BTK Inhibitor Active in Half of Patients With Richter Transformation

Half of patients with Richter transformation responded to the Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca), and most had received prior BTK treatment, a multicenter study showed.

Complete responses occurred in 11 of 82 patients (13%), and 30 patients (37%) had partial responses. Almost half of the responses lasted 12 months or longer. Eight patients discontinued pirtobrutinib while still in response to undergo stem-cell transplantation. A majority of patients had grade ≥3 adverse events (AEs), but relatively few patients discontinued treatment because of AEs, reported William Wierda, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

“Pirtobrutinib … shows promising activity and safety in the largest known prospective population of patients with Richter transformation,” the authors concluded in the September issue of Lancet Haematology. “For a disease with few treatment options, pirtobrutinib offered single-agent activity and, as is often the goal for some patients, a bridge to a potentially curative treatment option.”

“This subgroup with Richter transformation included many heavily pretreated patients, who historically have a poor expected overall survival [OS],” they added.

The study population was particularly challenging, as patients had received a median of two prior therapies for Richter transformation, and three-fourths had prior treatment with a covalent BTK inhibitor, noted the author of an accompanying editorial.

“The results of this monotherapy approach are encouraging,” commented Tamar Tadmor, MD, of Bnai-Zion Medical Center in Haifa, Israel. “However, patients had a short median progression-free survival [PFS] of 3.7 months with a median follow-up of 13.8 months.”

“Pirtobrutinib monotherapy appears promising and has a favorable safety profile in patients with Richter transformation, thereby moving us closer to overcoming the unmet need of Richter transformation,” she added. “Pirtobrutinib should also be used in combination with other drugs to increase the likelihood of a patient reaching complete remission. Lastly, chimeric antigen receptor T-cell therapy or an allogeneic stem-cell transplantation are the only treatments that can lead to the potential cure of patients with Richter transformation and should be the true target in terms of treatment focus.”

An aggressive, diffuse, large B-cell lymphoma, Richter transformation represents a devastating complication of chronic lymphocytic leukemia (CLL), occurring in as many as 10% of patients, Wierda and coauthors noted in their introductory material. The condition has a historically poor prognosis associated with a median OS of 3 to 12 months.

Most patients with Richter transformation have previously undergone treatment for CLL, which is associated with worse outcomes, the authors continued. No approved therapies exist for Richter transformation. Allogeneic stem-cell transplantation offers the only potentially curative therapy, but many patients are ineligible.

The authors’ literature review identified nine published studies of Richter transformation with both safety and efficacy data. The studies had a median of 25 patients and reported limited data on previous therapies.

To address the dearth of published data, Wierda and colleagues performed a subgroup analysis of the phase I/II BRUIN study that included 773 patients with B-cell malignancies treated with pirtobrutinib, which currently has accelerated approval for previously treated CLL/small lymphocytic leukemia and for relapsed/refractory mantle cell lymphoma.

The BRUIN study population included 82 patients with Richter transformation. The subgroup had a median age of 67, and men accounted for two-thirds of the patients. The data showed that 65 of the 82 patients (79%) had received treatment for CLL and 74 patients (90%) for Richter transformation. In addition, 51 patients (62%) had prior exposure to a covalent BTK inhibitor.

The overall response rate of 50% included a response rate of 48.6% in patients with previous Richter transformation-directed therapy. In a subgroup of 21 patients with clonality data, pirtobrutinib led to objective responses in 61.1% of those with clonally related Richter transformation, including three complete responses. Median duration of response overall was 7.4 months, and 45.9% of patients had responses that lasted 12 months or longer. Median response duration was 5.4 months in the 36 patients who had received prior therapy for Richter transformation.

As Tadmor noted, the median PFS was 3.7 months. Median OS was 12.5 months (median follow-up 18.5 months), and the 18-month OS was 44.3%.

A total of 19 patients (including 14 responders) subsequently opted for curative-intent therapy, eight who pursued stem-cell transplantation while still in response to pirtobrutinib and 10 who received CAR T-cell therapy after progression. One patient received CAR T-cell therapy after discontinuing pirtobrutinib because of a treatment-related AE (TEAE).

All but five patients had one or more TEAE, including 49 patients who had at least one grade ≥3 TEAE. The most common all-grade TEAEs were neutropenia (24 patients), fatigue (20), and dyspnea, pyrexia, diarrhea, and contusion (15 each). The most common grade ≥3 TEAEs were infections (21), neutropenia (19), and decreased platelet count. Two fatal TEAEs occurred, one attributable to COVID-related pneumonia and one to septic shock.

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