Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results

Abstract

Key Points• Ibrutinib demonstrates durable responses and sustained single-agent activity in relapsed or refractory MCL at median 26.7-month follow-up.• Ibrutinib shows a favorable benefit-risk profile over time, with a manageable safety profile.Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N 5 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ‡2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ‡3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ‡3 bleeding events in ‡2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391. (Blood. 2015;126(6):739-745)

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

“…The BTK inhibitor ibrutinib, with or without weekly dex, demonstrated promising activity and was well tolerated in this heavily pre‐treated RRMM population with a median of 4 prior lines of therapy, including 74% of patients who had disease that was refractory to their most recent therapy. The AEs reported in this trial were consistent with the safety profile of ibrutinib observed across other B‐cell malignancies (Burger et al , 2015; Wang et al , 2015; Castillo et al , 2016; Falchi et al , 2016). The majority of AEs reported were grades 1–2 and were managed with supportive care.…”

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…Such constructs have a long blood retention time compared to blinatumomab and could be applied more conveniently. Despite improved FcγR affinity, this type of antibodies show only few side effects when applied in patients, 9 , 15 and, importantly, side effects of T-cell activation such as CRS and encephalopathy may be avoided. Despite such expected advantages compared to blinatumomab or CAR T cells, it remains to be determined whether Fc engineered antibodies will be equally efficient in the clinic.…”

“…An important approach for that purpose is the use of immunotherapies, and therapy with Fc engineered CD19 antibodies may represent a powerful option with few side effects. 8 , 9 , 15 , 16 …”

“…In our preclinical study, outgrowth of CD19-negative subclones in PDX animals was not observed and such a phenomenon was not reported in early clinical studies of similar constructs in patients. 9 , 11 , 15 CD22 specific immunotherapies (e.g. the ADC inotuzumab ozogamicin 35 and CD22 CAR T cells 28 ) or antibodies against myeloid targets may represent valid treatment options in that situation.…”

Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

“…Temsirolimus versus single‐agent IC (primarily, gemcitabine and fludarabine) showed consistently longer PFS across sex, performance status, disease stage at diagnosis, bone marrow involvement and number of prior regimens in exploratory subgroup analyses of a phase III trial (Hess et al , 2009) and in a recent retrospective analysis, across MIPI risk categories (Hess et al , 2015). Subgroup analyses of a single‐arm phase II trial of ibrutinib in 111 patients with relapsed/refractory MCL found similar ORRs, irrespective of multiple baseline factors, including tumour bulk (≥5 and ≥10 cm cut‐offs), ≥2 prior treatment regimens and refractory disease (less than partial response to last prior therapy) (Wang et al , 2015). More recently, an open‐label phase III study showed that ibrutinib was superior to temsirolimus with regard to improvements in PFS overall and when broken down by subgroups (Dreyling et al , 2016).…”