Frontline Acalabrutinib Plus Venetoclax/Obinutuzumab Shows Promising Activity in CLL

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The frontline triplet combination comprised of acalabrutinib, venetoclax, and obinutuzumab proved to be highly active and well tolerated when used in the treatment of patients with chronic lymphocytic leukemia.

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc

The frontline triplet combination comprised of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva) proved to be highly active and well tolerated when used in the treatment of patients with chronic lymphocytic leukemia (CLL), according to data from a phase 2 trial (NCT03580928) published in Lancet Oncology.1

Results showed that the proportion of patients who achieved a complete remission (CR) and undetectable minimal residual disease (MRD) in the bone marrow at the start of cycle 16 was 38% (95% CI, 22%-55%; n = 14/37). However, because this rate was lower than the alternative hypothesis, which was set at 60%, the study did not meet its primary end point.

The CR rate with undetectable MRD went from 14% (n = 5/37) at the start of cycle 8 to 38% (n = 14/37) at the start of cycle 16; notably, these patients continued to be in CR with undetectable MRD at the start of cycle 25. Of the 5 patients who achieved a CR with undetectable MRD, all had IGHV-unmutated disease and 1 had TP53-aberrant disease.

“We found that acalabrutinib, venetoclax, and obinutuzumab is an active chemotherapy-free treatment option for previously untreated patients with high-risk disease,” Matthew S. Davids, MD, MMSc, lead study author, director of Clinical Research in the Division of Lymphoma and physician at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, and colleagues, wrote. “The safety profile is favorable, with low rates of grade 3 or higher adverse effects [AE] and few occurrences of tumor lysis syndrome [TLS] with a more convenient 4-week venetoclax ramp-up.”

The emergence of BTK and BCL-2 inhibitors in the CLL treatment paradigm has transformed care for this population, but the use of these agents in the first-line setting has provided suboptimal benefit. It has been shown that when BTK inhibitors like acalabrutinib are administered with or without anti-CD20 antibodies, they can elicit durable responses; however, this requires continuous treatment, which is linked with certain safety risks and financial toxicity.

Although treatment with venetoclax plus obinutuzumab has been shown to be beneficial for patients with higher-risk TP53- or IGHV-mutated disease, room for improvement remains. Moreover, although fixed-duration treatment with the novel triplet comprised of ibrutinib (Imbruvica), venetoclax, and obinutuzumab has been explored in the first-line setting, toxicity challenges have prevented the extended use of this regimen in older patients who have comorbidities.

As such, study investigators hypothesized that a combination comprised of the more specific BTK inhibitor acalabrutinib plus venetoclax and obinutuzumab could be administered as a MRD-guided, time-limited regimen that would result in deep remissions and favorable tolerability for a broader population of patients with CLL, even though considered to have high-risk disease.

The single-arm, open-label phase 2 trial enrolled patients from either Dana-Farber Cancer Institute or Beth Israel Deaconess Medical Center who had a diagnosis of previously untreated CLL or small lymphocytic leukemia who needed initial therapy, were at least 18 years of age, had an ECOG performance status of 0 to 2, and measurable disease.

Patients also needed to have total bilirubin of 1.5 x the upper limit of normal (ULN) or lower, aspartate aminotransferase and alanine aminotransferase 2.5 x ULN or lower, creatinine clearance of 50 mL/min or higher, an absolute neutrophil count of 750 cells/mm3 or higher, and a platelet count of 50,000/mm3 or higher.

Study participants received treatment in 28-day cycles. In the first cycle, patients were administered oral acalabrutinib at a twice-daily dose of 100 mg. Intravenous (IV) obinutuzumab was initiated on day 1 of cycle 2 and was given at 100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15; the agent was given with continuous acalabrutinib. Obinutuzumab was continued at the 1000-mg dose on day 1 of cycles 3 through 7.

On day 1 of cycle 4, oral venetoclax was started in an accelerated ramp-up, beginning at 20 mg on day 1, 50 mg on days 2 through 7, 100 mg on days 8 through 14, 200 mg on days 15 through 21, and 400 mg daily from day 22 of cycle 4.

Patients who were determined to be high risk for TLS at the time of venetoclax initiation on day 1 of cycle 4 needed to receive the 20- and 50-mg doses of the agent as an inpatient. Those with low or medium risk of TLS at the start of cycle 4 were able to begin venetoclax in either the inpatient or outpatient setting based on clinician choice.

When patients were done receiving obinutuzumab at the end of cycle 7, they continued to receive acalabrutinib at a twice-daily dose of 100 mg and venetoclax at a once-daily dose of 400 mg until 15 cycles of therapy were completed. Patients then were able to discontinue the 2-drug regimen if they achieved a CR with undetectable MRD in the bone marrow at the start of cycle 16. If this was not accomplished, patients remained on the doublet until the start of cycle 25.

Notably, patients needed to receive prophylaxis with trimethoprim-sulfamethoxazole and aciclovir while receiving the study drugs. Those who experienced neutropenia were able to receive pegfilgrastim (Neulasta) or filgrastim (Neupogen).

The primary end point of the trial was rate of CR with undetectable MRD in the bone marrow at the start of cycle 16, and secondary end points included rates of CR with undetectable MRD in the bone marrow at the start of cycles 8 and 25, rates of partial remission and CR at the start of cycle 16, undetectable MRD in the bone marrow and peripheral blood, best overall response rates, best rate of CR, best overall rates of undetectable MRD in bone marrow and peripheral blood, and link between established prognostic factors for disease and response rates and undetectable MRD.

Other end points included rates of treatment discontinuation at the start of cycle 16, as well as the correlation between undetectable MRD in the peripheral blood and the bone marrow at the start of cycles 8, 16, and 25. Prespecified secondary end points were focused on safety.

Among the 37 patients included in the trial, the median age was 63 years (range, 57-70), 73% were male, 89% were non-Hispanic White, 54% had an ECOG performance status of 1, and 35% had Rai stage 2 disease at the time that treatment was started.

Additionally, 49% of patients had tumors that harbored a 13q deletion, 35% had a 11q deletion, 27% had a 17p deletion, 19% had a complex karyotype, 14% had trisomy 12, and 5% had a 6q deletion. Twenty-four percent of patients had tumors that harbored an IGHV mutation, 49% had negative ZAP-70 status, and 27% had both TP53 mutations and a 17p deletions.

At a median follow-up of 27.6 months (range, 25.1-28.2), all 37 patients had received at least 1 dose of all 3 agents and 36 of the patients were determined to be evaluable for secondary end points at the beginning of cycles 8, 16, and 25. At this time point, no patients had experienced clinical progression, and all were still alive.

Additional data from the trial showed that all patients responded to the triplet regimen. The best CR rate with the regimen was 46% (n = 17/37). Notably, CR rates to the treatment approach were similar, irrespective of IGHV or TP53 mutational status.

Moreover, the best overall rate of undetectable MRD in the peripheral blood was 92% (n = 34/37) and 86% (n = 32/37) in the bone marrow. Rates of undetectable MRD proved to be comparable between the IGHV and TP53-aberrant subsets, as well as the total population.

Undetectable MRD rates in both the blood and bone marrow were reported to be 71% concordant at the start of cycle 8, 94% concordant at the beginning of cycle 16, and 92% concordant at the start of cycle 25. In peripheral blood, the median time to undetectable MRD was 6.7 months (95% CI, 6.5-11.1); in the bone marrow, the median time was 10.3 months (95% CI, 6.6-13.9).

Eighty-six percent of patients discontinued therapy; 32% of patients discontinued at the beginning of cycle 16 following a CR and undetectable MRD in the bone marrow. These patients have been off therapy for a median of 13.6 months (range, 10.4-13.9); notably, none of them have needed to resume treatment. An additional 19 patients discontinued the triplet at the start of cycle 25. In this subset, no patients have experienced disease recurrence at a median time off treatment of 5.3 months (range, 3.8-6.7).

At the start of cycle 25, 11% of patients had detectable MRD in the bone marrow and continued to receive acalabrutinib/venetoclax. Half of these patients (n = 2/4) had IGHV-unmutated and TP53-aberrant disease, and 2 had IGHV-mutated and TP53­ wild-type disease.

Median progression-free survival and overall survival have not yet been reached; these data will be shared in a future publication.

All participants reported at least 1 AE, but grade 3 or 4 toxicities were not common. Notably, no treatment-associated or all-cause deaths were reported.

The most common grade 3 or 4 hematologic toxicities experienced with the triplet regimen were hyperglycemia (8%) and hypophosphatemia (8%). Twenty-four percent of patients reported infusion-related reactions to obinutuzumab; 1 of these cases was grade 3 and was experienced during the first infusion. One patient had atrial fibrillation in the perioperative setting. Fifty-nine percent of patients reported bruising; however, no major bleeding was observed.

In terms of second malignancies, 1 developed recurrent thymoma while on the study following initial resection of the disease 14 years prior. Thirty-eight percent of patients experienced infection, with 22% of patients reporting upper respiratory tract infection. One patient experienced grade 3 or higher infection in the form of pneumonia; this was resolved with the use of oral antibiotics.

A total of nine patients reported serious toxicities with the regimen, with neutropenia reported in 3 of these patients. Seventy-eight percent of the serious AEs were considered to potentially be associated with 1 of the study agents.

Two patients reported TLS, both with the start of obinutuzumab prior to venetoclax initiation. The cases were managed with supportive care and patients went on to receive more obinutuzumab without experiencing any issues.

Notably, the 3 cycles of lead-in therapy with acalabrutinib and obinutuzumab was considered to substantially reduce the risk of TLS. Specifically, 97% of patients were at medium or high risk of TLS at baseline. Prior to day 1 of cycle 4 and the start of venetoclax, 92% of patients were at low risk for TLS; at this time, no patients were considered to be at high risk for the toxicity.

“Acalabrutinib, venetoclax, and obinutuzumab is now being studied in a registrational phase 3 trial and has the potential to become a new standard frontline therapy option for patients with CLL,” the study authors concluded.


  1. 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. Published online September 14, 2021. doi:10.1016/S1470-2045(21)00455-1
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