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Relapsed del(17p) CLL
What Is the Optimal Treatment for Patients With Relapsed del(17p) CLL?

Released: October 31, 2016

Expiration: October 30, 2017

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Patient Case
A 71-year-old white male with past medical history of hypertension, diabetes, inflammatory bowel disease, poorly controlled atrial fibrillation on rate control, and anticoagulation with warfarin presented for the management of his relapsed chronic lymphocytic leukemia (CLL). The patient was diagnosed with del(17p), unmutated IGHV CLL 2 years ago and was treated with 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR). He relapsed within 12 months of therapy and was followed with watchful waiting. He now presents with symptomatic anemia, lymphadenopathy, and splenomegaly requiring treatment. Prognostic workup shows the continued presence of unmutated IGHV and del(17p). What would you recommend as second-line therapy for this patient?

Clinical Data Guiding Choice of Therapy
Based on existing data, several choices can be offered to patients with relapsed del(17p) CLL who have not received previous therapy with kinase inhibitors. These include ibrutinib, idelalisib with rituximab, and venetoclax. Below, I summarize the data that I consider when making treatment recommendations for patients like this.

Venetoclax is an oral inhibitor of the antiapoptotic Bcl-2 protein that was recently approved by the FDA for treatment of patients with del(17p) CLL who have received at least 1 other treatment. Early evaluation of this agent was interrupted because of deaths related to tumor lysis in patients with high disease burden, but mitigation strategies including stepwise, deliberate dose escalation, and periodic inpatient monitoring successfully reduced the risk of this complication. Initial results in relapsed patients with predominantly high-risk disease were very encouraging and unprecedented, with an ORR of 79%, including CR in 20% and minimal residual disease (MRD) negativity in 5% of patients. A subsequent phase II trial of 107 patients with relapsed del(17p) disease demonstrated a similar ORR of 74%, a CR rate of 16%, and a 12-month PFS of 72%. Based on these data, venetoclax was approved as second-line therapy for patients with del(17p) CLL. These results are extremely promising given that outcomes with the best available chemoimmunotherapy in patients with del(17p) disease are dismal. Venetoclax is also generally well tolerated, with cytopenia as the most common adverse event. With appropriate patient classification and institution of mitigation strategies, the incidence of tumor lysis was < 1%.

Idelalisib in combination with rituximab is also a reasonable option for patients with relapsed del(17p) disease. Single-agent idelalisib demonstrated an ORR of 54% in patients with del(17p) with a median PFS of 3 months in an early evaluation of the drug. When used in combination with rituximab, the ORR was 73% with a median PFS of 20 months. However, idelalisib therapy can be complicated by the development of diarrhea and colitis, transaminitis, pneumonitis, and infectious complications in a subset of patients, which could be problematic for this particular patient.

Similarly, ibrutinib is also approved for the treatment of patients with del(17p) disease. Early results from the use of ibrutinib in patients with relapsed/refractory del(17p) CLL demonstrated an ORR of 55% with a median PFS of 28 months. A subsequent study in patients with either previously treated or untreated disease revealed an ORR of 97% with a PFS of 82% at 24 months. In a recent pooled analysis of 243 patients with del(17p) treated with ibrutinib, the ORR was 80% and median PFS was 32 months. The estimated 30-month PFS and OS surpassed those reported for all other existing therapies for del(17p) CLL. Similar to idelalisib, ibrutinib is fairly well tolerated but is associated with an increased risk of atrial fibrillation, especially in patients with a previous history of atrial fibrillation. Moreover, ibrutinib increases bleeding risks in patients on concurrent anticoagulants. Based on these issues, I would prefer to use an alternative agent for this patient.

In summary, there are multiple options currently available for the management of patients with relapsed del(17p) CLL. The outcomes observed with these agents compare favorably with historic first-line data from the use of FCR or alemtuzumab, with reported median PFS of 15 and 18 months, respectively, in this patient population. In addition to discussing the pros and cons of each of these therapeutic options, I also discuss the possibility of a reduced-intensity allogeneic stem cell transplant with eligible patients as a potential therapeutic option and refer these patients for transplant evaluation.

Patient Case Conclusion
Based on the data summarized above, in this particular patient, after a detailed discussion about the pros and cons of the various available therapies, including consideration of this patient’s pre-existing comorbid conditions, the patient elected to proceed with venetoclax treatment.

New Tool to Help Guide CLL Treatment Decisions
To help address the challenges associated with treatment decisions for your patients with CLL, my colleagues (Steven E. Coutre, MD; Jeffrey A. Jones, MD, MPH; Michael J. Keating, MBBS; and Andrew D. Zelenetz, MD, PhD) and I are updating an interactive treatment decision tool along with other online activities and several more commentaries from CLL experts, so check back in on the CCO Web site for more information on managing your patients with CLL. An older version of this treatment decision tool is available here and an updated version will be published on the CCO Web site in October 2016. This tool is designed to help you rapidly select individualized treatment options based on your patient’s specific disease characteristics and overall fitness by offering recommendations from each of the experienced faculty listed above specifically for the case you enter into the tool.

Please share your questions or thoughts on your current management approaches for patients with CLL in the comment box below.

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For your patients with relapsed del(17p) CLL who have not received a tyrosine kinase inhibitor, which of the following do you most often choose?
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