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Management of del(17p) CLL
Ibrutinib and the Management of Patients With del(17p) CLL

Released: March 23, 2015

Expiration: March 21, 2016

Farrukh Awan
Farrukh Awan, MD, MS
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Chronic lymphocytic leukemia (CLL) is a disease that is characterized by myriad clinical presentations and outcomes. There are various genetic or molecular markers that can help with prognostication which have been established and validated and are routinely used in clinical practice. Among these are β2-microglobulin, cytogenetics, IGVH mutational status, ZAP-70 expression, CD38 expression, and del 17p13.1. One way to stratify patients regarding outcomes is by using interphase FISH analysis of the malignant B cells. Del 17p13.1 is present in < 10% of patients with CLL and frequently involves the deletion of the TP53 gene that encodes the p53 protein. The presence of p53 is critical for cellular apoptosis or repair specifically in response to cytotoxic stimuli. Patients with del(17p) typically experience rapidly progressive disease with significantly inferior survival outcomes and poor response to therapy. The disease is also generally chemoresistant, and therefore, responses to conventional chemotherapy-based regimens have been disappointing.

Ibrutinib for CLL With del(17p)
Ibrutinib is a first-in-class, irreversible inhibitor of BTK, which is an integral component of B-cell receptor mediated survival signals for the malignant CLL B cell. Ibrutinib received FDA approval as first-line therapy for patients with del(17p) disease in July 2014. The approval was primarily based on early studies in which patients with relapsed/refractory CLL with del(17p) achieved an ORR of 55.9% with a median duration of response of 25 months. These early results are extremely promising and were partly validated when a single-institution, retrospective comparison of ibrutinib vs cyclin-dependent kinase inhibitors or other conventional therapies previously used for patients with del(17p) revealed a significantly improved response rate and PFS with ibrutinib. Extended follow-up in the multicenter phase II RESONATE-17 trial of previously treated patients with del(17p) disease who received single-agent ibrutinib has established a median PFS of 28 months. This result is extremely favorable even when compared with historic first-line data from the use of fludarabine/cyclophosphamide/rituximab or alemtuzumab, which reported median PFS of 11 and 18 months, respectively, in this patient population.

Moreover, ibrutinib is extremely well tolerated with a much better toxicity profile than either of those therapies. In contrast to conventional chemotherapy-based treatments that result in the development of immune dysfunction, patients treated with ibrutinib experienced a progressive decline in the incidence of infectious complications with ongoing therapy. This outcome can partly be attributed to disease control and to the ability of ibrutinib to induce a favorable immune response. Infectious complications constitute the leading cause of morbidity and mortality in patients with CLL, but patients treated with ibrutinib generally do not require routine antimicrobial prophylaxis and frequently are able to discontinue ongoing prophylactic antibiotics when using ibrutinib in the relapsed setting. Improvements have also been reported in stress, depressive symptoms, fatigue, and quality of life for patients being treated with ibrutinib.

Based on these data, the recommendation is to treat all patients with CLL with del(17p) disease with ibrutinib prior to considering conventional therapies or stem cell transplantation.

Patients who present with del(17p) disease and require therapy should be considered for treatment with either ibrutinib or on a clinical trial of ibrutinib in combination with novel therapeutics. Other treatment options that have shown promising early results include PI3-kinase inhibitors (idelalisib, duvelisib), Bcl-2 inhibitor (venetoclax), and Syk inhibitor (entospletinib).

Your Thoughts?
Have you integrated ibrutinib into your treatment strategies for patients with CLL? I invite readers to post their thoughts and experiences in the comments section below.

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1.
A 45-year-old patient is diagnosed with CLL, IGHV unmutated with del(17p) in 90% of his cells on FISH evaluation. Along with referral to a tertiary care center for potential transplant evaluation, what other treatment should be considered since he meets IWCLL-2008 criteria for treatment given his thrombocytopenia?
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