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ASH 2016 Ibrutinib in CLL
CLL Studies Presented at the 2016 Hematology Meeting Confirm Ibrutinib’s Long-term Efficacy and Suggest Benefit From Second-line Agents

Released: January 06, 2017

Expiration: January 05, 2018

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In the setting of chronic lymphocytic leukemia (CLL), the advent of small-molecule inhibitors of B-cell receptor signaling pathway kinases—most notably the BTK inhibitor ibrutinib—has revolutionized management of both treatment-naive patients and those with relapsed/refractory CLL. At the 2016 ASH annual meeting, investigators presented mature outcomes from key ibrutinib clinical trials and emerging data to guide treatment for patients with CLL who progress during or after ibrutinib therapy.

Long-term Follow-up From Ibrutinib Clinical Trials
Five-year follow-up from the pivotal phase II PCYC-1102/1103 trial of single-agent ibrutinib for patients with either treatment-naive or relapsed/refractory CLL (N = 132) confirmed a durable clinical benefit, most notably among previously untreated patients and relapsed/refractory patients who lack high-risk genetic features such as del(17p) or del(11q) or who have a complex abnormal karyotype. For treatment-naive patients, 92% remained progression free at 5 years. Median PFS was 52 months in the relapsed/refractory group as a whole but has not yet been reached among patients without high-risk genetic features. Responses have deepened over time, with CRs increasing to 29% from 13% at 2 years and 23% at 3 years of follow-up in previously untreated patients and from 3% at 2 years and 7% at 3 years to 10% at 5 years of follow-up in relapsed/refractory patients. A total of 65% of previously untreated patients and 30% of relapsed/refractory patients continue to receive treatment at 5 years of follow-up.

Outcomes are likewise encouraging for patients with non-del(17p) CLL who received ibrutinib as first-line therapy in the phase III RESONATE-2 study, which randomized 269 older, previously untreated patients with non-del(17p) CLL to ibrutinib vs chlorambucil. With a median treatment duration of 29 months, ibrutinib was associated with an 88% reduction in risk of progression or death compared with chlorambucil. Estimated 24-month PFS was 89% in the ibrutinib arm vs 34% with chlorambucil, and 18% of ibrutinib-treated patients have thus far achieved a CR/CRi with continued treatment. Treatment-limiting adverse events have declined in frequency over time, such that 79% of this elderly patient population continues daily ibrutinib.

Potential Treatment Options for Patients Intolerant or Refractory to Ibrutinib
Complementing these clinical trial reports were retrospective data suggesting that up to 40% of patients with CLL will discontinue ibrutinib therapy across all practice settings and indications, most commonly for intolerance. Whereas outcomes remain excellent overall, these discontinuation rates are higher than reported from clinical trials and suggest a higher incidence of treatment-related toxicity in clinical practice, lower threshold for discontinuation given alternative choices, and/or a learning curve for toxicity management. Second-generation inhibitors with greater specificity for the BTK target appear to have the potential to limit toxicity. For example, 36% of ibrutinib-intolerant patients enrolled on a phase I/II study of acalabrutinib experienced recurrent adverse events, but none has thus far discontinued treatment with the newer agent. Similarly, severe adverse events of clinical interest during ibrutinib treatment, such as atrial fibrillation and major bleeding, have not yet been observed among patients treated with another second-generation BTK inhibitor BGB-3111. Later-stage clinical trials of both agents are ongoing.

On the other hand, for patients with high-risk CLL—defined by the presence of del(17p) and/or a complex abnormal karyotype—treatment failure with ibrutinib and development of refractory CLL remains a significant risk. The majority of patients who relapse while on ibrutinib acquired mutations in BTK and/or PLCG2, and data suggested that emergence of these mutations may have utility as biomarkers to predict relapse. Retrospective data suggest that idelalisib, a small-molecule inhibitor of PI3Kδ approved for previously treated CLL, can induce objective responses in approximately 50% of patients who have previously received ibrutinib. However, only venetoclax, an oral inhibitor of BCL2 recently approved for relapsed del(17p) CLL, has been prospectively studied in this increasingly important clinical context. Updated data from the M14-032 phase II study of single-agent venetoclax demonstrated manageable AEs and a high ORR in 64 patients with CLL progressing after ibrutinib, idelalisib, or both (70% by independent review for patients progressing after ibrutinib; 62% for patients progressing after idelalisib). Responses are thus far durable, and median PFS and OS have not been reached after at least 12 months of follow-up.

Finally, Richter’s transformation remains a particularly vexing pattern of treatment failure among a significant proportion of patients with CLL treated with novel therapies. A phase I/II trial of acalabrutinib enrolled a cohort of patients with biopsy-proven Richter’s transformation. However, whereas the ORR was 38%, including 3 of 9 patients who received previous ibrutinib, median PFS was a disappointing 2.1 months. Perhaps more promising were studies assessing the utility of immune checkpoint inhibitors in these patients. Nivolumab in combination with ibrutinib and single-agent pembrolizumab both appear active in this setting, and mature results are awaited from both studies presented the 2016 meeting.

How have you approached treating patients with CLL who progress on ibrutinib? Share your thoughts in the comment boxes below.

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