COMPREHENSIVE ANALYSIS OF PROGNOSTIC FACTORS, OUTCOMES AND MUTATION PROFILE IN PATIENTS WITH AGGRESSIVE HISTOLOGY (BLASTOID/PLEOMORPHIC) OR TRANSFORMED MANTLE CELL LYMPHOMA

Introduction: Analysis of clinical, molecular features and prognostic factors in aggressive histology MCL (AH-MCL; blastoid or pleomorphic) is not described. AH-MCL can be [de novo (dnMCL) or transformed from classic morphology (t-MCL)]. Methods: We reviewed 183 pts with AH-MCL (108 were dn-MCL and 75 were t-MCL). Overall, 152 were blastoid and 31 pleomorphic. Pt characteristics were collected at the time of diagnosis in dnMCL and at transformation. Overall survival (OS) - time of initial diagnosis of AH-MCL to death/last follow-up and failure free survival (FFS) - time of starting first-line treatment of AH-MCL to treatment discontinuation. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from biopsy samples from 44 pts (dnMCL = 32, t-MCL = 12). Results: Median follow up after diagnosis of AH-MCL was 19.6 months (0.1-168). Clinical features of AH-MCL were - 20% B symptoms, 6% had ECOG PS (3-4), CNS involvement in 4%, 19% with GI involvement, 67% with marrow involvement and 27% had leukemic phase. The median Ki-67% was 70% (10-100), complex karyotype 13%, LDH > ULN in 45%, Sox-11 positive in 81%, median β2M of 2.9 mg/dL. Pts with t-MCL were distinct from dnMCL in having significantly higher median age, poor PS, lower WBC count, lower marrow involvement and lower rate of achieving CR with first line treatments. All pts with t-MCL had prior treatment for MCL before transformation with median lines of prior therapy 2 (range 1-8). The median OS after diagnosis of AH-MCL was 33 months (48 and 14 months for dnMCL and t-MCL respectively; p = 0.001; Figure-1A-B). Univariate and multivariate (MVA) analyses were performed. Recursive partitioning analysis revealed that Ki-67% ≥50% (Fig. 1C), LDH ≥1519, β2M ≥ 4, hemoglobin <14 and platelet count <63,000 had increased risk of death. In MVA, factors significantly associated with inferior OS in AH-MCL were age (>72 yrs), t-MCL category, Ki-67% ≥50%, ECOG-PS (1-4 compared to 0). Presence of t-MCL, high Ki-67%, CNS involvement were predictive of inferior FFS. Pts who received ibrutinib based or R-HCVAD based therapies had lower hazard ratio for FFS. Subset analysis of blastoid vs pleomorphic MCL did not reveal any significant difference in clinical features of survival but FFS was inferior in pleomorphic category. Frequently mutated genes in AH-MCL were ATM, CCND1, NOTCH1, KMT2D, KMT2C, TP53, SPEN, SMARCA4 and NSD2. There was no statistically significant difference in the mutation profile of dnMCL vs t-MCL. Significant differences in the mutation burden between pts with high Ki-67 (≥50%) and those with low Ki-67%, were noted - ATM (p = 0.001), CCND1 (p<0.001), NOTCH1(p = 0.001), TP53 (p = 0.006), SMARCA4 (p = 0.006), NSD2 (p = 0.02), NOTCH3 (p = 0.02) Figure-1E. Keywords: mantle cell lymphoma (MCL).