 pts received 200 mg qd]) was given until progressive disease (PD) or intolerance. The primary endpoint was safety. Secondary endpoints included overall response rate (ORR), duration of response (DOR), pharmacokinetics (PK) and pharmacodynamics. Results: Thirteen TN and 27 R/R pts were treated. In all pts, the median age was 66 years (range 32-83), 98% of pts had ECOG PS ≤1, and 88% had stage III/IV disease. R/R pts received a median of 2 prior therapies (range 1-5). At a median follow-up of 22 and 7.6 months, 62% of TN and 26% of R/R pts, respectively, were still on treatment. Discontinuations were primarily due to PD (TN 15%; R/R 56%) and adverse events (AEs; TN 8%; R/R 11%). BTK occupancy and PK parameters were consistent with previous acalabrutinib studies. In all pts, common AEs (any grade) were fatigue (48%), headache (43%), diarrhea (40%), nausea (30%) and sinusitis (25%). Common Gr 3/4 AEs were hypertension (8%), increased alanine aminotransferase, increased aspartate aminotransferase, and cellulitis (all 5%), with no Gr 5 events. There were no cases of atrial fibrillation or Gr ≥3 hemorrhage. Efficacy outcomes are reported in the table. Conclusions: Acalabrutinib, alone and combined with R, was well-tolerated and yielded promising response rates in FL. These results support further evaluation of acalabrutinib in FL. (Table Presented).

This phase Ib/II trial studies the side effects and efficacy of maintenance acalabrutinib following cellular therapy in treating patients with large B-cell lymphoma at very high risk of the cancer coming back. Acalabrutinib is a small molecular inhibitor that may interfere with the ability of cancer cells to grow and spread.

This is a phase II trial, with the aim of developing a chemotherapy-free regimen for untreated patients with mantle cell lymphoma (MCL).

Acalabrutinib (ACP-196) is a next generation bruton tyrosine kinase (BTK) inhibitor, more selective than ibrutinib, and without in vitro antagonism of anti-CD20 directed immunotherapies, indicating that its combination with rituximab may be more active than the combination of ibrutinib and rituximab.

In this trial proposal, we will also assess the activity of this combination in comparison to a historical control of ibrutinib + rituximab, consisting of the experimental arm of ibrutinib + rituximab in the randomized ENRICH trial (EudraCT number 2015-000832-13), and data from our previous trial with R-bendamustine-lenalidomide (NLG-MCL4).

The duration of treatment will be a minimum of 12 months. Patients in molecular remission in blood and bone marrow and in complete remission according to CT, will then stop acalabrutinib, but continue on rituximab for a maximum of 36 months. Patients that are minimal residual disease positive (MRD+) will be evaluated again every 6 months and continue on acalabrutinib for a maximum of 36 months.

Patients without a molecular marker, that cannot be followed with MRD, will stop treatment if in CR with PET at 12 months, and be followed by PET-CT every 6 months for a maximum of 36 months.

Patients who convert back to MRD positive after stopping acalabrutinib are reinstalled on acalabrutinib until progression.

Patients with TP53 aberrations and/or blastoid histology, will monitor MRD but continue with treatment until progression regardless of MRD results.

A planned interim analysis will be performed when 40 patients have undergone response assessment after 6 months, for futility and efficacy.

If less than 16 of 40 patients obtain a CR, the trial will be stopped due to futility.

This study is evaluating the safety and efficacy of the combined use of acalabrutinib and ACP-319, for the treatment of chronic lymphocytic leukemia (CLL)

The study will measure the safety, tolerability, and efficacy with acalabrutinib in combination with rituximab in treatment-naïve elderly and/or frail patients with diffuse large B-cell lymphoma (DLBCL), who are otherwise unsuitable for standard front line chemoimmunotherapy treatments.

Chronic lymphoid leukemia (CLL) is a common adult leukemia that has been treated with chemoimmunotherapy, which has significant toxicity among patients. Advances in CLL understanding have led to targeted therapies, such as Bruton's tyrosine kinase (BTK) inhibitors. Acalabrutinib is one of the second-generation BTK inhibitors and offers improved selectivity, reducing off-target effects. This systematic review and meta-analysis analyze data from multiple clinical trials to assess acalabrutinib efficacy and safety among patients with CLL. A literature search was carried out in PubMed, Cochrane Controlled Register of Trials (CENTRAL), MEDLINE (Medical Literature Analysis and Retrieval System Online), and Ovid databases for articles published until 2024. The outcomes included the overall response rate (ORR), complete response rate (CRR), 24-month progression-free survival rate, and grade ≥3 adverse events (AEs). Meta-analysis was performed using jamovi software. The search strategy yielded 823 records. After assessing the eligibility of the retrieved studies, the systematic review finally included six clinical trials, including 808 patients. The findings demonstrated significant efficacy of acalabrutinib, with a pooled ORR (P < 0.001) and a pooled CRR (P = 0.001). The pooled 24-month progression-free survival (PFS) rate showed a significant improvement in maintaining patient safety and treatment effectiveness (P <0.001). However, hematological AEs such as neutropenia, anemia, and thrombocytopenia were reported across studies. The pooled grade ≥ 3 AEs rate was 0.51 (95% CI.: 0.21-0.81, I² = 98.21%, P <0.001), indicating a notable incidence of severe side effects. Acalabrutinib is an active drug in treating CLL that induces significant clinical benefits concerning response rates and PFS. However, acalabrutinib should be managed carefully to mitigate the risk of severe AEs. Further trials should be focused on assessing and modulating the safety of acalabrutinib.

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