Continued Maintenance With Obinutuzumab Plus Acalabrutinib/Venetoclax Boosts uMRD Rate in R/R CLL

Kiyomi Mashima, MD, PhD

The undetectable minimal residual disease (uMRD) rate achieved with bendamustine followed by obinutuzumab (Gazyva), acalabrutinib (Calquence), and venetoclax (Venclexta) increased as the regimen was continued as maintenance treatment in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to updated findings from the phase 2 CLL2-BAAG study (NCT03787264) presented during the 2023 International Workshop on CLL.¹

Earlier data showed that following 6 months of combination treatment, 76% of patients achieved uMRD in the peripheral blood.2 With continued maintenance treatment, the best uMRD rate increased to 93%.1 The median time to uMRD by flow cytometry was 5.4 months.

All patients are now off treatment, with 58% reported to have been able to stop maintenance treatment early because they had achieved deep remissions with uMRD. At a median observation time of 34 months, the 30-month progression-free survival (PFS) rate was 88.2% and the 30-month overall survival rate was 100%.

“However, the regimen is clearly not ready to be used in routine practice. We need further randomized trials on this triple combination. [That said,] the MRD guidance is something that’s really interesting, [and should] be further evaluated,” lead study author Paula Cramer, MD, of the University of Cologne in Cologne, Germany, said in a presentation of the data.

The open-label, multicenter, phase 2 trial enrolled patients with relapsed or refractory CLL requiring treatment per the 2018 International Workshop for Chronic Lymphocytic Leukemia criteria.² Patients needed to be at least 18 years of age and have an ECOG performance status of 0 to 2; however, a status of 3 was allowed if deemed to be associated with their disease.

If patients recently received treatment they were required to have recovered from any acute toxicities. Moreover, the regimen must have been stopped at least 28 days prior to inclusion for chemotherapy, at least 14 days for antibodies, and at least 3 days for kinase inhibitors, BCL-2 agents, or immunomodulatory drugs. Patients were allowed to have received corticosteroids, but they must have been reduced to an equivalent of 20 mg or less of prednisolone daily during the study period.

Participants with a higher tumor burden received debulking with 2 cycles of bendamustine given intravenously (IV) at 70 mg/m2 on days 1 and 2 and repeated after 28 days. This was followed by induction and maintenance treatment with: IV obinutuzumab at 1000 mg on days 1 to 2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2 to 6, and then every 12 weeks in the maintenance phase; oral acalabrutinib at a twice-daily dose of 100 mg given continuously from day 1 of the second induction cycle and thereafter; and venetoclax, which was started in the third induction cycle, with a daily dose of 20 mg, and a weekly dose ramp-up over 5 weeks to the target daily dose of 400 mg.

“From cycle 4 and onward, patients received the triple combination,” Cramer noted.¹

The primary end point of the trial was uMRD of less than 10-4 in the peripheral blood at the end of induction treatment, evaluated centrally at the final restaging, 12 weeks after the last induction cycle was initiated.²

“After the final restaging, which was the primary end point of the trial, [there] was maintenance treatment, where patients continued treatment until they achieved a complete remission and uMRD,” Cramer added.¹

A total of 49 patients were screened for eligibility, but 3 patients were not included due to a diagnosis other than CLL (n = 2) and patient decision (n = 1). Because an additional patient was found to violate eligibility criteria, the study population ultimately comprised a total of 45 patients.

The median age was 60 years (range, 37-81), with a median Cumulative Illness Rating Scale score of 2 (range, 0-15). “This was a rather young cohort of [patients with] CLL, with only a little comorbidity,” Cramer noted. “However, the cohort was enriched for adverse risk factors, including three-quarters of IGHV-unmutated patients [76%], one-third each with TP53 abnormalities [32%] and complex karyotype [30%].”

The median number of prior treatments received was 1, with a range of 1 to 4 lines. Forty-seven percent of patients previously received a targeted agent, with 8 patients having received a BTK inhibitor, 7 having received venetoclax, 3 patients having received venetoclax plus a BTK inhibitor, and 3 patients having received idelalisib (Zydelig).

Of the 45 patients, 18 received debulking and 27 did not. Forty-five patients received induction treatment, with 2 patients discontinuing treatment early because of leucopenia (n = 1, in cycle 4) or neutropenia (n = 1, in cycle 6). Forty-three patients went on to receive maintenance treatment, with 9 patients discontinuing early because of adverse effects (n = 6), disease progression (n = 1), planned allogeneic stem cell transplant (n = 1), and physician decision (n = 1). Twenty-five patients discontinued maintenance treatment because they achieved uMRD and 9 patients completed the full 2 years of maintenance treatment.

Data regarding the induction phase of the trial have been previously published.2 At a data cutoff date of February 25, 2021, and with a median follow-up of 13.8 months (interquartile range, 10.4-18.4), all patients had completed induction treatment. Seventy-six percent of patients (95% CI, 61%-87%; P = .26) achieved uMRD in the peripheral blood after 6 months of the triplet combination, which failed to reach the expected rate of 90%.

“The primary end point analysis showed that all patients responded and 13 already achieved a CR [complete remission] at this early time point of 6 cycles, 6 months of combination treatment,” Cramer said. “Seventy-six percent of patient achieved uMRD at this time point. Now, with the continued maintenance treatment, we saw an improvement of responses—the CRs improved to 44% and the rate of [best] uMRD improved to 93%.” At the time of last maintenance staging, the objective response rate was 95%.

“If you look at the 25 patients who were able to stop treatment a bit earlier due to achievement of a CR and uMRD, you can see that they remained in uMRD remission for quite a while after the end of treatment,” Cramer noted. “So far, we see 6 cases of MRD conversion.”

In the subset of patients who had already received a targeted treatment before the trial (n = 21), 10 of whom having previously received a venetoclax-containing regimen, the uMRD rates were 91% and 90%, respectively. The 30-month PFS rate in the total population of patients who previously received targeted treatment was 89.6%. “We see that there’s not much of a difference with regard to the uMRD rates for these 2 groups, and also not regarding the PFS,” Cramer said.

The regimen of bendamustine followed by obinutuzumab, acalabrutinib, and venetoclax did not lead to cumulative or unexpected toxicity.

“We already published the safety data on the induction treatment. With the continued maintenance treatment, there’s nothing new to be expected,” Cramer said. “We saw mainly infections and cytopenias, and the main cause of infections was COVID-19. Unfortunately, 1 patient died of COVID-19 on this trial, but there are no new safety signals or other cumulative toxicities.” The patient with COVID-19 died 18 months after end of treatment.

Cramer added that there are plans to launch the phase 3 CLL18 trial, which will be comprised of 3 arms, and will enroll an all-comer population of patients with treatment-naïve CLL, irrespective of fitness, comorbidity, and disease risk factors. Arm A will evaluate fixed-duration venetoclax plus obinutuzumab for 12 months, arm B will examine fixed-duration venetoclax plus pirtobrutinib (Jaypirca) for 15 months, and arm C will assess an MRD-guided approach with venetoclax plus pirtobrutinib for 15 to 36 months.

“This will be another European trial with a lot of countries involved, and I’m really looking forward to that,” Cramer concluded.

Dr Cramer received research support from AbbVie, Inc, Acerta, BeiGene, Hoffman-LaRoche, Gilead, GlaxoSmithKline, Janssen-Cilag, and Norvartis. She received honoraria for scientific talks and advisory board participation from AbbVie, Inc, Acerta, AstraZeneca, BeiGene, Bristol Myers Squibb, F. Hoffman-LaRoche, Gilead, Janssen-Cilag, and Novartis. Travel support was provided by AbbVie, Inc., AstraZeneca, BeiGene, F. Hoffman-LaRoche, Gilead, Janssen-Cilag, and Novo Nordisk.

References

1. Cramer P, Fürstenau M, Robrecht S, et al. Bendamustine, followed by obinutuzumab, acalabrutinib and venetoclax in patients (pts) with relapsed/refractory chronic lymphocytic leukemia (CLL): updated results of the CLL2-BAAG trial of the German CLL Study Group (GCLLSG). Presented at: 2023 International Workshop on CLL; October 6-9, 2023; Boston, Massachusetts. Abstract 1554032.
2. Cramer P, Fürstenau M, Robrecht S, et al. 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;9(10):e745-e755. doi:10.1016/S2352-3026(22)00211-3