Ibrutinib Discontinuation in CLL Examined to Help Develop Salvage Approaches

William G. Wierda, MD, PhD

Patients with chronic lymphocytic leukemia (CLL) who stopped treatment with ibrutinib for toxicities had longer survival than those who discontinued for other reasons, including progression and Richter transformation (RT), as reported in a study published in the journal Cancer.¹

Median survival was 33 months for patients who discontinued ibrutinib (Imbruvica) because of intolerance/toxicities, 16 months for progressive disease, and 11 months for those who discontinued for miscellaneous reasons. Median survival was just 2.3 months in patients who developed RT (P <.0001). Patients with progressive CLL had superior survival than patients who developed RT (HR = 6.7; P <.0003).

Prior treatment status did not play a significant role in survival of patients.

“As the use of ibrutinib treatment continues to increase in patients with CLL, it is essential to delineate the pattern of mutations and dynamics of clonal evolution in those patients who discontinue ibrutinib because of disease progression/transformation and to identify pathways for therapeutic targeting to improve the survival outcomes for these patients,” the researchers wrote.

Median overall post-ibrutinib survival was 20.6 months. After a median of 38 months, 40 patients (44%) were alive at the time of last follow-up.

“The survival after ibrutinib failure is not as short as we initially reported,” coauthor William G. Wierda, MD, PhD, said in an interview with OncLive. “Patients who stop ibrutinib due to side-effects do typically well with their next treatment.”

Jain et al reviewed charts from a total of 320 patients who were treated with ibrutinib-based regimens during various clinical trials at The University of Texas MD Anderson Cancer Center from 2010 through 2015. Ten of 68 patients discontinued ibrutinib after first-line therapy and 80 of 252 discontinued after salvage therapy. Forty-seven patients received ibrutinib monotherapy, 31 were treated with a combination of ibrutinib and rituximab (Rituxan), and 12 received a combination of ibrutinib, rituximab, and bendamustine (Treanda).

Median time to discontinuation was 15 months overall, 19 months for previously untreated patients, and 14.5 months for patients with relapsed/refractory disease. Twenty-nine patients discontinued for intolerance/toxicity; 28 for miscellaneous reasons, including 9 who underwent stem cell transplantation and 8 who developed other cancers; 19 patients discontinued after developing progressive CLL; 9 had disease transformation; and 5 patients transitioned to commercial supply. Ten patients discontinued on first-line therapy; 80 patients with relapsed/refractory disease discontinued.

Among the 9 patients who underwent transplantation, 4 were in complete remission and remained under observation.

Researchers noted 37 deaths, 28 from CLL progression and 9 from disease transformation.

Eight of the 19 patients (42%) who progressed during ibrutinib treatment responded to subsequent therapy. Five patients, 3 of whom also did not respond to idelalisib (Zydelig), had partial response on venetoclax (Venclexta). Two patients responded to ofatumumab (Arzerra) monotherapy and 1 (12%) responded to a combination of idelalisib and rituximab.

There were no incidents of progressive, refractory disease in first-line treatment, but 2 patients developed RT. Both of those patients had unmutated IGHV status, 1 in VH3 and another in VH1-69, Rai stage I disease, overexpression of CD38 and Zap-70, and 17p deletion (del[17p]) by fluorescence in situ hybridization (FISH) before starting ibrutinib. Overall, most patients had high-risk features before starting ibrutinib—91% had unmutated IGHV status, 41% had del(17p) by FISH, 35% had a complex karyotype, and 55% had advanced Rai stage disease.

At the 2016 ASH Annual Meeting, results from a small phase II study also led by researchers from MD Anderson showed that the combination of ibrutinib and nivolumab (Opdivo) was associated with an ORR of 60%, including 2 complete responses in patients who developed RT.²

“The development of effective salvage strategies for patients who develop progression/RT while receiving ibrutinib therapy is of critical importance,” the researchers wrote. “Ideally, these strategies should be guided by knowledge of the molecular mechanisms of resistance in an individual patient. Several molecular mutations associated with ibrutinib resistance have been identified, but whether these specifically predict for response to subsequent salvage therapy is unclear and should be systematically studied in the future.”

References

1. Jain P, Thompson PA, Keating M, et al. Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib [published online February 7, 2017]. Cancer. doi: 10.1002/cncr.30596.
2. Jain N, Basu S, Thompson PA, et al. Nivolumab Combined with Ibrutinib for CLL and Richter Transformation: A Phase II Trial. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 59.