Using Targeted Inhibitors in the Management of Chronic Lymphocytic Leukemia: Are We There Yet?

Oncology (Williston Park). 30(11):1016, 1018.

The article by Drs. Jeyakumar and O’Brien in this issue of ONCOLOGY nicely reviews the clinical data that led to US Food and Drug Administration approvals over the last several years of ibrutinib, idelalisib, venetoclax, ofatumumab, and obinutuzumab as treatments for chronic lymphocytic leukemia (CLL).[1] These drugs have transformative clinical activity and have revolutionized the therapeutic landscape for high-risk patients in particular. Yet, even in the first blush of excitement about these new treatment options, many questions remain unanswered. I would like to highlight several critical issues that need to be addressed during the next several years if we are to reach the true potential of these drugs-which conceivably could ultimately cure CLL.

Jeyakumar and O’Brien note how well tolerated these inhibitors are, and certainly their hematologic toxicity is much less than that of chemoimmunotherapy. However, each agent has a distinct pattern of toxicity that can be very problematic, especially for older patients. For example, the ibrutinib clinical trials enrolled relatively young patients with CLL and few comorbidities, and in that context discontinuation rates were only about 10%.[2,3] In contrast, an institutional series reported that the rate of discontinuation was strongly age-dependent, reaching approximately 30% among patients 70 to 80 years of age to 70% among patients over the age of 80.[4] Given that the median age of CLL diagnosis is 72, most of our patients are over 70 at the time of treatment, and these institutional data suggest that their ability to tolerate ibrutinib is significantly lower than that seen in clinical trials. A large retrospective series of non-trial ibrutinib-treated patients identified the primary causes of discontinuation as atrial fibrillation, infection, hematologic toxicity, bleeding, and pneumonitis.[5] The rates of idelalisib discontinuation due to adverse events are even higher, at 52% in a recent combined analysis of two registration trials in the relapsed setting.[6] Although next-generation inhibitors may reduce these toxicities, we still need a better understanding of risk factors and management strategies that will enable us to keep patients on therapy.

Another key issue lost in the enthusiastic rush to move ibrutinib to frontline therapy is the concern about relapse, and our ability to salvage patients who experience relapse on ibrutinib. As noted by Jeyakumar and O’Brien, reported overall survival after progression on ibrutinib in the relapsed and refractory settings is extremely poor,[4,7] and data on patients who relapse after frontline thrapy are extremely limited. The analysis that the authors cite in their review-the only analysis currently available-includes only 23 patients treated in the first or second line, with 5- to 9-month median follow-up.[8] These limitations of the existing data make it difficult to advise patients who are considering their options for first-line therapy, a treatment group whose post-relapse survival duration should be long.

The era of the kinase inhibitor is still very young, with most studies reporting no more than 2-year follow-up; the longest reported follow-up of patients treated with ibrutinib is 36 months.[9] Hence, the future of patients who receive this drug for extended periods is unknown from the standpoints of both efficacy and toxicity. Most patients do not achieve complete remissions, and therefore are likely to eventually relapse. Furthermore, if ibrutinib is stopped when patients are starting to show disease progression, we know that patients can exhibit severe disease flare. This disease flare may be a result of the biology of ibrutinib resistance, if the relapse clones carrying resistance mutations are intrinsically more aggressive.[10] If so, these relapses are still likely to be aggressive even when they occur after frontline therapy. Currently, we do not have good evidence of any effective therapy in this setting; only venetoclax yields an acceptable reported response rate, and the depth and durability of response to this agent is unclear.[11] Whether we can effectively use chemoimmunotherapy in patients who relapse after frontline ibrutinib is completely unknown. For all of these reasons, more data are needed before we can safely move ibrutinib into wide use in unselected patients in a frontline setting. These considerations of aggressive relapse are most acute in patients treated continuously with single-agent therapy, which over time will select for resistant clones. One obvious mechanism for decreasing the risk of outgrowth of these resistant clones is to employ combination therapy, which will result in deeper remissions and suppress resistance from the outset. Deeper remissions would also have the important advantage of enabling breaks in treatment, which would be of particular benefit to patients receiving first-line therapy. Treatment breaks may lead to cost savings, as well as a lower likelihood of resistance and eventual disease progression. To date, however, no studies have planned kinase inhibitor discontinuation, leaving this critical question unanswered.

Thus, the current era seems to be a crossroads as we move into the future of therapy for CLL. The model of continuous sequential targeted agents is currently popular, but this model invites the development of resistance, and present data suggest that after treatment with the first-line agent, subsequent response duration may be limited. Given our lack of long-term follow-up data, if in fact our ability to salvage relapsing patients is limited, we risk a less favorable overall outcome by using ibrutinib alone as the first therapy. Although a long remission with a single targeted agent may be adequate for older patients with low-risk disease, for those who are young or who have higher-risk disease, we need a next generation of trials that look at time-limited combination therapy driven by the goal of achieving minimal residual disease negativity as a first step on the road to eventual cure for CLL. We must not forget that for fit younger patients with mutated IgHV (immunoglobulin heavy chain variable region gene), three different studies now demonstrate that a long-term disease- and treatment-free plateau frequently can be achieved by administration of the fludarabine-cyclophosphamide-rituximab regimen,[12-14] which can serve as the foundation for achieving even better outcomes in that group. For patients with unmutated IgHV, we can move to novel-novel combinations, likely including Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors with an anti-CD20 antibody; these trials are just beginning. Much work still lies ahead to find an optimized, personalized approach to achieving long-term remission or eventual cure for CLL-one that takes individual disease risks and other patient factors into consideration.

Financial Disclosure:Dr. Brown has served as a consultant to AbbVie, Astra-Zeneca, Gilead, Infinity, Janssen, Pharmacyclics, Roche/Genentech, and Sun.

References:

1. Jeyakumar D, O’Brien S. The next generation of targeted molecules for the treatment of chronic lymphocytic leukemia. Oncology (Williston Park). 2016;30:1008-15.

2. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-23.

3. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.

4. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80-7.

5. Mato A, Nabhan C, Barr PM, et al. Favorable outcomes in CLL pts with alternate kinase inhibitors following ibrutinib or idelalisib discontinuation: results from a large multi-center study. Blood. 2015;126:719.

6. Brown JR, Ghia P, Jones JA, et al. Discontinuation of idelalisib treatment due to disease progression in patients with relapsed and refractory CLL: an evaluation of outcomes. Haematologica. 2016;101:230.

7. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062-7.

8. O’Brien S, Byrd J, Hillmen P, et al. Outcomes with ibrutinib by line of therapy in patients with CLL: analyses from phase III data. J Clin Oncol. 2016;34(suppl):abstr 7520.

9. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-506.

10. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286-94.

11. Jones J, Mato AR, Coutre S, et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to ibrutinib or idelalisib therapy. Blood. 2015;126:715.

12. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208-15.

13. Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126:1921-4.

14. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303-9.