Venetoclax Shows Promise as Salvage Therapy in CLL

Steven Coutre, MD

Steven Coutre, MD

Venetoclax (Venclexta) induced a response in two-thirds of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who had progressed after receiving prior therapy with idelalisib (Zydelig), according to findings of a phase II study recently published inBlood.

Venetoclax was associated with a 67% investigator-assessed overall response rate (ORR) among patients who had received prior idelalisib (n = 36). Two patients achieved a complete remission (CR), a third had CR with incomplete bone marrow recovery (CRi), and 21 (58%) had a partial remission (PR). Ten patients had stable disease as best response and 2 had disease progression.

The phase II, open-label, multicenter trial was designed to evaluate the efficacy of venetoclax therapy following treatment with a B-cell receptor pathway inhibitor (BCRi), either idelalisib or ibrutinib (Imbruvica).

A total of 21 patients were enrolled in the main cohort and 15 in the expansion cohort. Patients had received a median of 3 prior therapies (range, 1-11), including other investigational BCRis, and received prior idelalisib for a median of 9 months (range, 1-45). While receiving idelalisib, 22 patients had CR or PR as best response to therapy, 7 had stable disease, 2 had no response, and 5 had progressive disease.

Patients received 20 mg of venetoclax daily for 1 week, followed by a weekly dose escalation to achieve the target of 400 mg daily by week 5. In the expansion cohort, the washout period for prior treatment was reduced from 7 to 3 days. A compressed dose ramp-up was permitted in patients who had a high tumor burden and had clinical signs of progression during screening to enable the administration of the target dose by week 3. Patients who had not achieved a response by week 12 could increase to a dose of 600 mg of venetoclax.

Eligible adults had an ECOG performance score of 0 to 2, adequate bone marrow function, and creatinine clearance ≥50 mL/min. All patients were screened for Richter transformation by PET at enrollment and were excluded if Richter transformation was confirmed on biopsy. Patients with active and uncontrolled autoimmune cytopenias, unresolved toxicity from prior therapy, or a history of allogeneic stem cell transplantation within 1 year of study entry were also excluded.

Investigators performed disease assessments for all patients at screening and at each office visit, and assessed subsequent responses for patients in the main cohort at weeks 8 and 24 and every 12 weeks afterwards for up to 1 year. In the expansion cohort, patients underwent response assessments at weeks 12 and 36.

Most patients had at least 1 high-risk prognostic feature, including unmutatedIGHV(88%), or chromosomal abnormality, such as del(17p) (22%) and/orTP53mutation (14%). At baseline before dosing, tumor lysis syndrome risk was determined to be low for 28% of patients, medium for 47%, and high for 25%.

As assessed by the independent review committee, the ORR at 24 weeks was 62% for the 21 patients in the main cohort. All responses were PRs. Investigator-assessed ORR was 57% at 24 weeks in this group, with 2 CRs, 1 CRi, and 9 PRs.

Patients received venetoclax for a median of 14 months (range, 1-29). The median progression-free survival (PFS), duration of response, and overall survival (OS) have not yet been reached. By investigator assessment, the 12-month PFS rate was an estimated 79% (95% CI, 62%-90%) for all patients, and the estimated 12-month OS rate was 94% (95% CI, 78%-99%).

At week 24, 20 patients from across the study were assessed for peripheral blood minimal residual disease (MRD). Eight (40%) of 17 patients assessed had undetectable MRD in the peripheral blood. Two of these patients, both with PR, demonstrated subsequent undetectable MRD in bone marrow based on 10^−4sensitivity. The 6 other patients did not yet have bone marrow assessments. All 8 patients with MRD negativity remain on treatment.

At the time of data cutoff, the median time on venetoclax for all patients was 14 months. Median time receiving venetoclax was 20 months (range, 1-29) for the main cohort and 10 months (range, 2-16) for the expansion cohort. Twenty-two patients remain on venetoclax treatment.

The primary reasons for discontinuation were progression (n = 9) and Richter transformation (n = 2). One patient discontinued due noncompliance, another elected to proceed to allogeneic stem cell transplantation, and a third patient had preexisting well-controlled immune thrombocytopenic purpura (ITP) whose treatment for ITP did not allow for continuation on the study.

For the 11 patients who discontinued venetoclax due to progression or Richter transformation, the median number of prior CLL therapies was 4 (range, 2-9), 88% had unmutatedIGHV, 20% had del(17p) CLL, and 43% had aTP53mutation. Seven of these patients had discontinued prior idelalisib because of progressive disease, 3 because of toxicity with subsequent progression, and 1 was deemed to have treatment failure. Four patients died due to progression.

Grade 3/4 adverse events (AEs) were primarily hematologic, including neutropenia (50%), thrombocytopenia (25%), and anemia (17%), and hypokalemia (11%). Fourteen patients (39%) received granulocyte-stimulating growth factor during the study for neutropenia with or without infection. Febrile neutropenia was not observed during the study.

Reference:

Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy.Blood. 2018; 131:1704-1711. doi: 10.1182/blood-2017-06-788133.

Serious AEs were infrequent and included pneumonia (n = 2) and cholecystitis (n = 2). There were no deaths attributed to AEs and no reported cases of clinical tumor lysis syndrome.