Medicine by Sfakianakis Alexandros

 Future Medicine: International Journal of Hematologic Oncology: Table of Contents

Chronic lymphocytic leukemia paradigm continues to be refined: news from the American Society of Hematology 2018 annual meeting

International Journal of Hematologic Oncology, Ahead of Print.

Future Medicine: International Journal of Hematologic Oncology: Table of Contents

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There were a number of important updates and advances presented at the 2018 Annual American Society of Hematology meeting. With respect to the treatment of chronic lymphocytic leukemia, the American Society of Hematology 2018 was notable for an improved understanding of ibrutinib-based therapies. In fact, three prospective Phase III trials presented at the meeting indicate, in turn, that ibrutinib alone, ibrutinib plus rituximab, or ibrutinib plus obinutuzumab, should be the new standard of care for chronic lymphocytic leukemia. However, additional clinical trials comparing chemo-immunotherapy with ibrutinib alone or in association with an anti-CD20 monoclonal antibody remain a reasonable avenue to complete results of these large studies. Keywords: CLLibrutinibupfront therapy A variety of encouraging data across various hematologic disease settings have been presented this year at the American Society of Hematology (ASH) 2018 annual meeting. In the realm of chronic lymphocytic leukemia (CLL), three landmark trials presented at the meeting have suggested, in turn, that ibrutinib alone, ibrutinib plus rituximab or ibrutinib plus obinutuzumab should be the new standard of care for CLL [1–3]. The first of these trials is the Alliance A041202, a multicenter study from the National Cancer Institute's National Clinical Trials Network. The study enrolled the more typical CLL patient population represented by the elderly, generally excluded from clinical trials due to the high rate of comorbidities. The merit of Alliance A041202 is that of establishing ibrutinib as the new standard of care for older patients with CLL because of its superiority over the best available chemo-immunotherapy regimen, the association of bendamustine and rituximab (BR) [1]. In detail, patients with treatment-naïve, symptomatic CLL were randomized to receive ibrutinib alone (n = 182), ibrutinib plus rituximab (n = 182) or BR (n = 183). At the time of progression, patients receiving the combination of BR were allowed to cross over and receive ibrutinib. Patients had a median age of 71 years and two thirds were men. According to modified Rai staging, slightly more than half (54%) had high-risk disease, 53% had ZAP70-unmethylated disease (a surrogate for IGVH-unmutated status) and 27% had del(17p13.1) or del(11q22.3) disease. After a median follow-up time of 38 months, median progression-free survival (PFS) was not reached for patients in either ibrutinib group and was 43 months for patients in the BR group. The 2-year PFS was 87% with ibrutinib, 88% with the ibrutinib–rituximab combination and 74% for the BR combination (p < 0.001). With hazard ratios (HR) of 0.39 for ibrutinib and 0.38 for ibrutinib–rituximab combination compared with BR, patients in either ibrutinib group was at a greater than 60% reduced risk for progression or death. Of note, in the low-risk subgroup of patients who are IGVH-mutated, there does not appear to be a difference in PFS at this time between the three regimens; however, it will require a longer follow-up time to really be able to answer this question [1,4]. Many of the side effects related to ibrutinib occurred early with some persisting throughout treatment; 14% of patients on each ibrutinib arm discontinued therapy due to toxicity. In young, fit, CLL patients, the combination of ibrutinib and rituximab was shown to beat the current gold standard represented by fludarabine, cyclophosphamide and rituximab (FCR), according to the results of E1912 study a large trial sponsored by the National Cancer Institute [2]. In this prospective Phase III study, patients were randomized to receive ibrutinib plus rituximab (n = 354) until progression or unacceptable toxicity for standard six cycles FCR (n = 175). Patients enrolled were ≤70 years of age and those with 17p deletion were excluded due to poor disease response to FCR. The median age of patients was 58 years and 41% were ≥60 years; 75% of patients had IGVH-unmutated disease. After a median follow-up of 33.4 months the combination of ibrutinib and rituximab was associated with a 65% reduced risk for progression or death (HR), 0.35; 95% CI: 0.22–0.5; p < 0.00001). Three-year PFS was 89% for the ibrutinib-rituximab combination and 73% for FCR. Overall survival was also found to be superior for the combination of ibrutinib and rituximab (HR, 0.17; 95% CI: 0.05–0.54; p < 0.0003). The superiority of the combination of ibrutinib and rituximab was seen regardless of age, performance status, disease stage or presence or absence of del11q23. The superiority was also established for IGVH unmutated but not IGVH-mutated disease. Compared with ibrutinib plus rituximab, FCR was associated with a significantly higher incidence of grade 3/4 neutropenia (22.7 vs 43.7%), anemia (2.6 vs 12.0%), thrombocytopenia (2.9 vs 13.9%) and infectious complications (7.1 vs 19.0%) [2]. The third landmark trial presented at the 2018 annual ASH meeting was the industry sponsored ILLUMINATE study [3]. In this Phase III trial, patients older than 65 years or, if younger than 65, with Cumulative Illness Rating Score >6, creatinine clearance