Ibrutinib Discontinuation Outcomes Reported for CLL

Single-centre experience sheds light on the prognosis for chronic lymphocytic leukaemia patients who discontinue ibrutinib

medwireNews: Chronic lymphocytic leukaemia (CLL) patients who discontinue ibrutinib on disease progression have a poor prognosis, suggests research, with survival particularly short in patients with Richter’s Syndrome.

The study published in JAMA Oncology reports the outcomes of 308 patients who participated in one of four trials of the Bruton Tyrosine kinase (BTK) inhibitor while being treated at the Ohio State University Comprehensive Cancer Center in Columbus, USA, between 2010 and 2014.

“It is possible that patterns at our institution may not be generalizable to the entire ibrutinib-treated population, and it will be important to confirm these findings in larger multicentre patient populations”, say Jennifer Woyach and co-authors from the institution, but they note that larger series with long-term follow-up will not be available for many years.

Patients were followed up for a median of 20 months, during which time 45 patients discontinued ibrutinib for non-relapse reasons. This occurred almost always early in the course of treatment and these patients had poor median survival of just 5 days. This was driven by a high death rate associated with discontinuation for infection, with patients who discontinued treatment for other adverse events or reasons having a median survival of 238 days.

A further 31 patients discontinued treatment on disease progression. The 12-month cumulative incidence of Richter’s Syndrome and progressive CLL was 4.5% and 0.3%, respectively. By 18 months, 8.9% of patients had discontinued treatment.

Median survival after the development of Richter’s Syndrome was just 3.5 months with a third of the 18 patients affected receiving no further treatment, the researchers observe.

For the 13 patients with CLL progression, median survival after progression was 17.6 months.

But the team notes that patients tended to have “rapid” progression after discontinuing ibrutinib, so that patients with at least 1 week between switching treatments had a mean increase in lymphocyte count from 0.75 x 109/L per day before discontinuing ibrutinib, to 4.6 x 109/L per day thereafter.

And for the three patients with palpable lymph nodes and more than 1 week between switching treatments, there was a significant increase in the rate of change in the three largest nodes before and after discontinuing ibrutinib.

This “points to a need for clinical trials to allow shorter washout periods for these patients”, the researchers suggest.

“Also, physicians may consider waiting before discontinuing ibrutinib therapy until an alternative therapeutic plan can be formed and potentially even continuing ibrutinib therapy in combination with [Richter’s Syndrome]-directed therapy in select patients.”

Deep sequencing of peripheral blood revealed that all 11 patients with CLL progression were found to have developed Mutations in BTK and/or its downstream target PLCG2 over the course of ibrutinib treatment, indicating that these changes may be from “selective pressure” associated with ibrutinib.

By contrast, BTK mutations were found in just two of the Richter’s Syndrome patients, both of whom had worsening lymphocytosis and may have also had progressive CLL.

Jennifer Woyach et al note that the low incidence of recurrence reported in their patients is likely to increase with extended follow-up and emphasise the need for new targets and treatments for CLL recurrence, especially for Richter’s Syndrome patients.

“[T]he question of whether high-risk patients may benefit more from transplant or kinase inhibitor is unanswered”, they add.

“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.”

Reference

Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol2015;Advance online publication 26 February. doi:10.1001/jamaoncol.2014.218

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