Acalabrutinib Produces 38% ORR in Richter Transformation

The next-generation BTK inhibitor acalabrutinib produced an objective response rate (ORR) of 38.1% as a monotherapy for patents with Richter transformation (RT), according to findings from the phase I/II ACE-CL-001 study presented at the 2016 ASH Annual Meeting.

Peter Hillmen, MD, PhD

According to findings from the phase I/II ACE-CL-001 study, next-generation BTK inhibitor acalabrutinib produced an objective response rate (ORR) of 38.1% as a monotherapy for patents with Richter transformation (RT). Results of the study were presented at the 2016 ASH Annual Meeting.

In the ongoing trial, the median progression-free survival with acalabrutinib was 2.1 months. The median duration of response was 5.2 months (range, 0.3-6.5+) and the median time on treatment was 3.4 months (range, 1.7-12.0). Two patients who experienced a response went on the receive a stem cell transplant.

“Acalabrutinib induced complete response and partial responses in a heavily pretreated group of patients with Richter transformation, which is a poor prognostic group of patients," said lead investigator Peter Hillmen, MD, PhD, Department of Haematology, Churchill Hospital Cancer Centre, Oxford, United Kingdom. "Initial data of acalabrutinib monotherapy in Richter transformation suggest that further investigation in combination with chemoimmunotherapy or other targeted therapies is warranted."

The phase I/II study enrolled 29 patients with RT, with primary histologies of diffuse large B-cell lymphoma (DLBCL) with underlying chronic lymphocytic leukemia (CLL; n = 25), CLL transformed to prolymphocytic leukemia (PLL; n = 3), and follicular lymphoma to DLBCL (n = 1). In the study, acalabrutinib was administered at 200 mg twice daily, which is double the standard dose used in other studies. This higher dose was used to counter the aggressiveness of RT, Hillmen explained.

Patients in the study had received a median of 4 prior therapies (range, 0-13), and nearly half of patients had received prior ibrutinib (48%). The median time from initial diagnosis of CLL was 5 years (range, 1-21). The ECOG performance status was ≤1 for 79% of patients and those with CNS involvement and cardiovascular disease were excluded.

The complete response rate was 9.5% and the partial response rate was 28.6%. An additional 23.8% of patients had stable disease. In patients with CLL-related DLBCL, the ORR was 32%. Both CRs were in patients with DLBCL, 1 of which received a stem cell transplant. A second patient with a PR also received a stem cell transplant.

In ibrutinib-naive patients (n = 12), the ORR was 42% (95% CI, 15-72). In those pretreated with ibrutinib, the ORR was 33% (95% CI, 8-70). "Three of the nine patients who developed Richter transformation on ibrutinib had a response to acalabrutinib," Hillmen noted.

At the time of the September 2016 analysis, 17.2% of patients remained on the study. Progressive disease was the leading cause for discontinuation (48.3%), followed by death (17.2%). There were no discontinuations due to AEs.

The most commonly observed adverse events (AEs) of any grade were headache (41%), diarrhea (35%), anemia (31%), fatigue (24%), arthralgia (17%), and back pain (17%). Grade ≥3 AEs occurred in 62% of patients, the most common were anemia (14%), neutropenia (14%), hypercalcemia (10%), and back pain (10%).

Serious AEs were experienced by 55% of patients, including hypercalcemia (10%), fatigue (7%), and acute kidney injury (7%). Two patients experienced a grade 5 AE (cerebellar abscess and sepsis). Both grade 5 events were deemed unrelated to study drug.

"The 200 mg twice daily dose of acalabrutinib is demonstrated to be tolerable, with no unexpected adverse events," said Hillmen, who added that many of the AEs experienced were due to the underlying disease.

In addition to RT, acalabrutinib has shown promise as a treatment for patients with CLL. In previously reported findings published inThe New England Journal of Medicine, monotherapy with acalabrutinib at 100 mg twice daily resulted in an ORR of 95% for patients with relapsed/refractory CLL/SLL. In findings from the frontline CLL setting that were presented at the 2016 ASCO Annual Meeting, the ORR was 97% with acalabrutinib.

Acalabrutinib is currently being compared with ibrutinib in a phase III study for high-risk patients with relapsed CLL (NCT02477696). Additionally, the agent is being explored alone or in combination with obinutuzumab versus chlorambucil and obinutuzumab (NCT02475681).


Hillmen P, Schuh A, Eyre TA, et al. Acalabrutinib Monotherapy in Patients with Richter Transformation from the Phase 1/2 ACE-CL-001 Clinical Study. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 60.