Short Time to Treatment Is Associated with Inferior Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma
Authors: Epperla Narendranath , 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 , Bond David A. , Badar Talha , Blum Kristie A. , Hamadani Mehdi , Fenske Timothy S. , Malecek Mary-Kate , Martin Peter , Guo Jin , Kahl Brad S. , Flowers Christopher R. , Cohen Jonathon B. 
Published: November 2019

Introduction: Time to treatment (TTT) is an important prognostic factor in patients with newly diagnosed diffuse large B-cell lymphoma (Maurer et al JCO 2018) where patients who initiate therapy quickly after diagnosis have an inferior event free survival compared to those who do not require such immediate treatment initiation. More recently, TTT has shown to be associated with adverse clinical factors and inferior outcomes in mantle cell lymphoma (MCL; Maurer, et al ASH, 2018). However, there is a paucity of data on the impact of TTT on overall survival (OS). We sought to validate these findings and to evaluate the impact of TTT on survival outcomes in newly diagnosed patients with MCL.
Methods: We included patients from 12 medical centers in the United States with MCL diagnosed between January 1, 2000, and January 1, 2018, who had information on the TTT and initiated treatment within 60 days of diagnosis (to exclude patients whose treatment was purposefully deferred). TTT was defined as the time in days from first lymphoma diagnosis to initiation of therapy. Patients who received treatment within 14 days were categorized into short TTT group. We compared differences between the two groups (TTT<=14 days vs TTT> 14 days and ≤ 60 days, longer TTT group) using chi-squared test, Fisher's exact tests, or ANOVA tests as appropriate. OS was defined as the time from diagnosis to death or last follow-up. Patients not experiencing an event were censored at their last known follow-up. OS was determined using the Kaplan-Meier method, and univariable and multivariable models were developed to identify predictors of OS.
Results: Of 1,168 patients with newly diagnosed MCL, seven hundred fifty-five patients met the inclusion criteria and were included in this analysis, including 205 (27%) with short TTT and 550 (73%) with longer TTT. Median time to treatment was 7 days (range, 0-14) for the short TTT group vs 31 days for the longer TTT group (range, 15-60 days). The median age for the entire cohort was 63 years, 75% of patients were male, and 93% of patients had ECOG 0-1. The proportion of patients with stage 4 disease (93 vs 86%, p=0.015), elevated LDH (58 vs 39%, p<0.001), >3 cytogenetic abnormalities (29 vs 14%, p=0.005), B symptoms (47 vs 29%, p<0.001) and high MIPI score (49 vs 27%, p<0.001) was higher in short TTT group compared to longer TTT group. 65% received intensive induction therapy in the short TTT group relative to 57% in the longer TTT group (p=0.046) (Table).
On univariable analysis, factors associated with inferior OS included, TTT<=14 days (HR=1.66, 95%CI=1.23-2.27, p<0.001), ECOG >=2 (p<0.001), stage IV disease (p=0.01), elevated LDH (p<0.001), WBC >10k (p=0.002), BM involvement (p<0.001), splenomegaly (p<0.001), ≥3 cytogenetic abnormalities (p<0.001), non-intensive regimen (p=0.03), B symptoms (p<0.001), and high MIPI score (p<0.001). With a median follow-up of 3.4 years, the median OS was 8.8 years (95%CI=7-NA) for patients with short TTT group and 12.5 years (95% CI: 11.4-18.7) for patients with longer TTT group (Figure; p<0.001). In the multivariable model including ECOG, LDH, intensive regimen and B symptoms, short TTT (HR=2, 95%CI=1.25-3.22; p=0.004), ECOG >=2 (HR=2.25, 95%CI=1.22-4.14; p=0.009), elevated LDH (HR=1.81, 95%CI=1.16-2.85; p=0.01), and receipt of non-intensive regimen (HR=1.61, 95%CI=1.04-2.50; p=0.03) were significant predictors of OS while B symptoms was not.
Conclusions: Short TTT for patients with newly diagnosed MCL is associated with aggressive disease features and inferior OS despite an increased likelihood of receiving intensive induction regimens. Further studies are needed to identify molecular determinants of such aggressive disease behavior that can be assessed quickly and utilized to initiate appropriate therapy in a timely manner. Ongoing front-line clinical trials in MCL should be developed in a way to facilitate enrollment of patients requiring urgent therapy, including potentially permitting a cycle of off-study treatment to manage symptoms while a patient is screened and enrolled.

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