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Ibrutinib discontinuation linked to poor prognosis in CLL
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Discontinuation of ibrutinib therapy for chronic lymphocytic leukemia due to progressive disease was associated with a poor prognosis, especially among patients with Richter's transformation, according to study results.
Results also indicated BTK and PLCG2 mutations were associated with CLL progression and resistance to ibrutinib (Imbruvica, Pharmacyclics).
Jennifer A. Woyach
Jennifer A. Woyach, MD, of the department of internal medicine at The Ohio State University, and colleagues evaluated data collected from 308 patients enrolled in four sequential ibrutinib trials conducted between 2010 and 2014. The median patient age was 65 years, and males comprised 70% (n = 217) of the study group.
Median follow-up was 20 months, at which time 232 patients remained on therapy.
Of the 76 patients who discontinued treatment, 31 did so due to disease progression. This group included 18 patients with Richter’s transformation and 13 with progressive CLL. The other 45 patients who discontinued treatment did so for other reasons.
The most common reason for non–relapse-related discontinuation was infection. Median survival after discontinuation in this cohort was 8 days (95% CI, 0-56).
Richter’s transformation tended to occur earlier than CLL progression. The 12-month cumulative incidence of Richter’s transformation was 4.5%, whereas the cumulative incidence of progressive CLL at that time was 0.3%.
Eleven of the 18 patients with Richter’s transformation went on to receive additional treatment. Median survival following transformation was 3.5 months (95% CI, 10 days to 6 months).
Patients with progressive CLL demonstrated accelerated disease progression following therapy discontinuation. Eleven of 13 patients with progressive CLL received additional therapy shortly after ibrutinib discontinuation (median, 10 days; range, 1-42). Median survival from progressive CLL onset was 17.6 months (95% CI, 4.7-not reached).
Woyach and colleagues also evaluated peripheral blood samples from 11 patients with progressive CLL. Each of these patients had mutations in BTK or PLCG2 that were acquired during therapy.
Researchers concluded that further investigation is needed to increase the likelihood of survival among high-risk patients with CLL.
“Scientific progress cannot stop even with a breakthrough drug like ibrutinib,” Woyach and colleagues concluded. “Patients with Richter’s transformation remain a high research priority to identify new targets and new therapies. Also, the question of whether high-risk patients may benefit may benefit more from transplant or kinase inhibitor drugs is unanswered. There remains much to be learned about the biological mechanisms of CLL from the use of kinase inhibitor drugs, and the ideal drug, target or combination for all patients is likely yet to be identified.” – by Cameron Kelsall
Disclosure: Woyach reports no relevant financial disclosures. Other researchers report research funding from and consultant roles with from Janssen and Pharmacyclics.
Perspective
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Kanti R. Rai, MD
The study by Maddocks and colleagues is an important contribution. In this era of post-BCR inhibitors, such as ibrutinib and idelalisib (Zydelig, Gilead), for relapsed and/or refractory chronic lymphocytic leukemia, it is very understandable to worry whether patients might develop resistance to these new drugs. This study is important because it covers a rather large sample size, and all patients were treated and investigated at one institution. The investigators cover many reasons why patients stopped ibrutinib. Most did so because of infections and other adverse reactions, and some did so because of development of Richter’s transformation. I will focus my comments only on those patients who developed progressive CLL, had to stop ibrutinib therapy and were found to have developed resistance to this drug.Maddocks and colleagues have done a remarkably thorough investigation into why 13 patients (out of 308 who were treated) developed resistance to ibrutinib. Twelve patients had received ibrutinib for a relatively long period (15 to 43 months), whereas one only received the agent for less than 4 months.
The researchers identified to key types of mutations in these patients. One was a cysteine-to-serine mutation in BTK at position 481 (C481S), which was found in 11 of 13 patients. The other was PLCG2, which was found in five of 13 patients.
Fortunately, these data indicate that the overall estimated cumulative incidence of developing resistance to ibrutinib is rather low, equating to 0.3% at 12 months and less than 5% at 3 years. It also is worth noting that clinical trials are currently ongoing with other newer and even more effective drugs. Thus, in my opinion, patients with CLL have every reason to remain optimistic.
Resistance to ibrutinib and development of mutations have already been reported. Two very interesting papers recently were published in the same issue of The England Journal of Medicine. These papers — one by Woyach and colleagues (Woyach JA, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1400029), the other by Furman and colleagues (Furman RR, et al. N Engl J Med. 2014;doi:10.1056/NEJMc1402716) — already set the background on this topic of development of resistance to ibrutinib. Maddocks and colleagues have done a truly elegant work of putting this entire matter in a realistic context.
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