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Ibrutinib-Refractory Non-del(17p) CLL
How I Manage Ibrutinib-Refractory Patients With CLL Without Del(17p)

Released: April 13, 2017

Expiration: April 12, 2018

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Patient Case
A 69-year-old white male presents to your clinic with relapsed chronic lymphocytic leukemia (CLL). He was diagnosed 12 years ago with CLL that included both del(13q) and mutated IgHV but not del(17p). He was followed with watchful waiting initially but required treatment 2 years ago for symptomatic progressive disease.

His past medical history includes hypertension, diabetes, and coronary artery disease. For his initial treatment, the patient refused chemotherapy, was started on ibrutinib, and achieved a CR. He now has slowly progressive symptomatic anemia and lymphadenopathy. Staging workup reveals the presence of worsening lymphadenopathy that was not FDG avid on PET scan. Prognostic workup confirms the continued presence of del(13q) and no del(17p) mutation. Now that he has progressed on ibrutinib, he requires second-line treatment.

Second-line Options
Several choices are available for patients with ibrutinib-refractory CLL. The preferred options include enrollment on a clinical trial, treatment with idelalisib plus rituximab, or off-label treatment with venetoclax. Summarized below are the data I consider when making treatment recommendations for patients like our case patient who has non-del(17p) CLL but does not want to endure chemotherapy.

Venetoclax
Venetoclax is an oral inhibitor of the antiapoptotic BCL-2 protein and is approved for the treatment of patients with relapsed del(17p) CLL. The initial approval of venetoclax was based on a trial of 107 patients with relapsed del(17p) CLL that demonstrated an ORR of 74% (CR: 16%) by investigator assessment and an estimated 12-month PFS of 72%. However, there are increasing data with the use of this agent in all patients with relapsed CLL. The initial report in patients regardless of del(17p) mutations (N = 116) demonstrated a similar ORR of 79%, including CR in 20% and minimal residual disease negativity in 5% of patients. In this study, 30% of patients had del(17p), and response rates were similar in patients with or without del(17p). The ORRs were 71% vs 79%, respectively, with CRs in 16% vs 20%. A recent evaluation of venetoclax in patients relapsing after ibrutinib or idelalisib demonstrated very promising ORRs of 67% and 57%, respectively. For all patients, the estimated 12-month PFS was 80%. These results are a welcome contrast to earlier reports demonstrating an extremely poor prognosis for patients failing ibrutinib, with a median OS of approximately 17 months.

Development of this agent in clinical trials was delayed initially due to treatment-related deaths from tumor lysis syndrome. Subsequent stepwise dose-escalation strategies and careful monitoring of patients with high-disease burden have successfully lowered the incidence of this catastrophic complication, with tumor lysis syndrome observed currently in fewer than 1% of patients. Venetoclax is generally well tolerated overall, and cytopenias are the most common serious adverse events.

Idelalisib
Idelalisib in combination with rituximab is approved for the treatment of relapsed CLL based on data that demonstrated an ORR of 73% with a median PFS of approximately 20 months. However, therapy with idelalisib is complicated by the development of diarrhea and colitis, transaminitis, pneumonitis, and infectious complications in a subset of patients. This is a concern for the patient case example outlined above.

Which Option Is Best?
A retrospective analysis of patients with CLL who were treated with kinase inhibitors (KIs) or venetoclax showed that patients receiving idelalisib following ibrutinib discontinuation demonstrated an ORR of 46% (all PRs), and venetoclax therapy following ibrutinib failure resulted in an ORR of 74% (32% CR). This suggests that venetoclax may have better outcomes in patients failing ibrutinib compared with other alternatives. Conventional chemotherapeutic options, including FCR, BR, or anti-CD20 antibody-based combination treatment, might also be reasonable options for suitable patients in this setting. Furthermore, for eligible patients, I also discuss reduced-intensity allogeneic stem cell transplantation and CAR-T cell therapy and refer interested candidates for appropriate evaluation. Patients progressing on kinase inhibitors also tend to have rapid disease progression once therapy is discontinued. Therefore, patients should be monitored carefully during this time and transitioned to alternative therapy as soon as possible after discontinuing ibrutinib.

In summary, there are limited options currently available for the management of patients with ibrutinib-refractory CLL. These data suggest an advantage of venetoclax in this setting, but every effort should be made to treat these patients on a clinical trial.

Patient Case, Conclusion
Based on the data summarized above, in this patient case example, after a prolonged discussion about the benefits and risks of the various available therapies and especially after considering his various comorbid conditions, the patient elected to proceed with venetoclax treatment off-trial.

CLL Interactive Decision Support Tool
To help address the challenges in making treatment decisions for your patients with CLL, my colleagues (Steven E. Coutre, MD; Jeffrey A. Jones, MD, MPH; Michael J. Keating, MB BS; and Andrew D. Zelenetz, MD, PhD) and I have developed an Interactive Treatment Decision Support Tool for CLL along with expert-authored commentaries and other online activities. This tool is designed to help you select individualized treatment options based on your patient’s specific disease characteristics and overall fitness by offering recommendations from each faculty expert.

How would you treat this patient? Please share your questions or thoughts on your current management approaches for patients with CLL in the comment box below.

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Looking forward, which strategy are you most likely to use for your patients with CLL who fail initial ibrutinib therapy if a clinical trial is unavailable?
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