Upfront Ibrutinib/Rituximab Elicits High Responses in Indolent MCL

Frontline treatment with ibrutinib (Imbruvica) combined with rituximab (Rituxan) induced a high rate of complete responses (CRs) and minimal residual disease (MRD) undetectability in patients with indolent clinical forms of mantle cell lymphoma (MCL), according to results from the phase 2 IMCL-2015 study published in the Journal of Clinical Oncology.

Treatment of indolent MCL tumors may require an individualize approach, according to the study investigators. Also, considering the prognostic value of MRD in the field, a deeper look into its role in time-limited treatment may be viable. Thus, in the multicenter, single-arm, open-label IMCL-2015 study (NCT0268264), investigators assessed tailored frontline treatment with ibrutinib/rituximab in a previously untreated population of patients with indolent clinical forms of MCL following a Simon’s 2-stage design. The study was conducted across 12 sites in Spain.

In the overall patient population, the overall response rate (ORR) was 84% (95% CI, 74%-94%) which included CRs in 80% of patients (95% CI, 69%-91%), partial responses (PRs) in 4% (95% CI, 0%-9%), stable disease (SD) in 6% (95% CI, %-10%), and progressive disease (PD) in 1% (95% CI, 0%-15%). This result met the study’s primary end point and exceeded the hypothesis of a 50% CR rate with ibrutinib/rituximab in this patient population.

A total of 50 patients were allocated to receive ibrutinib plus rituximab in the study. Weekly doses of rituximab were administered at 385 mg/m2 via intravenous infusion during cycle 1 of a 28-day cycle, followed by 4 doses at day 1 of every other cycle. Oral ibrutinib was dosed on a fixed continuous schedule at 560 mg once daily. Patients receiving ibrutinib discontinued treatment after 2 years in the case of sustained undetectable MRD. Treatment was otherwise continued until disease progression or unacceptable toxicity occurred.

The primary end point of the study was the achievement of a CR at 12 months per Lugano criteria in the intention-to-treat population. The study also evaluated the secondary end points of safety and tolerability, overall response, rate of undetectable MRD, progression-free survival (PFS), and overall survival (OS). As noted, the study was powered to detect a 50% CR rate with ibrutinib plus rituximab compared with the 30% that is common for rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

Among the patients enrolled, the median age was 65 years (range, 40-85). The study population was largely male (66%). All patients in the study had an ECOG performance status of 0-1. The median spleen size was 13 cm (range 9-29), and the largest lymph node diameter was a median of 21 mm3 (range 13-43). Bone marrow involvement was seen in 88% of patients, and the majority (94%) were Ann Arbor stage III-IV. In accordance with the inclusion criteria, patients had adequate laboratory values and MIPI score classified 24% of patients as low risk, 38% as intermediate risk, and 38% as high risk.

In terms of the histologic, genetic, and molecular features of the study population, 49 patients had available material for testing. Cytologic variants were found in all 49 patients of which 39% were small cell and 61% were classical. Ninety-eight percent of patients tested positive for cyclin D1 expression, 65% were positive for SOX11 expression, 44 patients had Ki67 expression, but no patients were positive for TP53 expression. Of the patients with Ki67 expression, 95% had less than 30% Ki67 expression and Ki67 was highly expressed in only 5%.

Genetic and molecular evaluations showed t(11;14) (q13,q32) in 37 patients, cryptic CCND1 rearrangement in 1 patient,and CCND2 rearrangement in 1 patients. Further, 41% of patients had a complex karyotype, 38% had high genomic complexity, and 15% harbored TP53 alterations. Notably, 55% of the patients had non-nodal MCL (nnMCL)and 45% had conventional MCL (cMCL).

Forty-six of the patients enrolled were evaluable for response after a CR was achieved after a treatment period of 12 months and 37 were evaluable for response after 24 months.

In the cohort of patients with nnMCL (n = 17), the ORR was 88%, with CRs in 82%, PRs in 6%, SD in 6%, and PD in 6%. Patients with cMCL (n = 14) demonstrated an ORR of 86%, with CRs in 79%, and PRs, SD, and PD in 7% each.

Responses were also assessed per TP53 mutational status. In the subgroup with TP53 wild-type (n = 35), the ORR was 89%, with CRs in 83%, PRs in 6%, SD in 8%, and PD in 3%. Patients with TP53-mutated MCL (n = 6) had an ORR of 83%, which were all CRs; however, 1 patient had PD.

Survival probability including OS, PFS and event-free survival were evaluated during the study. The medians were not reached for either survival end point. “PFS according to MIPI was significantly different in the high-risk group (P =.002). PFS in 41 patients with TP53 mutational status was significantly poorer for TP53-mutated cases (P =.0001). No significant differences in PFS were observed according to the molecular or according to the genomic complexity available in 40 patients,” wrote the study authors, led by Eva Giné, MD, Hematology Department, Hospital Clínic of Barcelona.

The safety assessment showed expected toxicity with a predominance of hematologic toxicity. The most common treatment-related adverse events (AEs) were diarrhea (38%), neutropenia (36%), fatigue (32%), upper respiratory infection (24%), nausea (22%), and arterial hypertension (20%). Notably, 22% of the grade 3/4 AEs observed were hematologic.

“The IMCL-2015 study has shown the high activity, in terms of CR and undetectable MRD, of the upfront [ibrutinib/rituximab combination] in indolent clinical forms of MCL following a MRD-driven approach to limit the extent of treatment. The duration of molecular and clinical responses after ibrutinib discontinuation will be a key aspect to define the final role of such individualized approaches,” wrote Giné et al in conclusion.

_Reference:

_{Gine E, de la Cruz F, Ubieto AJ, et al. Ibrutinib in combination with rituximab for indolent clinical forms of mantle cell lymphoma (IMCL-2015): A multicenter, open-label, single-arm, phase ii trial. J Clin Oncol. Published online ahead of print January 14, 2022. doi: 10.1200/JCO.21.02321.}