In a Spanish phase II trial (IMLC-2015) reported in the Journal of Clinical Oncology, Giné et al found that the combination of ibrutinib and rituximab produced a high complete response rate in previously untreated patients with indolent clinical types of mantle cell lymphoma.
Study Details
In the multicenter study, 50 patients enrolled between June 2016 and December 2019 received 28-day cycles of ibrutinib at 560 mg once daily continuously and rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, followed by doses on day 1 of cycles 3, 5, 7, and 9, for a total of eight doses; ibrutinib could be discontinued after 2 years in the case of sustained undetectable measurable residual disease (MRD; at 10-5).
Patients with no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm were defined as those with indolent clinical forms of mantle cell lymphoma. Both leukemic non-nodal and nodal subtypes were permitted.
The primary endpoint was complete response rate after 12 cycles according to Lugano criteria.
Responses
Objective response after 12 cycles was observed in 42 patients (84%, 95% confidence interval [CI] = 74%–94%), including complete response in 40 (80%, 95% CI = 69%–91%). After 12 cycles, undetectable MRD in peripheral blood was achieved in 40 (87%, 95% CI = 77%–97%) of 46 evaluable patients, including 37 (93%, 95% CI = 86%–100%) of 40 with complete response. At 2 years, 24 (69%) of 35 evaluable patients discontinued ibrutinib on the basis of persistent undetectable MRD.
Among 41 patients with known TP53 status, 6 had a TP53 mutation. Among these, five achieved complete response, including four with undetectable MRD that allowed discontinuation of ibrutinib in two. All but one patient subsequently converted to detectable MRD. Disease progression occurred in four patients, with three having non-nodal MCL and exhibiting high genomic complexity and TP53 mutations at enrollment.
After a median follow-up of 36 months for surviving patients, estimated progression-free survival at 36 months was 93% (95% CI = 86%–100%). Median progression-free survival was 38.5 months among patients with a TP53 mutation vs not reached in those with wild-type TP53 (P = .0001). Overall survival at 36 months was 92% (95% CI = 84–100%). Median overall survival was 38.5 months in patients with a TP53 mutation vs not reached in those with wild-type TP53 (P = .0002).
Adverse Events
The most common treatment-related adverse events of any grade were diarrhea (38%), neutropenia (36%), fatigue (32%), upper respiratory infection (24%), nausea (22%), and arterial hypertension (20%). The most common grade 3 or 4 treatment-related adverse event was neutropenia (22%), with no other event occurring in more than one patient. Atrial fibrillation occurred in two patients, and stroke occurred in one. A total of three neoplasms (basal cell carcinoma, pancreatic adenocarcinoma, and bladder carcinoma) were observed in two patients at 1, 12, and 40 months from start of treatment. Severe aplastic anemia was observed in one patient at 5.5 months.
The investigators concluded, “Front-line ibrutinib/rituximab combination achieves a high rate of complete responses and undetectable MRD in indolent clinical forms of mantle cell lymphoma. Discontinuation seems appropriate in cases with undetectable MRD, except for TP53-mutated cases.”
Eva Giné, MD, of the Hematology Department, Hospital Clínic of Barcelona, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was funded through unrestricted Janssen Clinical Investigator-Initiated Study Research Support. For full disclosures of the study authors, visit ascopubs.org.
