Follow-Up With Ibrutinib Shows Continued Efficacy in CLL

Jeffrey A. Jones, MD, MPH, Associate Professor of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center

Jeffrey A. Jones, MD, MPH

Ibrutinib (Imbruvica) continued to demonstrate impressive antitumor activity in a pooled analysis of 243 patients with deletion 17p (del17p) chronic lymphocytic leukemia (CLL), according to a combined analysis of 3 studies that was presented at the 2016 European Hematology Association congress.

The objective response rate (ORR) across the combined analysis was 84%, which included a complete response rate of 9%. The estimated 30-month progression-free survival (PFS) was 55% (95% CI, 48-62), with a median that was not yet reached. The estimated 30-month overall survival (OS) rate was 67% (95% CI, 59-74).

"The estimated 30-month progression-free and overall survival surpassed those reported for all other existing therapies for del17p CLL," said lead investigator Jeffrey Jones, MD, from the Ohio State University Comprehensive Cancer Center. "Overall response rate was consistent across studies, approximately 84% in all of the studies."

For the analysis, findings were assessed from the PCYC-1102, 1112, and 1117 studies, which examined ibrutinib once daily at 420 mg (n = 232) or 840 mg (n = 11). The phase I/II PCYC-1102 study enrolled patients with both treatment-naive and relapsed/refractory CLL. The phase III PCYC-1112 study, also known as RESONATE, and the phase II PCYC-1117 study, known as RESONATE-17, only enrolled patients with relapsed/refractory CLL.

"This integrated analysis tries to provide a more robust estimate of clinical outcomes in ibrutinib-treated patients with deletion 17p CLL," said Jones. "Three large multinational trials were included in the trial. All patients received ibrutinib until progressive disease or intolerable toxicity."

Across the combined analysis, the median age of patients was 65 years, with 37% aged ≥70. Sixty-eight percent of patients presented with cytopenias at baseline. The majority of patients had relapsed/refractory disease, with 2 treatment naive patients enrolled. The median number of prior therapies was 2 (range, 0-12). The median time on study was 28 months.

Sixty-three percent of patients had Rai stage III/IV disease and 53% had bulky disease ≥5 cm. Del17p was determined by FISH locally (PCYC-1112) or in a central laboratory (PCYC-1102/1117). Eighty percent of patients had IGHV unmutated tumors. The study also explored the efficacy of ibrutinib in patients with complex karyotypes, which was defined as ≥3 unrelated chromosomal abnormalities.

Following treatment with ibrutinib, 61% of patients experienced sustained improvements in hemoglobin, and 68% had improvements in platelet counts. Sixty-eight percent of patients had improvements in absolute neutrophil count with ibrutinib.

For those with progressive disease, Richter's transformation (RT) typically occurred earlier following treatment with ibrutinib compared with those who experienced disease progression. Across the 3 studies, RT developed in a median of 253 days (range, 31-786) compared with a median of 594 days for disease progression (range, 26-1572).

In the PCYC-1102 and 1103 studies, those with complex karyotypes (n = 22) had received a median of 4 prior therapies. The ORR in this group specifically was 82% compared with 80% for those with del17p alone. The estimated median PFS was 25 months for those with complex karyotypes versus 52 months for those with del17p alone. The estimated median OS was 32 months for those with complex karyotypes and was not reached for those in the rest of the trial.

At the time of the analysis, 45% of patients remained on treatment. The most common grade 3/4 adverse events were neutropenia (19%), pneumonia (12%), hypertension (11%), thrombocytopenia (10%), and anemia (8%). Grade 3/4 atrial fibrillation and hemorrhage occurred in 3% and 7% of patients, respectively.

"The severe adverse events declined over time, and only 15% of patients discontinued therapy because of an adverse event," said Jones.

Although the response rate with single-agent ibrutinib was dramatic, studies exploring new treatment sequences and combination approaches are still needed to further improve complete response rates, according to Jones. For those with del17p CLL, the most promising current combination studies are exploring ibrutinib plus the BCL2 inhibitor venetoclax (Venclexta), he said.

"Venetoclax is approved specifically for the del17p indication," said Jones. "Investigators around the world are keenly interested in that combination, since venetoclax appears uniquely able to improve bone marrow disease, which is often where patients treated with ibrutinib fail to achieve complete remission."

A phase I/II study led by Jones is assessing the safety and efficacy of venetoclax in combination with ibrutinib and the CD20 inhibitor obinutuzumab (Gazyva) for patients with CLL. The primary endpoint of the study is the identification of a maximum tolerated dose and the assessment of minimal residual disease. The estimated enrollment is 68 patients (NCT02427451).

A phase II study known as CLL2-GiVe is opening soon to explore ibrutinib with venetoclax plus obinutuzumab for physically fit individuals with untreated CLL. The study hopes to enroll 40 participants (NCT02758665). A second phase II study will soon be exploring venetoclax with ibrutinib for those with relapsed/refractory or high-risk CLL. This study plans to enroll 78 patients (NCT02756897).

Jones J, Coutre S, Byrd JC, et al. Evaluation of 243 patients with deletion 17p chronic lymphocytic leukemia treated with ibrutinib: a cross-study analysis of treatment outcomes. Presented at: 21st Congress of the European Hematology Association; June 9-12, 2016; Copenhagen, Denmark. Abstract S429.

"In 1102 and 1103 studies, at 3 years approximately 20% of patients, including those with del17p, had achieved a complete response,” said Jones. "It's clear that patients receiving ibrutinib earlier in their disease course appear to have better survival outcomes. Across the board, depth of response appears to be greater when ibrutinib is utilized earlier in the disease course.”