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

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.

Mutations in the RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia.

Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.