As reported in The Lancet Oncology by Dr. Andrew Zelenetz and colleagues and reviewed in this issue of The ASCO Post, an international phase III trial in 416 patients with refractory or recurrent chronic lymphocytic leukemia (CLL) addressed the benefit of adding the first-in-class phosphoinositide 3-kinase (PI3K) inhibitor idelalisib (Zydelig; n = 207 on idelalisib and n = 209 on placebo) to standard therapy with bendamustine and rituximab (Rituxan) both during induction and as maintenance given indefinitely until disease progression or death.1 At a median follow-up of 14 months, they found that the addition of idelalisib resulted in improved progression-free survival (20.8 months for idelalisib and 11.1 months for placebo) and overall survival (median not reached for idelalisib and 31.6 months for placebo) compared with bendamustine and rituximab alone.
The HELIOS Study
Although this is the first study to show an advantage to the addition of the PI3K inhibitor idelalisib, it is not the first study to show that the addition of a B-cell receptor pathway (BCR) inhibitor improves outcome in relapsed or refractory CLL. The HELIOS study reported by Chanan-Khan et al2 demonstrated an improvement in progression-free survival (but not overall survival) with the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in a similar group of patients.
Small-molecule inhibitors targeting the BCR pathway can be added to standard therapy for relapsed or refractory CLL, provided appropriate measures to prevent and monitor infectious complications are taken.— Leo I. Gordon, MD, FACP
In the HELIOS study, the curves for the ibrutinib and placebo arms begin to separate at about 6 months, suggesting the difference in progression-free survival might indeed be a result of maintenance. In the current study, however, the progression-free survival curve (shown in Figure 2A in Zelenetz et al1) begins to separate earlier, at about 4 months, whereas the overall survival curve (Figure 2B in Zelenetz et al1) separates at about 6 months, which is when induction therapy ends. If one looks at patients without TP53 mutations or del17p (Figure 3A in the article1), progression-free survival differences are seen early in the course of induction in favor of idelalisib.
These data suggest that although there is still likely a benefit of maintenance therapy to account for the improvement in progression-free and overall survival, it is not the only reason for these -differences. There may be some true synergy between the PI3K inhibitor and bendamustine/rituximab, which could account for the improvement in progression-free and overall survival.
Cause for Concern
These happy results do not come without some cause for concern. During this study, it became clear that the risk of infection in patients treated with idelalisib was greater; this not only included the risk of common bacterial infections such as pneumonia and upper respiratory infections, but also life-threatening risks of cytomegalovirus reactivation and -Pneumocystis jirovecii pneumonia infection. This observation, as well as the data across three GILEAD studies involving idelalisib and various combinations of bendamustine and rituximab in first-line CLL treatment and relapsed indolent non-Hodgkin lymphoma, led to the U.S. Food and Drug Administration mandates to use Pneumocystis jirovecii pneumonia prophylaxis and cytomegalovirus screening in patients receiving BCR inhibitors.
Although this observation is important with respect to BCR inhibitors, it is also clear that patients who are treated with bendamustine, especially as second-line therapy, are at risk for opportunistic infection. Our experience is that when measured, T-cell counts are quite low in this group of patients. Our practice has been to use Pneumocystis jirovecii pneumonia prophylaxis and cytomegalovirus monitoring routinely in patients on bendamustine—a practice that I think will lower the risk of serious infection.
Another toxicity that might have been expected in this trial was the immunologically mediated diarrhea or pneumonitis observed with idelalisib.3-5 Interestingly, diarrhea was not as common as previously reported, an observation suggesting that in previously treated patients, the T-cell immunosuppression extant might have a protective effect; so patients treated in the first-line setting with this class of drugs might be at greater risk for diarrhea and pneumonitis than patients treated in the second-line setting.
Clarifying the Way Forward
The overall impact of these findings is high and suggests that small-molecule inhibitors targeting the BCR pathway can be added to standard therapy for relapsed or refractory CLL, provided appropriate measures to prevent and monitor infectious complications are taken. What cannot be answered by this study, however, is whether the outcome would have been the same if idelalisib were used alone, perhaps with less toxicity. Another as yet unanswered question is whether idelalisib and ibrutinib are equivalent or could be combined in a doublet of small-molecule inhibitor therapy. As new agents (eg, venetoclax [Venclexta]) are developed, the proper sequencing and combination of this new approach to CLL will have to be studied in carefully conducted clinical trials to clarify the way forward. ■
Dr. Gordon is Abby and John Friend Professor of Cancer Research; Director, Lymphoma Program; Medical Director, John and Lillian Mathews Cellular Therapy Laboratory, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago.
DISCLOSURE: Dr. Gordon has served on an advisory board for Gilead.
1. Zelenetz AD, Barrientos JC, Brown JR, et al: Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: Interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 18:297-311, 2017.
2. Chanan-Khan A, Cramer P, Demirkan F, et al: Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): A randomised, double-blind, phase 3 study. Lancet Oncol 17:200-211, 2016.
3. Coutré SE, Barrientos JC, Brown JR, et al: Management of adverse events associated with idelalisib treatment: Expert panel opinion. Leuk Lymphoma 56:2779-2786, 2015.
4. Graf SA, Gopal AK: Idelalisib for the treatment of non-Hodgkin lymphoma. Expert Opin Pharmacother 17:265-274, 2016.
5. Davies A: Idelalisib for relapsed/refractory indolent B-cell non-Hodgkin’s lymphoma: An overview of pharmacokinetics and clinical trial outcomes. Expert Rev Hematol 8:581-593, 2015.