Higher mean dose intensity of ibrutinib may improve PFS in CLL

Issue: December 25, 2015

NEW YORK — A higher mean dose intensity of ibrutinib appeared to prolong PFS among patients with previously treated CLL, regardless of deletion 17p and TP53 mutational status, according to study results presented at Lymphoma & Myeloma 2015.

Perspective from Deborah M. Stephens, DO

Previous data have shown 420 mg once-daily ibrutinib (Imbruvica; Pharmacyclics and Janssen) leads to complete or near complete Bruton’s tyrosine kinase (BTK) active site (median ˃ 90%) occupancy at 4 hours, which was sustained at 24 hours. However, simulated analyses indicated that at lower doses, such as 140 mg or 280 mg, fewer patients achieve BTK occupancy.

Jacqueline Claudia Barrientos, MD, a physician at North-Shore-LLJ Cancer Institute in Lake Success, New York, and colleagues compared dose intensity — defined as the proportion of actually administered vs. planned doses of 420-mg ibrutinib — in the first 8 weeks of treatment with post-week 8 PFS. Missed doses had to be on consecutive days with an intent to restart ibrutinib, and mean duration of missed doses per event was based on the sum of all missed doses for 8 or more days.

The mean dose intensity among 195 patients treated with ibrutinib was 95% (median, 100%) after 8.6 months of treatment.

Overall, 4.1% of patients had a dose reduction due to adverse events, including 3.6% of patients who reduced their dose to 280 mg, and 0.5% who reduced their dose to 140 mg. Half of these patients eventually restarted or re-escalated their dose to 420 mg.

Of 79 patients who experienced events leading to missed doses, 73 restarted therapy at the original dose.

Fifty-eight patients missed 8 or more consecutive days. The mean duration of a missed dose event was 18.7 days (range, 8-56) and the mean number of missed dose events was 1.3 times per patient (range, 1-4).

Barrientos and colleagues found that a smaller proportion of patients who missed fewer than 8 consecutive days than those who missed 8 or more consecutive days experienced a PFS event (12% vs. 30%). This association persisted among patients with deletion 17p (n = 62; 22% vs. 33%) and TP53 mutation (n = 60; 8% vs. 33%).

Median PFS was not reached in the cohort of patients who missed fewer than 8 consecutive days, whereas median PF was 11.1 months in the cohort who did.

Further, patients with a dose intensity above the mean achieved longer PFS than patients with a dose intensity lower than the mean (not reach vs. 6.9 months; P = .0127).

“These results support the clinical utility of sustained adherence to the once-daily ibrutinib 420-mg dose in patients with previously treated CLL,” Barrientos and colleagues wrote. – by Alexandra Todak

For more information:

Barrientos JC, et al. Abstract P11. Presented at: Lymphoma & Myeloma 2015: An International Congress on Hematological Malignancies; Oct. 22-24, 2015; New York, New York.

Disclosure: HemOnc Today was unable to confirm the researchers’ relevant financial disclosures at the time of reporting.

Perspective

Deborah M. Stephens, DO

Barrientos and colleagues presented their data correlating dose intensity of ibrutinib (Imbruvica; Pharmacyclics, Janssen) with clinical outcomes in 195 patients with relapsed and refractory chronic lymphocytic leukemia treated with ibrutinib (420 mg daily) on the phase 3 RESONATE trial. The researchers found that a higher mean dose intensity of ibrutinib is associated with an improvement of median PFS. They conclude that sustained adherence to ibrutinib may improve patient outcomes.
The strength of this study is that the patients were treated on a stringently monitored phase 3 study with careful pill counts taken at each patient visit and patient diaries detailing medication compliance. Therefore, the number of missed doses or dose reductions is quite accurate, implying that there may really be a difference in outcomes based on dose intensity of ibrutinib. However, several key limitations of this study are as follows:

This study is an unplanned retrospective subset analysis comparing dose intensity and clinical outcomes. The study design was not powered specifically to detect differences in outcomes based upon dose intensity.
The researchers report that patients missing more than 7 consecutive days had more PFS events than those missing 8 or fewer consecutive days. One could argue that the patients missing more than 8 days in a row were intrinsically sicker than the other patients and thus more likely to have more PFS events regardless of dose of ibrutinib.
The researchers report no difference in median PFS with lower vs. higher pharmacokinetic (PK) exposure to ibrutinib. However, these PK measurements were only taken at weeks 1 and 4, which likely does not accurately reflect PK exposure at time of missed doses. A planned investigation of PK at time of missed dose would more accurately reflect how PK variables contribute to clinical outcome in this setting.
The researchers don’t report whether the patients progressed by developing a mutation in Bruton’s tyrosine kinase, transforming into a more aggressive lymphoma, or other causes. The final publication of these data may address this question. Prospective study of the reason for relapse may provide more information of the biologic impact of missed ibrutinib doses.
Is PFS a good surrogate marker of OS or general clinical outcomes in the CLL population who can live for years despite progression of disease? This question is recurrent in CLL research as PFS is clearly more feasible to assess. Long-term follow-up of this analysis may provide insight about the effect of ibrutinib dose intensity on OS.

Assuming that the conclusions of the study are accurate, clinicians are left with several dilemmas.
First, if multiple doses of ibrutinib were missed in this highly monitored clinical trial, it is safe to assume that the average patient in the community receiving ibrutinib without a patient diary or someone closely counting their pills is more likely to miss more doses of ibrutinib than the patients in this study. How can clinicians increase ibrutinib compliance?
Second, as instructed by the ibrutinib package insert, clinicians routinely recommend holding ibrutinib doses for 3 to 7 days prior to and after a surgical procedure to limit bleeding risk. Does this practice worsen patient survival?
Third, development of ibrutinib resistance is a potentially fatal outcome for patients with CLL. Is there a threshold on the number of held ibrutinib doses that might lead to ibrutinib resistance?
Until these questions are more accurately answered, clinicians should use all available resources to ensure ibrutinib compliance and limit progression of CLL. Such resources might include an advanced practitioner, clinic nurse or specialty pharmacist who could routinely evaluate compliance and educate patients about the importance of compliance. Alternatively, a clinician might advocate for the use of hand-held technology such as pill reminder or medication tracking applications. Clinicians will look forward to longer-term analyses of these data and future prospective studies to guide clinical practice.

Reference:

Byrd JC, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1400376.

Deborah M. Stephens, DO

Huntsman Cancer Institute

University of Utah

Disclosures: Stephens reports no relevant financial disclosures.