Phase II Trial of Ibrutinib in Previously Untreated High-Risk Smoldering Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) patients usually require immediate therapy, however about 20% of newly diagnosed MCL patients can be initially observed. A subgroup of patients who are suitable for initial observation but exhibit high-risk features are of particular concern as they have a propensity to progress. We consider these patients as high-risk smoldering MCL (defined below). Generally, these patients are observed without systemic therapy for 18-24 months. We investigated the impact of single-agent ibrutinib on time to progression for these patients who would otherwise be observed.

Methods: This is a single center, single arm, investigator-initiated phase 2 clinical trial (NCT03282396). High-risk smoldering MCL included one or more of the following criteria: non-blastoid/pleomorphic variant, Ki-67 of 15-30%, white blood cell count of 15-30 x 10^9/L, lymph nodes ≤5 cm, TP53 mutated or wild type, del17p, MYC positive, complex karyotype, presence of KMT2D, BIRC3, or ≥1 other somatic mutations, and were asymptomatic without any clinical indication to start systemic therapy. Major exclusion criteria included significant disease-related symptoms, blastoid/pleomorphic variants, Ki-67 >30%, bulky tumors >5 cm. Patients received ibrutinib 560 mg P.O. daily in 28-day cycles and continued until progression, transformation, drug intolerance, or up to 5 years. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, response rate, and duration of response (DOR). Response was measured using the Lugano criteria. It is expected that the current trial will achieve a median PFS time of about 18 months, which would be an improvement over PFS reported on high-risk patients under a watch and wait approach. The median follow-up time was 23.4 months.

Results: Twenty patients were enrolled (Table 1). The median age was 60.5 years (range 38-79). Most were male (n=15/20). At baseline, 13 patients (65%) had bone marrow involvement and 15 patients (75%) had gastrointestinal tract involvement. Seven patients (35%) had TP53 alterations. One patient was not evaluable for response due cessation of therapy after less than 1 cycle due to new onset atrial fibrillation. Among 19 evaluable patients, the best overall response rate was 94.7% (n=18/19). Of those who had a positive PET at baseline and were evaluable for PET response, 92.9% (n=13/14) achieved a PET complete response (CR). Of those with bone marrow involvement at baseline, 30.7% (n=4/13) achieved CR by flow cytometry. Of those with baseline gastrointestinal tract involvement, 33.3% (n=5/15) achieved histologically confirmed CR. The median number of cycles received was 16 (range 0-32). The median PFS and DOR were not reached. Seven patients discontinued therapy: atrial fibrillation (n=3), progressive disease (n=1), infection (n=1), lung cancer (n=1). The most frequent grade 3 toxicities were diarrhea (n=2, 10%), atrial fibrillation (n=1, 5%), infection (n=1, 5%), mucositis (n=1, 5%), and syncope (n=1, 5%). No grade 4 toxicities occurred. No deaths on study occurred.

Conclusions: Ibrutinib demonstrated significant efficacy with manageable toxicities in previously untreated patients with high-risk smoldering MCL.