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