Acalabrutinib Is Viable Option for Ibrutinib-Intolerant Relapsed/Refractory CLL

Article

Acalabrutinib elicited high rates of response as well as prolonged survival and was well tolerated in patients with chronic lymphocytic leukemia who demonstrated intolerance to ibrutinib.

Kerry A. Rogers, MD

Kerry A. Rogers, MD

Kerry A. Rogers, MD

Acalabrutinib (Calquence) elicited high rates of response as well as prolonged survival and was well tolerated in patients with chronic lymphocytic leukemia (CLL) who demonstrated intolerance to ibrutinib (Imbruvica), according to findings presented at the 15th International Conference on Malignant Lymphoma.

Following acalabrutinib treatment, the investigator-assessed overall response rate (ORR; ≥partial response [PR]) was 72% in ibrutinib-intolerant patients with relapsed/refractory CLL; the ORR plus ≥late PR (PRL) was 77%. The complete response (CR) rate was achieved by 5% of patients, 67% had a PR rate, 5% of patients had PRL, and 8% had stable disease (SD). Progressive disease occurred in 2% of patients, another 2% had unknown response, and 12% of patients were not evaluated.

Patients with del(17p) demonstrated an ORR (≥PR) of 71% (91% CI, 44%-90%).

“The primary reason patients discontinued the trial was intolerance in 50% to 63% of patients,” said lead study author Kerry A. Rogers, MD, assistant professor of internal medicine, Division of Hematology, of Ohio State University.

Both ibrutinib and acalabrutinib target BTK, which plays a key role in B-cell receptor signaling and has become a well-validated therapeutic target in CLL.

“Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activity; given the in vitro selectivity of acalabrutinib, we hypothesized that it would be tolerable in patients with CLL who were intolerant to ibrutinib,” she explained.

Rogers reported findings from this phase II trial evaluating acalabrutinib in ibrutinib‐intolerant patients with relapsed/refractory CLL who had received ≥1 prior therapy. The study population had a median age of 70 years (range, 43-88), 63% were male, 97% had ECOG performance score ≤1, 32% had bulky disease ≥5 cm, and 52% were Rai stage III/IV. Patients had also been treated with chemotherapy, rituximab (Rituxan), lenalidomide (Revlimid), and other agents. Regarding genetic mutations, 28% had del(17p), 23% had del(11q), 79% of patients had unmutated IGHV, and 95% of patients had available baseline samples were wild-type for BTK and PLCG2.

Eligibility criteria required patients to have progressive disease after discontinuing ibrutinib, and treatment discontinuation was due to grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs. The median duration of prior ibrutinib therapy was 6 months (range, <1-55). The most commonly reported AEs leading to ibrutinib discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). The median time from the last ibrutinib dose to acalabrutinib initiation was 9.2 months (range, 0.8-31.1). Sixty patients received oral acalabrutinib at 100 mg twice daily in 28&#8208;day cycles until progressive disease or unacceptable toxicity. The primary endpoint was ORR, and key secondary endpoints included PFS, overall survival (OS), duration of response (DoR), time to next treatment (TTNT), and safety. At a median follow-up of 19 months (range, 1-31), PFS was not reached; the 18-month PFS rate was 73.5% (95% CI, 59.2%-83.4%). Among patients who responded to acalabrutinib, the median DOR was not reached and the 21-month DOR was 77.1% (95% CI 59.1%-87.9%). The median OS was not reached; the 18-month OS rate was 89.7% (95% CI, not estimable).

At a median follow-up 23 months (range, 1-36), 62% of patients remained on acalabrutinib and 80% of patients remained on study. Acalabrutinib discontinuations occurred in 38% of patients and were due to progressive disease (16%), adverse events (12%), and either patient withdrawal, investigator decision or other (7%). AEs leading to acalabrutinib discontinuation included pneumonia (n = 2), and diarrhea, subdural hematoma, endometrial cancer, headache, and arthralgia (n = 1).

The most common grade ≥3 AEs occurring in ≥5% patients with acalabrutinib were pneumonia (10%), neutropenia (8%) decreased lymphocyte count (7%), lymphocytosis (7%), and decreased platelet count and anemia (3% each).

Bleeding events occurred in 37 (62%) patients and 2 (3%) patients had major hemorrhage. Hypertension was seen in 7 (12%) patients; one (2%) patient experienced it as a grade 3 event.

Eight (13%) deaths occurred on study, and of the 4 grade 5 AEs, none of them were considered to be treatment-related.

“Acalabrutinib is tolerable and effective in ibrutinib&#8208;intolerant patients; these data suggest that acalabrutinib may provide a potential strategy for retreatment with BTK inhibitor therapy after intolerance to ibrutinib,” said Rogers.

Rogers K. Phase 2 study of acalabrutinib in ibrutinib&#8208;intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 029.

Related Videos
Saad J. Kenderian, MB, CHB
Jennifer Brown, MD, PhD
Patrick I. Borgen, MD
Kari Hacker, MD, PhD, NYU Grossman School of Medicine
Janos L. Tanyi, MD, PhD, associate professor, Obstetrics and Gynecology, Hospital of the University of Pennsylvania
Reshma Lillaney Mahtani, DO
Christian Marth, MD, PhD, head, professor, Department of Obstetrics and Gynecology, Innsbruck Medical University
Mansoor Raza Mirza, MD, chief oncologist, Department of Oncology, Rigshospitalet, Copenhagen University Hospital
Judy Hayek, MD, gynecologic oncology fellow, State University of New York (SUNY) Downstate College of Medicine
Leslie M. Randall, MD, MAS, professor, division head, Department of Obstetrics and Gynecology – Gynecologic Oncology, Virginia Commonwealth University School of Medicine Obstetrics and Gynecology