Fixed-duration therapy with ibrutinib combined with veneclax has excellent efficacy in newly diagnosed CLL patients

Ibrutinib, an oral BTK inhibitor, has been shown to improve treatment-naïve chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma ( SLL) overall survival (OS)
.

Veneclax, an oral inhibitor of the anti-apoptotic protein BCL-2, is approved as a single agent or in combination with rituximab or otuzumab for the treatment of CLL/SLL
.

Veneclax monotherapy produced deep remissions in patients with relapsed-refractory (R/R) CLL with undetectable minimal residual disease (uMRD) rates in bone marrow (BM) of 16%
.

While continuous ibrutinib is the established standard of care for CLL and offers a survival benefit, physicians are increasingly looking to offer patients a convenient, all-oral, fixed-duration regimen in an outpatient setting
.

Through distinct and complementary modes of action, ibrutinib and veneclax preferentially target distinct cellular compartments and CLL subsets to eliminate dividing and resting CLL cells
.

Ibrutinib mobilizes CLL cells out of lymph nodes and other lymphatic niches and into peripheral blood (PB), where they are more susceptible to veneclax-induced apoptosis
.

In addition, a recent clinical study of ibrutinib combined with veneclax in the treatment of CLL/SLL showed that the uMRD rate was higher in both PB and BM of patients
.

Based on this, we conducted a multicenter, phase II study (CAPTIVATE trial) of ibrutinib in combination with veneclax as first-line treatment of CLL/SLL in 2 independent cohorts: MRD-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort)
.

Here, the investigators report the results of the primary analysis of the CAPTIVATE FD cohort of fixed-duration first-line treatment of CLL/SLL with ibrutinib plus veneclax
.

Methods The FD cohort in the CAPTIVATE study was sequentially enrolled after the MRD cohort
.

Inclusion criteria were patients aged ≥18 years and ≤70 years old, with treatment indications according to the 2008 International Symposium on Chronic Lymphocytic Leukemia (iwCLL) criteria, and previously untreated CLL/SLL patients
.

Patients in the FD cohort received all-oral fixed-duration therapy with 3 cycles of single-agent ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib plus veneclax (vitamin).
Necla is a standard 5-week post-dose escalation with a target dose of 400 mg once daily for tumor lysis syndrome (TLS) prevention and monitoring according to prescribing information, every 28 days as a treatment cycle
.

After completion of the fixed-duration regimen , and subsequently confirmed disease progression (PD) according to iwCLL criteria can be restarted with ibrutinib monotherapy until PD or unacceptable toxicity
.

For patients with PD > 2 years after completing the fixed-duration regimen, Retreatment with fixed-duration ibrutinib plus veneclax may be considered
.

The primary endpoint is the investigator-assessed complete response (CR) rate (CR or CR with incompleteness) in patients without del(17p) according to the 2008 iwCLL criteria BM recovery [CRi]), was prespecified for analysis in all treated patients
.

Safety assessments included adverse events (AEs), laboratory evaluations, and physical examination
.

AEs were monitored throughout treatment until the last dose of study treatment Post 30 days.
Study Results Enrolled patients
The
study enrolled 159 patients, including 136 patients without del(17p)
.

The median age was 60 years (range: 33-71 years) (Table 1)
.

Most patients had one or more cytogenetic high-risk features, including del(17p) (N=20; 13%), del(17p) and/or TP53 mutations (N=27; 17%), complex karyotype (N=31; 19%), IGHV unmutated (N=89; 56%), or del(11q) without del(17p) (N=28; 18%); 48 (30%) patients had large cysts block
.

With a median study duration of 27.
9 months, 153 of 159 patients completed 3 cycles of ibrutinib pretreatment and started ibrutinib plus veneclax (Figure 1)
.

Overall, 92% of patients completed the planned 12 cycles of ibrutinib plus veneclax
.

Table 1: Patient Baseline Characteristics Figure 1: Study Flowchart Patient Efficacy Results of this study showed that the primary endpoint was met, with a CR rate of 56% (95% CI, 48-64%) in patients without del(17p) assessed by investigators ( Figure 2A); this rate was significantly higher than the minimum CR rate of 37% (one-sided P<0.
0001) and 40% of historical controls in the FCR regimen
.

The CR rate was 55% (95% CI, 48-63%) in all treated populations and 56% (95% CI, 37-74%) in patients with del(17p)/TP53 mutations (Fig.
2A)
.

Investigator-assessed CR rates were high and broadly consistent across subgroups defined by baseline characteristics (Figure 2B)
.

Figure 2: Best ORR in patients: (A) Best ORR as assessed by investigators in all treated populations and patients without del(17p) or del(17p)/TP53 mutations; (B) by baseline characteristics across all treated populations Forest plot of investigator-assessed CR rates in subgroup of patients The best investigator-assessed overall response rate (ORR) across all treatment populations was 96% (95% CI, 93-99%) with no del(17p) patients was 96% (95% CI, 92-99) and 96% (95% CI, 89-100%) in patients with del(17p)/TP53 mutations (Figure 2A)
.

Across all treated populations, the optimal uMRD rate was 77% (95% CI, 70-83%) in peripheral blood (PB) and 60% (95% CI, 52-67) in bone marrow (BM) %) (Figure 3A)
.

Among patients without del(17p), the uMRD rate was 76% (95% CI, 69-84%) for PB and 62% (95% CI, 54-70%) for BM
.

The uMRD rate in patients with del(17p)/TP53 mutation was 81% (95% CI, 67-96%) in PB and 41% (95% CI, 22-59%) in BM
.

Across all treatment populations, uMRD rates in the BM of each patient subgroup were consistent based on baseline characteristics (Fig.
3B)
.

Figure 3: Best MRD responses in patients: (A) uMRD rates in PB and BM of patients without del(17p) or del(17p) and/or TP53 mutations; (B) subgroups of patients by baseline characteristics in all treated populations Forest plot of uMRD rates in group BM with a median follow-up of 27.
9 months, investigator-assessed estimated 24-month PFS rate of 95% (95% CI, 90-97%) in the full treatment population and 95% (95% CI, 90-97%) in patients without del(17p) 96% (95% CI, 91-98%) (Fig.
4A), and 84% (95% CI, 63-94%) in patients with del(17p)/TP53 mutations
.

The estimated 24-month PFS rate was 93% (95% CI, 85-97%) in patients with unmutated IGHV and 97% (95% CI, 88-99%) in patients with mutated IGHV
.

The estimated 24-month OS rate was 98% (95% CI, 94-99%) for all treated populations and 98% (95% CI, 93-99%) for patients without del(17p) (Fig.
4B), with 96% (95% CI, 76-99%) had del(17p)/TP53 mutations
.

As of August 4, 2021, 9 patients received ibrutinib monotherapy again after developing PD
.

Among patients who were restarted on ibrutinib monotherapy, the best response was PR in 7/9 patients, and response evaluation was pending in 2 patients
.

Another patient had disease progression after completing fixed-duration ibrutinib plus veneclax and subsequently received acalatinib with unknown response
.

Figure 4: Patient PFS and OS: (A) Investigator-assessed PFS and (B) OS patient safety in all treated populations and patients without del(17p) Median treatment duration was 13.
8 months (range: 0.
5- 24.
9)
.

The most common treatment-emergent adverse events (AEs) were diarrhea (62%), nausea (43%), neutropenia (42%), and arthralgia (33%) (Table 2); AEs were severe The degree is mainly 1/2 level
.

The most common grade 3/4 AEs were neutropenia (33%) and hypertension (6%)
.

One fatal AE (sudden death) occurred during the ibrutinib lead-in period
.

Serious AEs occurred in 36 patients (23%)
.

Among other AEs of clinical interest, atrial fibrillation of any grade occurred in 7 patients (4%) and ≥ grade 3 in 2 patients (1%) (Table 2)
.

AEs resulted in ibrutinib dose reductions in only 9 patients (6%), veneclax dose reductions in only 18 patients (11%), and both ibrutinib and veneclax doses in 6 patients (4%) decrease
.

Table 2: Conclusions of the study on treatment-related toxicity of all newly diagnosed CLL patients achieved deep, durable remissions and promising PFS
.

References: Constantine S Tam, John N Allan, Tanya Siddiqi, et al.
Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort.
Blood.
2022 Feb 23;blood.
2021014488.
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