Hope For Patients Who Discontinue Ibrutinib or Idelalisib

There is little question that the approval of kinase inhibitor therapies such as ibrutinib have revolutionized the care of patients with CLL. Ibrutinib is active in many circumstances where many traditional CLL-directed therapies no longer demonstrate clinical activity. Landmark trials presented over the past three years have consistently demonstrated favorable results for CLL patients receiving ibrutinib, particularly in the relapsed–refractory settings¹, as compared to ofatumumab², in patients with del17p³ and most recently in the front-line setting.⁴ These results have led the FDA to approve ibrutinib for patients with CLL in both the front-line and relapsed-refractory settings and there is little question that most CLL patients will have the opportunity to receive this important agent, should they require therapy.

At the most recent American Society of Hematology meeting (December 2015), our group was interested to study outcomes and treatment options for patients who discontinued either ibrutinib or the PI3K inhibitor idelalisib^5,6 and to observe what subsequent therapies were selected and whether they demonstrated activity. Among the 10 large cancer centers that participated, we identified 178 patients who discontinued either ibrutinib- or idelalisib-based therapies. The overall experience for this group of patients is particularly important because it gives us a real-world window into the relatively small number of patients who discontinue ibrutinib or idelalisib.

There were several key findings from this study which I would like to highlight:

• Based on the results of clinical trials and previously published series, most patients tolerate and respond to ibrutinib or idelalisib and do not discontinue these agents. They are expected to be long-term therapies for control of CLL.⁷
• Our study represented the largest experience of practice patterns and outcomes of patients following discontinuation of ibruntib or idelalisib in CLL (thought to be a relatively small number of patients).
• The majority of patients discontinued either idelalisib or ibrutinib due to side effects or worsening of CLL, not as a result of transformation to a large cell lymphoma (Richter’s transformation) as has been previously reported.
• We found that patients who experienced side effects requiring discontinuation of one of these agents were often able to tolerate the alternate agent and, in fact, obtain durable responses. 
• Similarly, patients with progression of CLL were able to respond to the alternate agent, although with a less durable period of response.
• Additionally, patients who discontinued either ibrutinib or idelalisib had documented responses to a new class of CLL therapy (BCL 2 inhibitor). Recent data presented at the same meeting demonstrated remarkable activity of the BCL2 inhibitor venetoclax in patients who failed either ibrutinib or idelalisib.⁸ We are eager for this agent to be approved and to be available to a wider number of CLL patients.

The take home message for this research is that agents such as ibrutinib and idelalisib are well tolerated and are very active treatments. For the small number of patients who discontinue these agents (either due to side effects or progression) the treating hematologist/oncologist may wish to consider a trial of an alternate kinase inhibitor (ibrutinib + idelalisib or idelalisib + ibrutinib), as this may be a reasonable treatment option. Additionally, recent research highlights the great promise of venetoclax for patients with high-risk CLL or for those who have failed kinase inhibitor therapy.⁸ Finally, although both ibrutinib and idelalisib have established side effect profiles which can occasionally make these agents difficult to tolerate, there are several next generation kinase inhibitors in development that appear to be similarly active with limited side effects and may potentially be even better tolerated than current therapies.^9-12

In summary, there is great opportunity for CLL patients treated with currently available targeted agents and great hope on the way in the form of next generation kinase inhibitors and BCL2 inhibitors for patients who discontinue these agents. The physicians treating CLL patients will have a wealth of choices to help fight against the disease. At the University of Pennsylvania Center for CLL, our primary focus is to provide CLL patients with access to state of the art therapies and prognostic tools through research and clinical expertise.

Key references for patients to consider:

1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2013;369(1):32-42.
2. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med 2014; 371:213-223.
3. O’Brien S, Jones JA,  Coutre S,  Mato AR, et al. Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial. Blood Abstract presented at the 2014 American Society of Hematology annual meeting, San Francisco, CA.
4. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med 2015; 373:2425-2437.
5. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2014; 370:997-1007.
6. 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(23):719-719.
7. 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(1):80-87.
8. 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(23):715-715.
9. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016; 374:323-332.
10. Burris HA, Patel MR, Brander DM, O’Connor OA,  Deng C, ,  Fenske TS, et al. TGR-1202, a Novel Once Daily PI3Kδ Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma. Blood Poster presented at the 2014 American Society of Hematology annual meeting, San Francisco, CA.
11. Lunning MA, Vose JM, Schreeder MT, Fowler N, Nastoupil LJ, Siddiqi T, et al. Ublituximab, a Novel Glycoengineered Anti-CD20 Monoclonal Antibody (mAb), in Combination with TGR-1202, a Next Generation Once Daily PI3kδ Inhibitor, Demonstrates Activity in Heavily Pre-Treated and High-Risk Chronic Lymphocytic Leukemia (CLL) and B-Cell Lymphoma. Blood Abstract presented at the 2014 American Society of Hematology annual meeting, San Francisco, CA.
12. Flinn I, Patel M, Kahl BS, et al. Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ, γ, In Patients With Chronic Lymphocytic Leukemia. Blood 2013;122(21):677-677.

Anthony Mato, MD, MSCE is Assistant Professor of Medicine at the Hospital of the University of Pennsylvania and sees patients at the Center for Chronic Lymphocytic Leukemia at the Abramson Cancer Center.

Originally published in The CLL Tribune Q1 2016.