Patients with chronic lymphocytic leukemia (CLL) and their doctors have seen the therapeutic landscape change rapidly in the past few years, with the introduction into practice of the kinase inhibitors ibrutinib and idelalisib, which block specific signalling pathways downstream of the B cell receptor (BCR), and more recently the BCL2 inhibitor, venetoclax. With durable responses now being common in many patients with previously relapsed CLL, it is timely that research continues to focus on the minority for whom treatment of CLL remains particularly problematic — those with CLL that has deletion of the long arm of chromosome 17, which bears the TP53 gene, and patients who fail one of the BCR pathway inhibitors.
Dr. Susan O’Brien and colleagues conducted a single-arm phase II study of ibrutinib in patients with deletion 17p CLL that was progressing after previous treatment (relapsed or refractory CLL). Such patients exhibit poor responses and survival after chemoimmunotherapy. The patient population was moderately heavily pre-treated, with more than one-third having had three or more prior lines of therapy. Using the standard dose of 420 mg once per day, 145 patients were followed for a median of 28 months. The overall response rate was 83 percent, and the 24-month progression-free survival (PFS) estimate was 63 percent, indicating durable benefit for some patients, but with an ongoing risk of progression. Fifty percent of patients had permanently discontinued ibrutinib, with progression being the most common reason (24% of all patients) and toxicity the second most frequent (17%). Common grade >3 adverse events included neutropenia (18%), pneumonia (13%), hypertension (13%), and atrial fibrillation (6%).
Dr. Anthony Mato and colleagues conducted a retrospective cohort study at multiple major U.S. centers to describe the outcomes of patients who discontinued treatment with either ibrutinib or idelalisib, addressing questions about the reasons for cessation of therapy and the efficacy of subsequent treatment with the alternative kinase inhibitor (i.e., ibrutinib if first treated with idelalisib, and vice versa). The group identified 178 patients who discontinued a BCR pathway inhibitor. The median time to discontinuation was five months (range, 0.25 to 41 months). Toxicity and disease progression were the two major reasons for discontinuation. Thirty-eight patients received subsequent treatment with the alternative kinase inhibitor (either alone or in combination), with 50 percent achieving an objective response. The response rate (56%) and durability of response (median not reached) was higher in patients who had discontinued the original kinase inhibitor due to intolerance rather than disease progression (40% response rate; median PFS, 7 months). Thirteen received a BCL2 inhibitor, with 76 percent responding; 12 received chemoimmunotherapy, with 25 percent responding; however, durability of benefit with these approaches was not reported. Overall, the median survival for discontinuers was 29 months, with progressors due to Richter transformation faring worst and those with intolerance having a much better prognosis.
In Brief
Together, these two papers highlight that while kinase inhibitors are a major advance in therapy for CLL, challenges remain, especially in patients at higher risk for relapse (e.g., deletion 17p CLL) and those who experience progression on a kinase inhibitor. The prospective data generated by Dr. O’Brien and colleagues confirm the benefit of ibrutinib in patients with deletion 17p CLL. The estimated 63 percent two-year progression-free survival is superior to those historically observed for chemoimmunotherapy where median PFS is typically less than six months. However, with 50 percent of patients discontinuing for progression or toxicity, the dilemma becomes how to treat them. The work of Dr. Mato and colleagues is informative, despite limitations in its retrospective design and the inherent risk of selection bias. Where patients fail ibrutinib- or idelalisib-based therapy because of intolerance, a treatment with the alternative kinase inhibitor, alone or in combination, seems to be a reasonable option, as responses may be durable. Where progression is the cause of treatment failure, then only a minority will respond to another kinase inhibitor and benefits may be short-lived. Different options are required. Theoretically, there should not be cross-resistance between BCL2 inhibitors and BCR pathway inhibitors. In deletion 17p patients, venetoclax achieves a 79 percent response rate and 72 percent progression-free survival at one year.1 Early data from Dr. Mato and colleagues in a small number of patients are consistent with this level of activity in patients discontinuing a kinase inhibitor, and publication of peer-reviewed data from a formal phase II study in that setting is anticipated in the near future. Most likely however, combination therapy will be required for those who progress on a kinase inhibitor, and indeed also for patients with deletion 17p CLL who are seeking a long-term disease-free survival. We should anticipate that the treatment revolution in CLL will continue as data emerge for combinations of novel therapies.
References
Competing Interests
Professor Roberts has received research funding from Janssen (sponsor for ibrutinib outside USA) and AbbVie (venetoclax). He is employed by the Walter and Eliza Hall Institute which receives milestone and royalty payments for venetoclax, but he receives no financial benefits personally.
