First-line Acalabrutinib Plus Venetoclax / Obinutuzumab Shows Promising Activity in CLL
The results showed that the proportion of patients who achieved complete remission (CR) and minimal undetectable residual disease (MRD) in the bone marrow at the start of cycle 16 was 38% (95% CI, 22% to 55% ; n = 14/37). However, since this rate was lower than the alternative hypothesis, which was set at 60%, the study did not meet its primary endpoint.
The rate of CR with undetectable MRD increased from 14% (n = 5/37) at the start of cycle 8 to 38% (n = 14/37) at the start of cycle 16; in particular, these patients continued to be in CR with undetectable MRD at the start of cycle 25. Of the 5 patients who achieved CR with undetectable MRD, all had IGHV-disease not mutated and 1 had TP53-aberrant disease.
“We have found that acalabrutinib, venetoclax and obinutuzumab are an active treatment option without chemotherapy for patients with high-risk disease not previously treated”, Matthew S. Davids, MD, MMSc, lead author of the study, 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 reactions [AE] and few cases of tumor lysis syndrome [TLS] with a more practical 4-week rise in venetoclax.
The emergence of BTK and BCL-2 inhibitors in the CLL treatment paradigm has transformed care for this population, but first-line use of these agents 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 long-lasting responses; however, this requires continued treatment, which is associated with certain security risks and financial toxicity.
Although treatment with venetoclax plus obinutuzumab has been shown to benefit high-risk patients TP53– Where IGHV– mutated disease, there is still room for improvement. In addition, although a fixed-course treatment with the new triplet of ibrutinib (Imbruvica), venetoclax and obinutuzumab has been explored as a first-line treatment, toxicity concerns have prevented the prolonged use of this regimen in older patients with co-morbidities.
As such, the study researchers hypothesized that a combination comprising acalabrutinib, a more specific inhibitor of BTK, plus venetoclax and obinutuzumab could be given as a limited treatment regimen in the time, guided by MRD, which would result in deep remissions and favorable tolerability for a larger population of patients with CLL, even though it is considered a high risk disease.
The single-arm, open-label Phase 2 trial recruited patients from the Dana-Farber Cancer Institute or Beth Israel Deaconess Medical Center who had a diagnosis of previously untreated CLL or small lymphocyte leukemia that required initial treatment, were at least 18 years of age, had an ECOG performance index of 0 to 2 and measurable disease.
Patients were also required to have total bilirubin equal to or less than 1.5 x upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase 2.5 x ULN or less, creatinine clearance equal to or greater than 50 ml / min, an absolute neutrophil count of 750 cells / mm3 or more, and a platelet count of 50,000 / mm3 or more.
Study participants received treatment in 28-day cycles. During the first cycle, patients received oral acalabrutinib at a dose of 100 mg twice daily. Intravenous (IV) obinutuzumab was started on day 1 of cycle 2 and was administered 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 administered with acalabrutinib continuously. Obinutuzumab was continued at a dose of 1000 mg on day 1 of cycles 3 to 7.
On day 1 of cycle 4, oral venetoclax was initiated with an accelerated acceleration, starting at 20 mg on day 1, 50 mg on days 2 to 7, 100 mg on days 8 to 14, 200 mg on days 15 to 21, and 400 mg per day from day 22 of cycle 4.
Patients who were determined to be at high risk for TLS at the time of initiation of venetoclax on Day 1 of Cycle 4 were to receive the 20 and 50 mg doses of the agent as an inpatient. People at low or moderate risk of TLS at the start of cycle 4 were able to start venetoclax in an inpatient or outpatient setting depending on the clinician’s choice.
When patients finished receiving obinutuzumab at the end of cycle 7, they continued to receive acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until ’15 cycles of treatment have been completed. Patients could then discontinue the 2-drug regimen if they achieved CR with undetectable MRD in the bone marrow at the start of cycle 16. If this was not accomplished, patients remained under the doublet until the start of the cycle. 25.
In particular, patients were to receive prophylaxis with trimethoprim-sulfamethoxazole and aciclovir while receiving study drugs. Those who experienced neutropenia may have received pegfilgrastim (Neulasta) or filgrastim (Neupogen).
The primary endpoint of the trial was the rate of CR with undetectable MRD in the bone marrow at the start of cycle 16, and the secondary endpoints included the rates of CR with undetectable MRD in the bone marrow at the onset of cycle 16. cycles 8 and 25, partial remission and CR rates at the start of cycle 16, undetectable MRD in bone marrow and peripheral blood, better overall response rates, better CR rate, better overall levels of undetectable MRD in marrow bone and peripheral blood, and link between established prognosis factors of disease and response rate and undetectable MRD.
Other endpoints included treatment discontinuation rates at the start of Cycle 16, as well as the correlation between undetectable MRD in peripheral blood and bone marrow at the start of Cycles 8, 16, and 25. Criteria for Pre-defined secondary assessments focused on security.
Among the 37 patients included in the trial, the median age was 63 years (range, 57-70), 73% were male, 89% were non-Hispanic Caucasian, 54% had an ECOG performance index of 1 and 35% had Stage 2 Rai disease at the time of initiation of treatment.
Additionally, 49% of patients had tumors that harbored a 13q deletion, 35% had an 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 the patients had tumors that harbored a IGHV mutation, 49% had negative ZAP-70 status and 27% had both TP53 17p mutations and deletions.
At a median follow-up of 27.6 months (range: 25.1 to 28.2), all 37 patients had received at least 1 dose of the 3 agents and 36 of the patients were considered evaluable for secondary endpoints at baseline. cycles 8, 16 and 25. At this point, no patient had experienced clinical progression and all were still alive.
Additional data from the trial showed that all patients responded to the triplet diet. The best CR rate with the diet was 46% (n = 17/37). Notably, CR rates at treatment approach were similar, regardless of IGHV Where TP53 mutational status.
In addition, the best overall level of undetectable MRM in peripheral blood was 92% (n = 34/37) and 86% (n = 32/37) in bone marrow. The rates of undetectable DRMs were found to be comparable between IGHV and TP53-aberrant subsets, as well as the total population.
The levels of undetectable MRD in blood and bone marrow were 71% concordant at the start of cycle 8, 94% concordant at the start of cycle 16, and 92% concordant at the start of cycle 25. In peripheral blood, the le median time to undetectable MRM was 6.7 months (95% CI: 6.5-11.1); in bone marrow, the median time was 10.3 months (95% CI, 6.6-13.9).
Eighty-six percent of patients discontinued treatment; 32% of patients discontinued at the start of cycle 16 following undetectable CR and MRM in the bone marrow. These patients were off treatment for a median of 13.6 months (range: 10.4-13.9); in particular, none of them needed to restart treatment. An additional 19 patients discontinued the triplet at the start of cycle 25. In this subset, no patient experienced disease recurrence after a median period of discontinuation of 5.3 months (range: 3.8 -6.7).
At the start of Cycle 25, 11% of patients had detectable MRM in the bone marrow and continued to receive acalabrutinib / venetoclax. Half of these patients (n = 2/4) had IGHV-not transferred and TP53-aberrant disease, and 2 had IGHV-mute and TP53 wild type disease.
Median progression-free survival and overall survival have not yet been achieved; this 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 have been reported.
The most common grade 3 or 4 haematological toxicities encountered with the triple diet 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 felt during the first infusion. One patient had atrial fibrillation perioperatively. Fifty-nine percent of patients reported bruising; however, no major bleeding was observed.
Regarding the second malignant tumors, 1 developed a recurrent thymoma during the study after initial resection of the disease 14 years previously. Thirty-eight percent of the patients developed an infection, of which 22% reported an upper respiratory infection. One patient developed 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 diet, with neutropenia reported in 3 of these patients. Seventy-eight percent of serious AEs were considered potentially associated with one of the study agents.
Two patients reported TLS, both with initiation of obinutuzumab prior to initiation of venetoclax. The cases were managed with supportive care and the patients continued to receive more obinutuzumab without experiencing any problems.
Notably, the 3 cycles of introductory therapy with acalabrutinib and obinutuzumab were considered to significantly reduce the risk of TLS. Specifically, 97% of patients had a moderate or high risk of TLS at baseline. Before cycle 4 day 1 and the start of venetoclax, 92% of patients were at low risk for TLS; at this time, no patient was considered to be at high risk of toxicity.
“Acalabrutinib, venetoclax and obinutuzumab are currently under investigation in a Phase 3 registration trial and have the potential to become a new standard first-line treatment option for patients with CLL », Concluded the authors of the study.
- Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as first-line treatment for chronic lymphocytic leukemia: a single-arm, open-label phase 2 study. Lancet Oncol. Published online September 14, 2021. doi: 10.1016 / S1470-2045 (21) 00455-1