Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial

Abstract

Purpose: The need for an individualized management of indolent clinical forms in mantle cell lymphoma (MCL) is increasingly recognized. We hypothesized that a tailored treatment with ibrutinib in combination with rituximab (IR) could obtain significant responses in these patients.

Methods: This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 12 Spanish GELTAMO sites (ClinicalTrials.gov identifier: NCT02682641). Previously untreated MCL patients with indolent clinical forms defined by the following criteria were eligible: no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. Both leukemic non-nodal and nodal subtypes were recruited. Patients received ibrutinib 560 mg once daily and a total of eight doses of rituximab 375 mg/m². Ibrutinib could be discontinued after 2 years in the case of sustained undetectable minimal residual disease (MRD). The primary end point was the complete response (CR) rate achieved after 12 cycles according to Lugano criteria.

Results: Fifty patients with MCL (male 66%; median age 65 years) were enrolled. After 12 cycles of treatment, 42 (84%; 95% CI, 74 to 94) patients had an overall response, including 40 (80%; 95% CI, 69 to 91) with CR. Moreover, undetectable MRD in peripheral blood was achieved in 87% (95% CI, 77 to 97) of cases. At 2 years, 24 of 35 evaluable patients (69%) could discontinue ibrutinib because of undetectable MRD. Four patients had disease progression; three were non-nodal MCL and carried high genomic complexity and TP53 mutations at enrollment. No unexpected toxicity was seen except one patient with severe aplastic anemia.

Conclusion: Frontline IR combination achieves a high rate of CRs and undetectable MRD in indolent clinical forms of MCL. Discontinuation seems appropriate in cases with undetectable MRD, except for TP53-mutated cases.

FIG 1.

CONSORT diagram of IMCL-2015. C12, cycle 12; C24, cycle 24; IR, ibrutinib, rituximab combination; MRD, minimal residual disease.

FIG 2.

Survival in the IMCL-2015 study. (A) OS, PFS, and EFS (medians not reached). (B) PFS according to MIPI was significantly different in the high-risk group (P = .002). (C) PFS in 41 patients with TP53 mutational status was significantly poorer for TP53-mutated cases (P = .0001). No significant differences in PFS were observed: (D) according to the molecular variant (cMCL and nnMCL assessed in 31 patients) or (E) according to the genomic complexity available in 40 patients. PFS was measured from the treatment start date until disease progression or death whichever occurs first. OS was measured from the treatment start date to the date of death or last follow-up. EFS was measured from the treatment start date to the failure of treatment or death as a result of any cause or the last follow-up. A total of 12 patients had an event as follows: unacceptable toxicity, six cases (treatment-related, two of the patients presented an ulterior progression); disease progression, two cases; pancreatic adenocarcinoma, one case (SUSAR); severe aplastic anemia, one case (SUSAR); vertebral fractures, one case (unrelated); and ischemic stroke, one case (unrelated). cMCL, conventional MCL; CNA, copy number alterations; EFS, event-free survival; HR, high risk; IR, intermediate risk; LR, low risk; MCL, mantle cell lymphoma; MIPI, Mantle cell lymphoma International Prognostic Index; mut, mutated; nnMCL, non-nodal MCL; OS, overall survival; PFS, progression-free survival; wt, wild-type.