Ibrutinib: the home run for cure in CLL?

In this issue of Blood, Byrd et al report that after nearly 4 years of follow-up, there is an impressive and sustained progression-free survival and overall survival benefit to using the Bruton’s tyrosine kinase inhibitor ibrutinib vs ofatumumab in patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL). Nevertheless, patients with specific high-risk features like TP53 or SF3B1 mutations showed a trend toward shorter progression-free survival, and altogether, only half of the enrolled patients were still receiving ibrutinib at the end of the observation period.¹ 

The once-daily oral Bruton’s tyrosine kinase inhibitor ibrutinib is an established treatment option in frontline and r/r CLL. The initial data on the value of ibrutinib monotherapy compared with the α-CD20 antibody ofatumumab were published in 2014 and lead to the approval of ibrutinib in r/r CLL in many countries. The report published in this issue of Blood provides long-term follow-up data (44 months) of that randomized phase 3 study (ie, the RESONATE trial).^1,2  Compared with an ofatumumab monotherapy, the risk for progression was reduced by 87%, and that for death by 41%, respectively, when patients with r/r CLL were treated with ibrutinib.

Ofatumumab is no longer marketed outside the United States. Treatment with ibrutinib has largely replaced other treatment options in r/r CLL, including chemoimmunotherapies such as bendamustine plus rituximab, fludarabine plus cyclophosphamide plus rituximab, or treatment based on the phosphoinositide 3-kinase inhibitor idelalisib plus rituximab (see table).^2-5 

Looking closer at the RESONATE trial, ibrutinib was effective in patients with high-risk CLL, but as a trend not at the same level as standard-risk patients. This includes patients with del(17)(p13.1), TP53 mutation, complex karyotype, and SF3B1 mutation. Despite its high efficacy in the majority of the study population, less than half of the patients continued therapy with ibrutinib during the observation period of roughly 4 years. Discontinuation was a result of progression (27%), including some Richter`s cases (7%), as well as a result of adverse effects (12%).

Long-term treatment with ibrutinib is not curative for the majority of patients with r/r CLL. For some patients, precise resistance mechanisms have been previously reported.⁶  Furthermore, many patients with CLL do not want to be treated indefinitely but are, rather, seeking time-limited treatment that can be integrated into their daily life. Last but not least, many patients are receiving a first-line treatment with ibrutinib based on data from RESONATE-2 trial (ibrutinib vs chlorambucil). This frontline indication will be further supported by positive results from recently published data from randomized phase 3 trials demonstrating a benefit of ibrutinib in comparison with chemoimmunotherapies.^7-9  Therefore, ibrutinib in the relapsed setting is no longer an option for a subgroup of patients with recurrent disease who were initially treated with this drug.

An alternative treatment option for patients with r/r CLL, even after being treated with ibrutinib, would be a therapy based on the BCL2 inhibitor venetoclax, especially in combination with rituximab, based on data from the MURANO trial.¹⁰  Seymour and colleagues reported impressive data with this 2-drug combination given for only 2 years.¹⁰  The treatment with venetoclax plus rituximab resulted in a very high response rate, including complete remissions, whereas roughly half the patients had no detectable minimal residual disease at the end of therapy. However, reports describing resistance mechanisms to venetoclax-based treatment regimens have already been published.¹¹ 

Many questions remain unanswered at this point, and have to be addressed by future clinical trials: Is a full-dosed ibrutinib (420 mg per day) necessary during long-term treatment? Can we rescue patients sufficiently with ibrutinib after treatment with venetoclax (plus rituximab); that is, what is the optimal sequence of the drugs? Is a combination of ibrutinib and venetoclax even more powerful than a sequential application? What comes after resistance has developed toward both drugs? For the time being, we have to accept that novel drugs such as ibrutinib and venetoclax represent a quantum leap in the armamentarium against CLL, but are not the home run for all patients suffering from this still-incurable disease, making further research necessary in the field.