Frontline Ibrutinib/Venetoclax Combo Leads to High Rates of Undetectable MRD in CLL

Constantine S. Tam, MD

The first-line combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) led to a 75% undetectable minimal residual disease (uMRD) rate in peripheral blood and 72% in bone marrow in the treatment of patients with chronic lymphocytic leukemia (CLL) <70 years old, according to findings from the MRD-cohort of the phase II CAPTIVATE trial presented at the 2019 ASH Annual Meeting.¹

“Ibrutinib plus venetoclax represents an all-oral, once-daily, chemotherapy-free regimen that provides high rates of undetectable MRD in peripheral blood and bone marrow in the first-line treatment of CLL,” lead study author Constantine S. Tam, MBBS, MD, hematologist and disease group lead, Low Grade Lymphoma and Chronic Lymphocytic Leukemia, said in a presentation during the meeting.

“These excellent results validate synergism shown in preclinical studies,” he added. “The favorable [safety] profile of the combination with a low rate of discontinuation because of an adverse event (AE)—5% of patients had to stop because of an AE—and [the fact that] 90% of patients completed the intended treatment, really underscores this treatment as a viable option for [these patients].”

In the international, multicohort, phase II CAPTIVATE trial (NCT02910583), investigators enrolled 164 treatment-naïve patients with CLL who required treatment as per International Workshop on Chronic Lymphocytic Leukemia criteria. Patients must have been <70 years old and had an ECOG performance status of 0 to 1.

Ibrutinib was initially administered alone in a lead-in stage at 420 mg daily for the first 3 cycles. After this stage, venetoclax was added and eventually escalated to a 400-mg daily dose. MRD was defined as <0.01% CLL cells by flow cytometry in the peripheral blood after 6 cycles of combination therapy and measured again by bone marrow after 12 cycles of ibrutinib plus venetoclax. Data presented at the 2019 ASH Annual Meeting were from the pre-randomization phase of the double-blind CAPTIVATE-MRD cohort.

Findings from the MRD-guided randomization phase of the trial are not yet available. In this phase, patients are randomized 1:1 to receive ibrutinib or placebo (undetectable MRD) or ibrutinib or ibrutinib/venetoclax (detectable MRD). Time-limited therapy with 12 cycles of ibrutinib combined with venetoclax are to be evaluated in a separate fixed-duration cohort (n = 159).

The median age of patients was 58 years (range, 28-69), and 32% had Rai stage III/IV disease. Twenty percent of patients had 17p deletion (del17p)/TP53 mutations, 17% had 11q deletions, and IGHV was unmutated for 59% of patients. The median creatinine clearance (CrCl) was 95.0 mL/min and 30% of patients had clearance <80 mL/min.

Although the trial was not intended to enroll high-risk patients, Tam explained that investigators ended up accruing a notable amount of those with high-risk cytogenetics.

Earlier findings from this study, which were presented at the 2018 ASCO Annual Meeting, showed that the frontline combination of ibrutinib and venetoclax demonstrated a 100% objective response rate (ORR) for patients with CLL, and 77% of patients tested negative for MRD in the peripheral blood after 6 cycles.²

Moreover, in 11 patients who were treated with 12 cycles of ibrutinib and venetoclax with available bone marrow data, the complete remission (CR) rate was 36% and the rate of CR with incomplete hematologic recovery (CRi) was 18%. Remaining responses consisted of nodular partial remissions (nPR; 9%) and PRs (36%). All patients with a CR/CRi had confirmed uMRD in the bone marrow. Sixty percent of those with a PR/nPR were MRD negative.

In the data presented at the 2019 ASH Annual Meeting, results showed that after 3 cycles of ibrutinib lead-in, hospitalization for tumor lysis syndrome (TLS) was avoided in 76% of at-risk patients. Among patients who had high baseline TLS risk, 90% became medium or low risk, and 74% were not hospitalized when initiating venetoclax. Additionally, no patients with medium or low TLS risk became high risk, Tam noted.

Five patients discontinued ibrutinib prior to starting venetoclax; 4 were because of AEs and 1 was due to Richter’s transformation. Seven patients discontinued the combination treatment due to AEs (n = 4), as well as disease progression, patient withdrawal, and investigator decision (n = 1 each). Ninety percent of patients (n = 152) completed all 12 cycles of ibrutinib/venetoclax combination therapy, with a median treatment duration of 14.7 months (range, 0.5-19.9) and 12 months (range, 0.8-12.7) with ibrutinib and venetoclax. No patients have died.

uMRD was evaluated in peripheral blood (n = 163) and bone marrow (n = 155). Results also showed that in patients with undetectable MRD at cycle 16 in the peripheral blood with matched bone marrow samples, 93% had uMRD in both peripheral blood and bone marrow.

In the intent-to-treat population (n = 164), uMRD was achieved in 74% and 68% of patients in peripheral blood and bone marrow, respectively, with ≤12 cycles of combination treatment.

High rates of uMRD were sustained over time in MRD-evaluable patients, according to Tam. “It is important to note that high rates [of uMRD] were achieved irrespective of adverse clinical characteristics, including those with del17p, TP53 abnormalities, those who are unmutated in IGHV status, and those with complex karyotype,” Tam said.

Regarding safety, the most common AEs with single-agent ibrutinib were diarrhea, arthralgia, fatigue, headache, nausea, upper respiratory tract infection, vomiting, hypertension, and thrombocytopenia, with neutropenia accounting for the majority of grade 3/4 AEs.

The most common AEs associated with the combination were primarily grade 1/2. Grade 3/4 AEs were most frequent during the first 3 cycles of combination treatment (39%) and then decreased to 15% in the last 3 to 4 cycles. Fifty-seven percent of patients experienced grade 3/4 treatment-related AEs (TRAEs), and serious TRAEs occurred in 11% of patients.

With the combination, grade 3/4 neutropenia was an AE of interest. Grade 3/4 atrial fibrillation, major hemorrhage, febrile neutropenia, and laboratory TLS were infrequent; 2 cases of atrial fibrillation occurred in the ibrutinib lead-in phase, and 1 case was reported during combination treatment. No patients developed clinical TLS; laboratory TLS was reported in 3 patients as an AE, 1 of whom met Howard criteria.

“Diarrhea, nausea, vomiting, and neutropenia are probably additional AEs caused by [the addition of] venetoclax to ibrutinib,” said Tam.

AEs that led to the discontinuation of either ibrutinib lead-in or ibrutinib/venetoclax combination therapy occurred in 8 patients (5%). Fourteen percent of AEs led to dose reductions of ibrutinib therapy compared with 9% of those that led to reductions of venetoclax. The rate of AEs that led to treatment discontinuation were 6% and 4% on ibrutinib and venetoclax, respectively.

Pharmacokinetics were also evaluated with the combination of ibrutinib and venetoclax. In his presentation, Tam noted that the venetoclax mean plasma area under the curve (AUC; n = 151) was higher when given with ibrutinib (58.6 μg·h/mL) versus the BCL-2 inhibitor alone (32.8 μg·h/mL); however, this was within the AUC range that was observed in prior study doses. The increase in venetoclax AUC also did not lead to any new safety findings. The mean AUC with ibrutinib (n = 112) did not change with concurrent venetoclax (646 ngh/mL) versus single-agent ibrutinib lead-in (641 ngh/mL).

References

1. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at: 2019 ASH Annual Meeting; December 7 to 10, 2019; Orlando, FL. Abstract 35. bit.ly/2RvawBV.
2. Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36(suppl 15; abstr 7502). doi: 10.1200/JCO.2018.36.15_suppl.7502.

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