PF375 IBRUTINIB AND RITUXIMAB AS FRONT-LINE TREATMENT FOR UNFIT PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). PRELIMINARY RESULTS FROM THE GIMEMA LLC1114 STUDY
Authors: F.R. Mauro, S. Molica, F. Paoloni, G. Reda, L. Trentin, M. Marchetti, D. Pietrasanta, M. Coscia, R. Marasca, P. Sportoletti, G. Gaidano, L. Orsucci, C. Stelitano, N. Di Renzo, A.M. Liberati, D. Gottardi, F. Re, F. Ilariucci, P. Zinzani, D. Mannina, A. Gozzetti, A.L. Molinari, M. Gentile, U. Consoli, L. Laurenti, L. Arcaini, A. Ibatici, R. Murru, M. Tani, M.S. De Propris, I. Del Giudice, I. Della Starza, S. Raponi, M. Nanni, P. Fazi, E. Crea, A. Neri, G. Specchia, A.R. Guarini, A. Cuneo, R. Foà
Journal: HemaSphere (2019)

Background: Single agent Ibrutinib (IBR), an inhibitor of Bruton's tyrosine kinase, is approved for the front-line treatment of patients with chronic lymphocytic leukemia (CLL). Aims: As in CLL patients, the addition of anti-CD20 monoclonal antibody provides superior efficacy to chemotherapy, in a prospective multicenter, study of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group the potential for improved efficacy with the addition of rituximab (R) to IBR was investigated in previously untreated and unfit patients with CLL. Methods: Eligible patients were CLL patients requiring front-line treatment who showed a Cumulative Illness Rating Scale (CIRS) score >6 and/or creatinine clearance <70 mL/min. During the first phase of this study patients received IBR, 420 mg once daily continuously, and R, 375 mg/sqm, on day 1 of months 1–6. Then, IBR was given as a single agent until progression, or severe toxicity, or complete response (CR) with no evidence of minimal residual disease (MRD) or for a maximum duration of 6 years. The primary endpoint of this study was progression-free survival (PFS). Results: Between March 2015 and April 2017 143 unfit patients with CLL were included in this study. The median follow-up was 22.4 months (range, 1–31.3). The median age of patients was 73 years, (range, 37–88), median CIRS score 6 with an ECOG 1–2 performance status in 37% of patients. Binet stage B/C was present in 81% of patients, increased beta-2 microglobulin in 71% and bulky nodes (size ≥ 5 cm) in 14%. The presence of del(17p) or del(11q) was recorded in 9% and 14% of cases respectively, TP53 mutations in 15% and 51% of patients were IGHV unmutated. Response to IBR+R combination was assessed in 141 patients. On an intention-to-treat basis, 114 (81%) patients achieved a response that was a CR in 20%, an L-PR in 13% and a PR in 52%. MRD was undetectable by flow cytometry (<10–4) in the peripheral blood and bone marrow of 3 patients and by PCR also in 2. Seven (5%) patients showed no response while a treatment failure was considered in 14% who experienced early discontinuation of treatment due to other reasons than no response. After the first phase of the study with IBR+R combination, 106 patients continued treatment with IBR as a single agent. PFS and OS rates at 24 months were 91% (95% CI, 85.45–97.16) and 93% (95% CI, 88.54–98.52) respectively. No significant differences in PFS and OS were observed according to the response to IBR+R combination (PFS and OS at 12 months from response, CR vs L-PR/PR: 100% vs 98.5%; p = 0.44); and the IGHV mutational status (mutated vs unmutated IGHV, PFS at 24 months: 92% vs 89%; p = 0.7; OS at 24 months: 93% vs 92%; p = 0.7), Patients with del(17p) and/or TP53 mutations showed a lower, though not significantly lower, survival (TP53 disruption, absent vs present, PFS at 24 months: 94% vs 77%; p = 0.08; OS at 24 months: 95% vs 87%; p = 0.2). Serious adverse events (AEs) were recorded in 18 (12%) patients. Most frequent severe AEs were infections (7 patients); cardiac disorders (7 patients, atrial fibrillation in 5); pyrexia/ neutropenic fever (5 patients), bleeding events (3, subdural hematoma in 2). Fatal AEs were recorded in 4 cases (leukoencephalopathy, 2; sepsis,1; myocardial infarction, 1). Summary/Conclusion: The addition of R to IBR resulted in a higher rate of CR than those seen with IBR given as a single agent. Front-line treatment with IBR+R given to old and unfit patients with CLL was relatively well tolerated and an effective treatment option with durable responses.