Blastoid Variant of Mantle Cell Lymphoma (MCL) Is Associated with P53 Abnormalities and Have a Shorter Progression-Free Survival (PFS) and Overall Survival (OS) Despite Upfront Chemo-Immunotherapy Followed by High Dose Chemotherapy and Autologous Stem Cell Support (HDC-ASCS)
Authors: Derby Lyudmyla , Pendurti Gopichand , Deeb George , Sait Sheila , Block Annmarie , Hernandez-Ilizaliturri Francisco J. 
Published: October 2019

Abstract
Abstract 1773
The outcomes of MCL patients have improved in recent years secondary to a better understanding of the biology of this disease, but also with the development of novel therapeutic agents and treatment modalities of this largely incurable subtype of aggressive lymphoma. The spectrum of clinical behavior observed in MCL patients suggests differences exist at the molecular level that impact clinical outcomes. Previously accepted biomarkers of response need to be re-evaluated in the post-rituximab and/or HDC-ASCS era to confirm their continued validity. We retrospectively studied the impact of pathological and additional cytogenetic abnormalities besides the t(11;14)(q13;q32) at the time of diagnosis in MCL patients treated at our institution in an attempt to identify potential prognostic biomarkers for this disease. Using the Roswell Park Cancer Institute (RPCI) tumor registry and NHL databases, MCL patients treated at RPCI between 2000 and 2009 were identified. MCL diagnosis was confirmed by our Pathology Department and required Bcl-1 (Cyclin-D1) overexpression or t(11;14)(q13;q32) by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), respectively. All available demographic, clinical (stage, IPI score, MIPI score, performance status, front- and second-line treatment), and pathologic data (blastoid vs. non-blastoid features, Ki67%, CD5 expression) were recorded and analyzed. Differences in response rate to front-line treatment, PFS and OS were compared between different pathological subsets of homogenously treated patients. The final analysis was restricted to 58 MCL patients (M:41/F:17) that received rituximab- and anthracycline-based multi-agent chemotherapy (R+CHOP=34, R+HyperCVAD-like =24) in the front-line setting. Majority of the patients were Caucasian, had an ECOG PS of 0–1, and their median age was 63 yrs (range 43–92). Stage III or IV disease at diagnosis was present in 92% of the cases, 85% had extra nodal site(s) of disease, and 33% had B-symptoms. At the completion of the front-line chemo-immunotherapy, 50% of the patients achieved a complete remission (CR), and 29% a partial remission (PR). Only 52% underwent HDC-ASCS in first remission. In accordance with prior reports, the IPI and MIPI score correlated with clinical outcomes (i.e. PFS and OS). In addition, the blastoid variant of MCL at the time of original diagnosis (40% of cohort) correlated with poor prognosis. Blastoid MCL patients had a statistically significant shorter median PFS (13 vs. 31.7 months, P=0.009) and OS (19.1 vs. 57 months, P=0.004) than patients with non-blastoid MCL. Moreover, the inferior clinical outcome of blastoid MCL was not influenced by the IPI score, MIPI score or the use of HDC-ASCS in first remission. Ki67 index of >40% (58% of studied cases) was associated with blastoid variant and with worse prognosis. The median OS but not the PFS was longer in MCL patients with a Ki67< 40% (not reached) than in MCL with Ki67 >40% (19.1 months, P= .016). In an attempt to identify additional genetic abnormalities seen in the blastoid variant that would explain the inferior prognosis, we analyzed by FISH diagnostic bone marrow and peripheral blood samples available from a selected group of 10 patients for additional molecular cytogenetic changes. Secondary cytogenetic aberrations, which included deletions of 17p (P53), 13q (RB and D13S25), and 9p (CDKN2A), were observed in 8 of 10 patients studied. Loss of P53 was restricted to blastoid MCL cases only (5 patients); two of these patients had a higher karyotypic complexity including both del(9p), and del(13q) in addition to 17p deletion. Multiple abnormalities were seen in 5/8 patients. ATM deletion was rarely seen (1/10 patients) and MYC rearrangement was not observed. In summary our data suggest that blastoid MCL have inferior clinical outcomes in terms of PFS and OS despite aggressive chemo-immunotherapy and HDC-ASCS. It is unclear if blastoid MCL represents a different clinical entity separate from non-blastoid MCL variants or is the result of the acquisition of additional genetic abnormalities leading to clonal evolution. Additional ongoing cytogenetic analysis will be presented at the annual meeting.

Disclosures:
Hernandez-Ilizaliturri: Genmab: Research Funding.