Clinical Trial Participation Is Associated with Improved Overall Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma
Authors: Cohen Jonathon B. , Switchenko Jeffrey M. , Shanmugasundaram Krithika , Goyal Subir , Calzada Oscar , Churnetski Michael C. , Kolla Bhaskar , Bachanova Veronika , Gerson James N. , Barta Stefan K. , Gordon Max J. , Danilov Alexey , Grover Natalie S , Mathews Stephanie , Burkart Madelyn , Karmali Reem , Sawalha Yazeed , Hill Brian T. , Ghosh Nilanjan , Park Steven I , Epperla Narendranath , Bond David A. , Badar Talha , Blum Kristie A. , Hamadani Mehdi , Fenske Timothy S. , Malecek Mary-Kate , Martin Peter , Guo Jin , Flowers Christopher R. , Kahl Brad S. 
Published: November 2019

Introduction: Mantle cell lymphoma (MCL) is a rare form of lymphoma with no current standard of care. As a result, clinical trials are critical to improving our understanding of the disease and its management. However, clinical trial participation is often limited due to lack of access to studies, restrictive eligibility criteria, and decisions by treating physicians or patients not to participate. We evaluated the rate of enrollment and outcomes associated with clinical trial participation of patients with MCL at 12 US Medical Centers.
Methods: We included patients from 12 medical centers in the United States with MCL diagnosed between January 1, 2000, and January 1, 2018, who were ≥ 18 years old, received any induction therapy, and for whom it was known whether initial treatment was on a clinical trial (CT) or not. We compared differences between the two groups (CT vs not) using Fisher's Exact and Chi-square tests as appropriate. We defined overall survival (OS) as time from diagnosis to death. Patients not experiencing an event were censored at their last known follow-up. OS was determined using the Kaplan-Meier method, and univariate and multivariable models were developed to identify predictors of OS.
Results: Eight hundred twelve patients were included in this analysis, including 164 (20%) patients who participated in a clinical trial during initial therapy. Rate of participation ranged from 4% to 36% across contributing sites. Median age for the entire cohort was 62 years, 572 (74%) of patients were male, and 95% of patients had ECOG 0-1. MCL International Prognostic Index (MIPI) risk score was high in 163 patients (31%), and 84% of patients had stage IV disease. Ki67 was &gt;30% in 169/225 (43%) patients with available data, and 19% of patients (65/271) had a complex karyotype with &gt; 3 chromosomal abnormalities. Four hundred sixteen (53%) of patients received an intensive induction regimen (defined as initial treatment with a high-dose cytarabine-containing regimen and/or receipt of autologous hematopoietic cell transplantation as consolidation), including 333 patients (43%) who underwent transplant consolidation. Patients with an increased lactate dehydrogenase (LDH) level (p&lt;0.001) and &gt; 3 cytogenetic abnormalities (p=0.015) were less likely to participate in clinical trials, but there was no significant difference in rates of participation based on MIPI (p=0.49) or ECOG performance status (p=0.22; Table). Patients treated on study were less likely to receive an intensive regimen compared to those treated off study (p=0.002). Median time to treatment from diagnosis was 35 days for patients enrolled on trial and 31 days for patients not enrolled on trial (p=0.83).
With a median follow-up of 3.8 years, the median OS was 13.6 years (95% CI: 11.5-21.1) for patients not treated on a trial and not reached (95% CI: 9.9 - Not Reached) for patients treated on trial (Figure; p=0.036). In a multivariable model including clinical trial participation, MIPI, time to initial treatment, and receipt of an intensive induction regimen, only clinical trial participation (HR 0.54, 95%CI: 0.31-0.93; p=0.028) and high risk MIPI score (HR 4.24, 95% CI: 2.37-7.56; p&lt;0.001) were significant predictors of OS while receipt of an intensive regimen and time to initial treatment were not.
Conclusions: Participation in a clinical trial is associated with improved OS among patients with untreated MCL, even when accounting for time to initial treatment and MIPI score. This study is unable to account for other factors that may predict trial participation including baseline comorbidities, socioeconomic status, social support, and distance to the treating center that are frequently factors that limit trial participation. However, these findings do suggest that enrollment on a clinical trial frequently leads to a successful outcome for patients in addition to providing answers to key clinical questions and should be considered for all eligible patients.

Disclosures
Cohen: Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; UNUM: Research Funding; LAM Therapeutics: Research Funding; Hutchison: Research Funding; Genentech, Inc.: Consultancy, Research Funding; ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Astra Zeneca: Research Funding. Calzada:Seattle Genetics: Research Funding. Kolla:Amgen: Equity Ownership. Bachanova:Incyte: Research Funding; Novartis: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Celgene: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding. Danilov:MEI: Research Funding; Seattle Genetics: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Curis: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Celgene: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Bayer Oncology: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Astrazeneca: Speakers Bureau; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Ghosh:Spectrum: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Speakers Bureau. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Hamadani:Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Janssen: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy. Martin:Karyopharm: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; Teneobio: Consultancy. Flowers:Pharmacyclics/Janssen: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Millenium/Takeda: Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; BeiGene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy.