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.

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“…Ibrutinib with rituximab in indolent MCL (n = 50) was investigated. 112 After 36 months follow-up and after 12 cycles, the overall response rate (ORR) was 84% with 80% CR. Among the patients, 87% were MRD negative and at 2 years, 24 patients discontinued ibrutinib with undetectable MRD.…”

“…Although not a standard practice, we sometimes refer the patients for leukapheresis to control lymphocytosis when the absolute lymphocyte count is >50 000 and then administer consolidation treatment. Ibrutinib with rituximab in indolent MCL ( n = 50) was investigated 112 . After 36 months follow‐up and after 12 cycles, the overall response rate (ORR) was 84% with 80% CR.…”

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“…Clinical data from phase 2 studies indicated that ibrutinib plus rituximab-induced durable and high response and prolonged survival in patients with TN [ 170 ], R/R [ 169 , 237 ], and indolent [ 171 ] MCL. The CR rate (44–80%) and PFS (3-year survival 87%) were significantly elevated than that reported with single-agent ibrutinib, although the head-to-head comparison is not available [ 167 , 235 ].…”

“…The CR rate (44–80%) and PFS (3-year survival 87%) were significantly elevated than that reported with single-agent ibrutinib, although the head-to-head comparison is not available [ 167 , 235 ]. This combination regime also yielded 87% cases of uMRD in the peripheral blood of indolent MCL patients, contributing to the discontinuation of ibrutinib [ 171 ]. It should be noted that the efficacy of this combination may be reduced in the context of TP53-mutation and Ki-67 high expression [ 171 , 237 ].…”

“…This combination regime also yielded 87% cases of uMRD in the peripheral blood of indolent MCL patients, contributing to the discontinuation of ibrutinib [ 171 ]. It should be noted that the efficacy of this combination may be reduced in the context of TP53-mutation and Ki-67 high expression [ 171 , 237 ]. Ibrutinib–rituximab induction followed by shortened R-HCVAD CIT regime induced an extremely high rate of overall response (98%) as frontline treatment in young MCL patients, with reduced chemotherapy-related AEs [ 172 ].…”