Obinutuzumab/Acalabrutinib/Venetoclax Triplet Misses the Mark in Relapsed/Refractory CLL

Article

Obinutuzumab, acalabrutinib, and venetoclax following optimal debulking with bendamustine failed to meet the prespecified rate of undetectable minimal residual disease in the peripheral blood at the end of induction treatment in patients with relapsed/refractory chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia

Obinutuzumab (Gazyva), acalabrutinib (Calquence), and venetoclax (Venclexta) following optimal debulking with bendamustine failed to meet the prespecified rate of undetectable minimal residual disease (uMRD) in the peripheral blood at the end of induction treatment in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to findings from the phase 2 CLL2-BAAG study (NCT03787264) were published in Lancet Haematology.

At data cutoff of February 25, 2021, and a median follow-up of 13.8 months (interquartile range, 10.4-18.4), all patients had completed the induction treatment. Thirty-four patients (76%; 95% CI, 61%-87%; P = .26) had uMRD in the peripheral blood after 6 months of triplet therapy, failing to reach the 90% expected rate of uMRD.

“This trial did not reach the prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine regimen requires further evaluation in larger trials to define its value compared with double treatment with a BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oral targeted drugs,” lead study author Paula Cramer, of the University of Cologne, and coauthors, wrote in the study publication.

“Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended,” the authors concluded.

BTK inhibitors enable long-term disease control in patients with CLL. However, these agents must be administered concurrently with BCL-2 inhibitors to elicit deep responses with uMRD, allowing for time-limited treatment.

The multicenter, open-label, investigator-initiated, phase 2 study evaluated sequential therapy with obinutuzumab, acalabrutinib, and venetoclax following a debulking. Debulking consisted of two, 28-day cycles of bendamustine administered intravenously (IV) at a dose of 70 mg/m2 on days 1 and 2 for patients with an absolute lymphocyte count of at least 25000 cells/μL or lymph nodes with a diameter of at least 5 cm in the absence of contraindications.

Patients subsequently received induction and maintenance therapy with 1000 mg of IV obinutuzumab on days 1, 2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2 to 6, and every 12 weeks in the maintenance phase. Acalabrutinib was administered orally at a dose of 100 mg twice daily from induction cycle 2 day 1 onwards. Patients received venetoclax starting in the third induction cycle at a dose of 20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mg per day.

Eligible patients were at least 18 years of age and had an ECOG performance score from 0 to 2 and relapsed/refractory CLL requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria. The primary end point was uMRD at a sensitivity of less than 10–4 in the peripheral blood at the end of induction treatment.

Forty-five evaluable patients with relapsed/refractory CLL enrolled in the study from January 14, 2019, to June 25, 2020. Thirteen (29%) patients were female, and 32 (71%) were male. A total of 21 (47%) patients had already received a targeted agent, and 14 (32%) had deletion 17(p13.1) or TP53 mutation.

Additional results indicated that by the end of induction treatment, all 45 patients responded: 8 patients (18%) had a complete response (CR) or CR with incomplete marrow recovery, and 37 (82%) had a partial response. Additionally, the median progression-free survival (PFS) and overall survival were not reached; the estimated 12-month PFS rate was 94% (95% CI 86%-100%).

Prior to data cutoff, 32 (71%) patients had started maintenance therapy and 9 (28%) were able to discontinue treatment with uMRD.

After a median observation time of 13.8 months (interquartile range, 10.4-18.4), there were two (4%) Richter transformations but no progressions or deaths.

In terms of safety, 44 (98%) of 45 patients had adverse effects (AEs) during induction; 22 (49%) were grade 3 or 4. The most common grade 3 and 4 adverse effects during treatment were thrombocytopenia (n = 12; 27%) and neutropenia (n = 12; 27%), tumor lysis syndrome and infections (n = five; 11%) infusion-associated reactions (n = 4; 9%), and anemia (n = 4; 9%). Most AEs were mild or moderate: (grade 1 or 2, n = 361; 84%), (grade 3, n = 50; 12%), (grade 4, n = 19; 4%), and none were fatal, though 29 (7%) were deemed serious.

Reference

Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial. Lancet Haematol. 2022;S2352-3026(22)00211-3. doi:10.1016/S2352-3026(22)00211-3

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