Acalatinib, veneclax, and octuzumab have excellent efficacy in newly diagnosed CLL

The introduction of BTK inhibitors and BCL-2 inhibitors has revolutionized the treatment paradigm of chronic lymphocytic leukemia (CLL); however, there are still many problems that need to be further addressed in the treatment of newly diagnosed CLL with these drugs
.

BTK inhibitors such as acalatinib with or without anti-CD20 monoclonal antibodies can provide patients with durable remissions, but require continued long-term treatment, are associated with ongoing risk of adverse effects, such as cardiovascular and bleeding complications, and cost of treatment higher
.

Fixed-duration therapy with the BCL-2 inhibitor veneclax combined with the anti-CD20 antibody octuzumab is also effective, but high-risk cytogenetics such as TP53 abnormalities (ie, TP53 mutation or 17p deletion, or both) or IGHV- Patients with unmutated CLL may not experience durable benefit
.

It is unclear whether the addition of octuzumab enhances the efficacy of the dual regimen of a BTK inhibitor and a BCL-2 inhibitor
.

Based on this, the researchers conducted a phase II, investigator-initiated clinical trial of acalatinib, veneclax, and octuzumab in patients with newly diagnosed CLL
.

Study Methods This single-arm, open-label, investigator-initiated Phase II clinical study recruited patients from two academic hospitals within the Dana-Farber Harvard Cancer Center network
.

According to the 2018 International Symposium on CLL (iwCLL) criteria, eligible patients were previously untreated CLL or small lymphocytic lymphoma (SLL) requiring initial therapy
.

Patients were treated in 28-day cycles
.

During cycle 1, patients received acalatinib monotherapy (100 mg orally twice daily)
.

Otuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15) was administered intravenously starting on day 1 of cycle 2, with continuous acalatizumab 1000 mg of Ortuzumab intravenously continued on Day 1 of Cycles 3-7
.

On Day 1 of Cycle 4, add veneclax, 20 mg on Day 1, 50 mg on Days 2-7, 100 mg on Days 8-14, 200 mg on Days 15-21, from 400 mg/day started on day 22
.

The primary endpoint of the study was the complete response (CR) rate with undetectable minimal residual disease (u-MRD) in the bone marrow (BM) at the beginning of cycle 16
.

Results 1.
Patient characteristics: A total of 37 patients were screened and enrolled in the study between August 2, 2018, and May 23, 2019 (Figure 1)
.

The median age of subjects was 63 years, 27 (73%) were male, and 20 (54%) had Rai stage 3 or 4 at the start of treatment (Table 1)
.

Twenty-seven (73%) patients were IGHV-unmutated, and 10 (27%) patients had TP53 abnormalities (both 17p deletions and concomitant TP53 mutations)
.

Figure 1: Study Flow Chart Table 1: Patient Baseline Characteristics 2.
Patient Efficacy: All 37 patients received at least one treatment with all three study drugs
.

Secondary endpoints were evaluable at the start of cycles 8, 16, and 25 in 97% of patients
.

As of the data cutoff date (May 11, 2021), with a median follow-up of 27.
6 months, no patients had clinical progression and all patients were still alive
.

All 37 patients achieved remission with an ORR of 100%; the degree of remission over time is shown in Figure 2
.

The best CR rate was 46%
.

CR rates were similar between IGHV-unmutated and IGHV-mutated patients
.

Likewise, the CR rate in the 10 patients with abnormal TP53 was similar to the overall patients
.

Figure 3 shows the u-MRD rates in peripheral blood (PB) and BM at the beginning of cycles 8, 16 and 25
.

The u-MRD rates in PB and BM were 92% and 86%, respectively
.

The u-MRD rate in patients was similar between the IGHV unmutated and mutated subgroups, and the u-MRD rate in patients with TP53 abnormalities was similar to the general population (Figure 3)
.

The u-MRD rates in PB and BM at the beginning of cycles 8, 16, and 25 were 71%, 94%, and 92%, respectively
.

Patient time to iwCLL remission, time to u-MRD, and the current status of each patient as of the data cutoff date are shown in Figure 4
.

The median time to u-MRD in PB and BM was 6.
7 months and 10.
3 months, respectively
.

Thirty-two (86%) patients discontinued treatment, with a median follow-up of 7.
6 months after completion of treatment
.

Twelve (32%) patients discontinued treatment at the start of cycle 16 after achieving CR and achieving u-MRD in BM; these patients had been off treatment for a median of 13.
6 months, and none required resumption
.

An additional 19 (51%) patients discontinued treatment at the start of cycle 25
.

Figure 2: Response at the start of a given cycle for the entire population (A), IGHV-mutated patients (B), IGHV-unmutated patients (C), and TP53-abnormal patients Figure 3: At the start of a given cycle, all patients ( A) Peripheral blood and proportion of u-MRD in bone marrow of all patients (B) bone marrow, IGHV-mutated patients (C), IGHV-unmutated patients (D) and TP53-abnormal patients (E) bone marrow 3.
Safety: All patients All had at least 1 adverse event (AE), but grade 3 and 4 AEs were uncommon, and there were no treatment-related or all-cause deaths
.

The most common grade 3-4 hematologic AE was neutropenia
.

The most common grade 3-4 non-hematologic AEs were hyperglycemia and hypophosphatemia
.

Hypocalcemia occurred in one patient during veneclax initiation and dose escalation, without other concurrent signs of tumor lysis syndrome (TLS)
.

Otuzumab infusion-related reactions occurred in 9 patients (24%), 1 of which was grade 3 and occurred during the first infusion, resulting in transient troponin elevations that did not preclude subsequent treatment
.

One patient (3%) developed atrial fibrillation during the perioperative period
.

Bruising occurred in 22 (59%) patients, but no major bleeding occurred
.

Infections occurred in 14 (38%) patients, the most common being upper respiratory tract infection
.

Only 1 case of grade ≥3 infection occurred; grade 3 infectious pneumonitis resolved after oral antibiotics
.

Serious adverse events (SAEs) occurred in 9 patients, the most common of which was neutropenia
.

CONCLUSIONS: Acalatinib, veneclax and octuzumab are clinically active and well-tolerated first-line treatment options for CLL
.

Although the primary endpoint of this study was not met, the high rate of u-MRD in the patient's BM supports further investigation of this protocol
.

Reference: Matthew S Davids , Benjamin L Lampson , Svitlana Tyekucheva, et al.
Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study.
Lancet Oncol.
2021 Sep 14 ;S1470-2045(21)00455-1.
Click "Read the original text", we will make progress together