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.

Gaulin:ADC Therapeutics: Consultancy; DeciBio: Consultancy. Jain:AstraZeneca: Consultancy, Honoraria. Iyer:Yingli: Consultancy, Research Funding; Drenbio: Research Funding; Salarius: Consultancy; Pfizer: Research Funding; Ono: Research Funding; Astra Zeneca: Research Funding; Legend: Research Funding; Acrotech: Consultancy, Research Funding; Innate: Research Funding; CRISPR: Consultancy, Research Funding; Merck: Research Funding; Seagen: Consultancy, Research Funding; CuraBio: Speakers Bureau; American Society of Hematology: Speakers Bureau; American Society of Transplant and Cellular Therapy: Speakers Bureau. Lee:Takeda: Research Funding; Korean Society of Cardiology: Honoraria; Seagen Inc.: Research Funding; Olson Research: Honoraria; Oncternal Therapeutics: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria; Guidepoint: Honoraria; Deloitte: Honoraria; Curio Sciences: Honoraria; Century Therapeutics: Consultancy; Celgene: Research Funding; Cancer Experts: Honoraria; Bristol-Myers Squibb: Research Funding; Aptitude Health: Honoraria. Vega:Geron: Research Funding; Allogene: Research Funding. Flowers:Allogene: Research Funding; Iovance: Research Funding; Denovo Biopharma: Consultancy; Takeda: Research Funding; Sanofi: Research Funding; Ziopharm: Research Funding; Cellectis: Research Funding; Karyopharm: Consultancy; Cancer Prevention and Research Institute of Texas: Research Funding; Bayer: Consultancy, Research Funding; Jannsen Pharmaceuticals: Research Funding; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Amgen: Research Funding; Guardant: Research Funding; Morphosys: Research Funding; Adaptimmune: Research Funding; Nektar: Research Funding; Kite: Research Funding; Beigene: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Burroghs Wellcome Fund: Research Funding; Abbvie: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Genentech Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Research Funding; Pharmacyclics Jansen: Consultancy; SeaGen: Consultancy; Spectrum: Consultancy; 4D: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; V Foundation: Research Funding; National Cancer Institute: Research Funding; Acerta: Research Funding; CPRIT Scholar in Cancer Research: Research Funding. Wang:Loxo Oncology: Research Funding; Juno Therapeutics: Research Funding; Genentech: Research Funding; Celgene: Other: Travel, Research Funding; WebMD: Honoraria; Oncology Specialty Group: Honoraria; Nurix: Honoraria; NIH: Honoraria; Moffit Cancer Center: Honoraria; MJH Life Sciences: Honoraria; MD Education: Honoraria; Meeting Minds Experts: Honoraria; Medscape: Honoraria; IDEOlogy Health: Honoraria; i3Health: Honoraria; Genmab: Honoraria, Research Funding; Eastern Virginia Medical School: Honoraria; Dava Oncology: Honoraria, Other: Travel; CAHON: Honoraria; Bantam Pharmaceutical: Honoraria; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Pepromene Bio: Consultancy; Parexel: Consultancy; Oncternal: Consultancy, Research Funding; Milken Institute: Consultancy; Miltenyi Biomedicine: Consultancy; Merck: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Other: Travel, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; InnoCare: Consultancy; Genentech: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; Deciphera: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Be Biopharma: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, Research Funding; Amphista Therapeutics Limited: Consultancy; ADC Therapeutics America: Consultancy; Acerta Pharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; OncLive: Honoraria; Studio ER Congressi: Honoraria; Physicians Education Resources (PER): Honoraria, Other: Travel; Scripps: Honoraria; Practice Point Communications (PPC): Honoraria; Molecular Templates: Research Funding; Vincerx: Research Funding.

Ibrutinib in previously untreated smoldering mantle cell lymphoma

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2023
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