Mark Wildgust

Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials

The first-in-class Bruton’s tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6–16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months versus 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation (clinicaltrials.gov identifier: 01578707, 01722487, 01611090, 01646021).

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B‐cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression‐free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non‐blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0–1, non‐bulky disease and non‐blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.

Comparing overall survival (OS) outcomes in patients with newly diagnosed chronic lymphocytic leukemia (CLL) with normal life expectancy.

7 Background: CLL is an orphan hematologic malignancy but also accounts for the most common adult leukemia in the Western Hemisphere, with a median age at diagnosis of 72 years. Median OS for symptomatic, treatment-naïve, elderly patients with CLL is approximately 5.3 years (CLL5; Eichhorst, et al. Blood 2009), whereas the life expectancy of a 72 year old (yo) is around 12 years (US Life Tables, 2006). Ibrutinib, an oral, first-in-class, covalent Brutons tyrosine kinase inhibitor, significantly improves OS. Early results from a phase 1/2 study in treatment-naïve elderly patients with CLL (PCYC-1102; median age, 71 years) suggest that single-agent ibrutinib extends OS, with survival at 3 years of approximately 97% (Byrd, et al. Blood 2015). Here we compare the OS in newly diagnosed patients with CLL treated with single-agent ibrutinib or chlorambucil with the normal life expectancy of a 72 yo adult. METHODS OS outcomes for patients treated with chlorambucil from the CLL5 study conducted in Germany (Eichhorst, et al. Blood 2009) were compared with long-term OS results from PCYC-1102 (Byrd, et al. Blood 2015). Life expectancy data were obtained from US Life Tables. RESULTS Results from CLL5 suggest that single-agent chlorambucil has a median OS of 5.3 years (median age, 71 years), with approximately 75% of patients alive at 3 years. The median OS for ibrutinib has not been reached (median follow-up, 3 years), with an estimated progression-free survival of 96% and OS of 97% at 3 years. Life expectancy for a 72 yo healthy person at 3 years is approximately 95%. Naïve comparisons suggest that single-agent ibrutinib may be altering the natural history of CLL, providing a longer OS versus chlorambucil and a similar OS as expected in a 72 yo in the general population. CONCLUSIONS Treatment outcomes in CLL are fundamentally changing with the advent of new targeted therapies. This indirect naïve comparison between ibrutinib-treated patients and a general population suggests we may be moving from palliative care for elderly patients with CLL to chronic care management. Implications for chronic care management of patients with CLL will be discussed.

Ibrutinib for chronic lymphocytic leukemia: international experience from a named patient program

After first approval of ibrutinib for patients with B-cell malignancies in the US, an international named patient program (NPP) was initiated to provide ibrutinib to patients before local country approval. In this observational retrospective analysis of data collected from the NPP, estimated time on treatment and its relationship with baseline characteristics were analyzed for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Ibrutinib outcomes were compared with those from the phase III RESONATETM study. Our findings suggest that ibrutinib is effective and well tolerated in the real world, with time on treatment similar to the clinical trial setting; younger age and complete response (CR)/partial response (PR) to prior therapy were predictive of longer time on treatment. In B-cell malignancies such as CLL, Bruton’s tyrosine kinase (BTK) is a rational target for therapy because it is needed for B-cell receptor signaling, plays a key role in Bcell maturation, and is overexpressed. Benefits of ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of BTK, have been demonstrated in phase II and III studies across multiple B-cell malignancies. Ibrutinib is approved in the EU, US and elsewhere to treat patients with CLL, Waldenström’s macroglobulinemia and relapsed/refractory mantle cell lymphoma. It is also indicated for marginal zone lymphoma in the US. NPPs enable controlled access to treatments that have shown a positive benefit-risk ratio for life-threatening conditions, in response to unsolicited requests by physicians and on behalf of patients, before the drug is licensed or commercially available in their country. NPPs can provide data on the clinical use, treatment duration, efficacy and relative safety of a drug in a real-world context. After the first approval of ibrutinib in the US in November 2013, an international ibrutinib NPP was initiated for patients with B-cell malignancies who met respective phase III trial eligibility criteria. Here we describe an observational retrospective analysis of data from patients with relapsed/refractory CLL enrolled in the international ibrutinib NPP from March 2014 through October 2015, to estimate time on treatment and explore related patient characteristics. Time on ibrutinib treatment in the international NPP was compared with the phase III RESONATETM (PCYC-1112) study of ibrutinib versus ofatumumab in patients with relapsed/refractory CLL. Inclusion criteria for the NPP were based on RESONATETM: age ≥18 years; confirmed diagnosis of CLL/small lymphocytic lymphoma (including patients with 17p deletion); Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of <2; relapsed/refractory disease after ≥1 prior therapy, defined as failure to achieve a PR with, or documented progression after, the most recent treatment regimen. Participation was approved by the local independent ethics committee or institutional review board as needed, and the enrolling physician obtained patients’ informed consent. Patients received oral ibrutinib 420 mg once daily continuously until progressive disease (PD) or unacceptable toxicity. Disease evaluations and safety monitoring were conducted by enrolling physicians, according to local standard of care. Ibrutinib was provided through the NPP until commercially available, at which point patients were transferred to commercial drug if appropriate, and follow up stopped. Data on the ordering/reordering of ibrutinib were collected. Treatment start and stop (discontinuation) dates were entered by the physician via a simple questionnaire on the Janssen Managed Access portal (MAcWeb; if not entered, reordering data were censored at the date of last ibrutinib supply). Patient baseline characteristics and reasons for stopping orders were collected from physicians at enrollment and treatment discontinuation, respectively, also via MAcWeb. Kaplan-Meier analysis and Cox proportional hazards regression were used to estimate time on treatment. Relationships between baseline characteristics and time on treatment were explored via multivariate analyses, included categorical variables of age, sex, number of prior therapy lines, time since CLL diagnosis, PD on prior therapy in the past 3 months, CR or PR to last therapy, relapsed disease and refractory disease. In total, 2908 patients with CLL from 30 countries were enrolled in the NPP. Baseline demographic and disease characteristics are shown in Table 1. Naïve comparison with patient baseline characteristics of the RESONATETM study ibrutinib arm suggests median age and proportion of males were similar, however, the proportion of patients with ≥3 prior lines of therapy was higher in the NPP (63% vs. 53% for NPP vs. RESONATETM). Fewer patients in the NPP relapsed after purine analogues (70% vs. 85%, respectively) or anti-CD20 therapy (68% vs. 94%, respectively). The estimated proportion of patients on treatment at 12 months was 77.3% (95% confidence interval [CI]: 74.7, 79.6) in the NPP, similar to RESONATETM (actual 12month time on treatment rate, 81.5%; 95% CI: 75.3, 86.3). Time on treatment for the international CLL NPP and RESONATETM populations were not statistically different (hazard ratio, 1.20 [95% CI: 0.86, 1.67]) (Figure 1). The median duration of follow up was 5.78 (range, 0.0318.73) months in the NPP, and 9.4 (range, 0.1-16.6) months in RESONATETM. In the multivariate analysis, younger age (<50 years) and achievement of CR/PR as a response to prior therapy were independent factors significantly associated with longer time on treatment. Having a CLL diagnosis for >5 years