ALBERT

Description: Introduction: Aggressive MCL has a poor prognosis with a 21-40% complete remission (CR) after CHOP and a duration of response of only 10-16 months. More intense therapy could improve these statistics. Rituximab is effective in MCL and has minimal toxicity. Methods: A prospective phase II trial of R-HCVAD (considered to be one cycle) alternating every 21 days with R- M/A (considered to be another cycle) as described earlier (Ann Oncol. 13, suppl 2, 2002 #24). Prophylaxis with mesna, calcium leucovorin, prednisone eyedrops, G-CSF, antibacterial, antifungal, and antiviral therapy. CBC with differential and platelet counts X 2-3/week. Re-staging every 2 cycles including upper and lower endoscopies. Patients in complete remission (CR) after 6 courses of a planned 6-8 cycles were not offered consolidation with stem cell transplant. Post-treatment evaluation was performed every 3 months for 1 yr, every 4 months for 2 yrs, every 6 months for 2 years, then annually. Results: Of 100 patients registered, one was ineligible and two decided to not receive the treatment after registration, leaving 97 evaluable for analysis of response, survival and toxicity. An analysis of response after the first 6 cycles shows an 87% CR/CRu rate. With a median follow up of 40 months, the 3-year FFS and overall survival (OS) were 67% and 81%, respectively. Adverse factors for FFS were: Grade 4 hematologic toxicity was significant. Five patients died during treatment of sepsis (3), pulmonary hemorrhage (1), and unknown cause (1). Four patients developed myelodysplasia/acute myelogenous leukemia after treatment and while in CR and three have died, for a total of 8 deaths in the study (8%). Conclusion: R-HCVAD alternating with R-M/A without stem cell transplant is an effective regimen for treatment of aggressive untreated MCL, specially for patients ≤ 65 years old. Toxicity is as expected for an intense regimen. This encouraging data warrants continued follow-up and comparison with existing/new therapies in future trials.

Description: Blastoid MCL has a very poor prognosis, with a median survival of 16–20 months after treatment with CHOP-like chemotherapy regimens. We recently described an intense regimen where R-HyperCVAD is alternated with R-M/A for 6–8 cycles, capable of achieving 87% complete remission (CR) rates and an overall 3-year FFS rate of 64% in a group of 97 patients with newly diagnosed aggressive MCL treated under an institutionally approved clinical trial from March 1999 to March 2001 (J Clin Oncol 23:7013–7023). Fourteen of these patients presented with the blastoid cytologic variant and the following clinical features were compared with those without a blastoid cytology: age 〉 65 years, beta 2 microglobulin ≥ 3 gm/dL, elevated serum lactic dehydrogenase (LDH), and high international prognostic score (IPI). Only serum LDH was significantly different, being higher for those with blastoid presentation (p = 0.03). Rates of complete remission were lower for blastoid when compared to non-blastoid cytology (79% vs 89%, respectively) but not statistically significant (p = 0.72). With a median follow up of 57 months, there is a plateau in the FFS curve for blastoid MCL as shown below. At 57 months the median overall survival has not been reached. Contrary to what we had expected, the improved outcome in this group of patients with blastoid cytology suggests a potential for long term remission after intense, non-myeloablative chemotherapy. Figure Figure

Description: Abstract 2406 The death receptor Fas has a key role in mediating homeostasis, elimination of defective cells and more recently promotion of cancer. Many effective anti-cancer therapies depend on Fas-mediated apoptosis to eradicate tumor cells and ineffective Fas- apoptotic signaling is a basis for primary as well as acquired resistance to chemotherapy. We hypothesized that Fas is subjected to direct regulation and inhibition of Fas attained by cancer cells and may explain the emergence of chemoresistance. To screen for potential binding modulators of Fas, we analyzed lymphoma cells for Fas binding proteins. We first purified Fas associated proteins by using activating CH-11 antibody bound to intact BJAB cells. After immunoprecipitation, any remaining Fas, considered activation–resistant, was subjected to the second immunoprecipitation with Fas antibody B-10 followed by liquid chromatography and tandem mass spectroscopy. This purification scheme identified high scoring peptides derived from nucleolin, a nuclear protein known to be overexpressed in cancer. Nucleolin is selectively expressed on the surfaces of cancer cells and blood vessels undergoing angiogenesis. In a cell culture system, we confirmed binding of nucleolin to Fas and the presence of nucleolin-Fas complexes on the surface of lymphoma cells by surface biotin labeling. Using deletion mutants of nucleolin, we identified RNA binding domain 4 and glycine/arginine rich region to be required for the binding to Fas. BJAB cells with partially knockdown (KD) nucleolin showed significantly higher rates of apoptosis in response to stimulation with CH-11 and FasL when compared to nontarget KD controls. Importantly, the lower levels of nucleolin in knockdown cells did not affect total and surface Fas expression. Nucleolin present on the cell surface prevented binding of FasL and CH-11 to the receptor and thus provides a mechanism for blocking activation of Fas apoptosis. To examine the role of nucleon in vivo, we transfected mice with nucleolin-expressing plasmids using the hydrodynamic transfection method. The mice overexpressing nucleolin showed significantly higher survival rates than vector control transfected mice (P=.01) after a challenge with a lethal dose of agonistic anti-Fas antibody. We next examined the expression of nucleolin in human lymphomas. Cell lines derived from lymphomas of different histological types consistently expressed nucleolin protein. We found nucleolin expressed on the surface of cells in over 20 primary lymphoma isolates, whereas peripheral blood lymphocytes showed low or undetectable levels. Lymphoma tissue microarray staining showed a correlation between nucleolin and Ki-67 expression. Whether nucleolin expression also correlates with adverse clinical features in lymphoma is currently under evaluation. Taken together, we show here that the known cancer associated protein nucleolin is overexpressed on surface of lymphoma cells where it binds to Fas receptor and blocks Fas signaling and apoptosis. We expect that further analysis of nucleolin properties will reveal how Fas-nucleolin interaction can be targeted to enhance killing of cancer cells leading eventually to cell surface nucleolin targeting therapy. Disclosures: Fayad: Roche: Research Funding.

Description: Background: Follicular lymphoma grade 3 has a natural history that is more akin to that of diffuse large B-cell lymphoma. The addition of rituximab to standard CHOP has resulted in improved response and survival in diffuse large B-cell lymphoma. Information about outcomes in follicular lymphoma grade 3 is lacking. Methods: A single institution retrospective review of patients with follicular grade 3 lymphoma evaluated at the UTMDACC from 1999 to 2004. Patients were located from the UTMDACC lymphoma database. All patients were initially treated with R-CHOP. Results: Forty-five patients were identified: 51% male, 47% ≥60 years, and 87% follicular grade 3b. The LDH was elevated in 24%, ECOG performance status was 〉1 in 2%, and 〉1 site of extranodal involvement was present in 10%. Stage distribution was 11% stage I, 11% stage II, 42% stage III, and 36% stage IV, bulky disease (〉7cm) was present in 11%, and B symptoms occurred in 13%. Beta-2 microglobulin was elevated in 57% with values 〉3 μg/dL in over 50%. IPI distribution was: 46% IPI Low, 38% LI, 11% IH, and 4% IPI High. Overall response rate was 100% with 96% complete responses. Relapse rate by IPI category was 24% for Low IPI, 18% for IPI LI, and 40% for IPI IH, and 100% for the two patients with High IPI. With median follow-up of 33 months, three year failure-free survival (FFS) is 73% (95% CI: 59 to 87%). One patient died (2%) with an overall survival (OS) at three years of 97% (95% CI: 93 to 100%). Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival in this group of mostly good prognosis patients. Relapses were still seen; longer follow-up is needed.

Description: Introduction: Both inter- and intra-tumoral heterogeneity are obstacles to improving oncology clinical outcomes. Mantle cell lymphoma (MCL) is an extremely heterogeneous disease in clinical, pathological, genetic, and transcriptomic profiling. Furthermore, MCL patients frequently develop therapeutic resistance after frontline therapies. In this study, we performed longitudinal transcriptomic analysis on primary patient MCL specimens at single-cell resolution, aiming to understand the dynamic and complex cellular and molecular changes underlying therapeutic resistance and identify potential targets to overcome dual resistance to ibrutinib and venetoclax. Methods: Sequential single-cell transcriptome sequencing (scRNA-seq) was performed on patient specimens collected during the course of treatment(s) from 5 MCL patients (3 ibrutinib responders and 2 ibrutinib-venetoclax non-responders). Integrative computational approaches were employed to characterize the cellular and molecular basis of therapeutic resistance and clonal evolution. An orthotopic PDX model derived from one of the non-responders was established and used to validate the novel findings and to investigate the in vivo efficacies of multiple novel potential targets. Results: The 3 ibrutinib responders and 2 ibrutinib-venetoclax non-responders were highly heterogeneous in clinical and pathological profiling. To dissect the inter- and intra-tumor heterogeneity underlying the therapeutic resistance, we performed sequential scRNA-seq analysis of 21 specimens collected at baseline, during treatment, and/or at disease remission/progression. The scRNA-seq analysis revealed a high degree of inter- and intra-tumor heterogeneity with distinct cellular and transcriptomic profiling within and across ibrutinib-responders and ibrutinib-venetoclax non-responders. Unsupervised pathway enrichment analysis identified more than 15 cancer hallmarks significantly upregulated in ibrutinib-venetoclax non-responders. We tracked the clinical ibrutinib-induced lymphocytosis at a single-cell transcriptomic level in ibrutinib responders and disease-progression-associated clonal evolution in non-responders. Multiple actionable targets were identified, and targeting these showed effective anti-MCL activity in the orthotopic PDX model derived from one of the ibrutinib-venetoclax non-responders. Conclusions: This study demonstrates the potential of longitudinal single-cell transcriptomic analysis to reveal the molecular mechanisms underlying tumor heterogeneity, clonal evolution, disease progress, and therapeutic resistance, and to identify potential novel targets to circumvent therapeutic resistance in mantle cell lymphoma and other diseases. Disclosures Wang: Pharmacyclics: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Loxo Oncology: Research Funding; VelosBio: Research Funding; BioInvent: Consultancy, Research Funding; Dava Oncology: Honoraria; Aviara: Research Funding.

Description: Introduction: Patients (pts) with transformed follicular lymphoma (t-FL) exhibit an aggressive clinical course and high risk of relapse. In this study we have analysed the clinical characteristics, prognostic factors, treatments and survival outcome of pts with pathologically confirmed t-FL. Methods: We reviewed pts with low grade lymphoma who developed a subsequent aggressive B-cell lymphoma at MDACC from 7/1998 to 07/2017. Transformation was defined as development of an aggressive lymphoma in the setting of a prior diagnosis of low grade NHL. Pts with composite histology or grade IIIb FL at dx were excluded. We identified a total of 273 pts who transformed from a low grade lymphoma, including 172 with an initial diagnosis of FL (63%), MZL (18%), and SLL (19%).Pts with t-FL were analyzed for clinical characteristics, treatments and outcome. Overall survival (OS) was defined from the time of initial diagnosis of t-FL to death/last follow up while failure free survival (FFS) was calculated from time of starting first line treatment after transformation to treatment failure/discontinuation/switch or death. Optimal cut off values for various prognostic markers associated with survival were identified using recursive partitioning. Results: Among the 172 pts with t-FL, 164 (95%) were diffuse large B cell lymphoma (DLBCL) and 8 (5%) with other histology. The median follow up time after transformation was 21.3 months (0.6-215 months). The median age at transformation was 63 (33 to 88) and 59% were males. The median time from initial diagnosis of FL to t-FL was 41 months (2 to 379 months). In the 122 pts where initial grading was available; 47, 43, and 32 were I, II, IIIa, respectively. Median lines of treatment received prior to transformation were 1 (range 0-11) and 124 pts (72%) had prior treatment with rituximab. Thirty one pts (18%) were in observation for FL prior to transformation. B symptoms in 13% pts, 12% has ECOG PS (3-4), CNS involvement was noted in 1% and median number of sites involved at transformation were 1 (range 1-6). 52 pts (30%) had transformation at a site distant from the initial site of FL. Twenty eight of 32 pts (87%) who had MYC testing (by IHC) were positive. Other characteristics included, 41% pts with lambda monoclonal light chain expression, median Ki-67 was 75% (8-100%), LDH 〉 ULN in 47%, MUM-1 + in 56%. Median β2M was 2.3 mg/dL. Overall, the median OS from transformation was 106.7 mo (36.8-Not Estimable) and the median FFS = 8.77 mo (5.6-10.5). There was no survival difference between pts with DLBCL and HD. At the time of last follow up, 107 pts were alive and 65 died, including 45 due to progression. . Overall, 161 pts received treatment for t-FL, 58 with R-CHOP (Rx1), 52 with R-non-CHOP (Rx2), 27 with R-EPOCH based (Rx3), and 24 with miscellaneous treatments (Rx4). In univariate analysis, we identified factors significantly associated with inferior OS, (lower hemoglobin, low platelet counts, lower absolute lymphocyte counts, higher LDH, and higher β2M). Advanced ECOG-PS and presence of B symptoms also correlated with inferior OS. Using recursive partitioning, age ≥ 81 years, Hb 〈 12 gm/dL, WBC 〈 5K/uL, LDH ≥1184, β2M ≥ 4 mg/dL were associated with significantly increased risk of death (Figure-1 A-E). In multivariate analysis, age ≥ 81 years (HR=3.95, 95% CI 1.82-8.60; p=0.001), presence of double hit lymphoma (DHL) (HR=4.15, 95% CI 1.74-9.91; p=0.001) and Rx2 treatment (R-non-CHOP based regimen, compared to Rx1, Rx3 and Rx4) (HR=2.36, 95% CI 1.27-4.38; p=0.001) had inferior OS. We also analysed FFS in pts with information available on their initial therapy for t-FL (n=161). Presence of DHL and treatments other than R-CHOP were predictive of inferior FFS in MVA. Pts who received non-CHOP based regimens had inferior FFS (Figure-1F; p=0.007). Conclusions: Patients with t-FL have a heterogeneous disease course and most pts can be salvaged with subsequent therapies. R-CHOP based regimens appear to have most benefit following transformation. Common laboratory tests hemoglobin, WBC, platelet count, LDH and beta2 microglobin help in predicting the survival of t-FL pts. In pts where MYC was tested, most were positive. Comprehensive cytogenetic and molecular analyses are needed to recognize various pathogenic mechanisms and identify novel therapeutic targets in t-FL. Disclosures Nastoupil: Janssen: Research Funding; Karus: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Juno: Honoraria; Celgene: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Spectrum: Honoraria; TG Therappeutics: Research Funding. Samaniego:ADC Therapeutics: Research Funding. Westin:Celgen: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Wang:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; Dava Oncology: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Description: Introduction: Mantle cell lymphoma (MCL) patients (pts) who progress after ibrutinib and other lines of treatment "ultra-refractory MCL" have poor outcomes and exhibit BTK mutations infrequently (Jain P et al BJH 2018, Martin P et al Blood 2016). Venetoclax has shown promising efficacy in Phase I trial in NHL (Davids M et al JCO 2017) and is now under trials in MCL. Venetoclax response in pts with MCL after progression on ibrutinib was reported (Eyre T et al Haematologica 2018), however, genomic alterations associated with venetoclax resistance are not described. We present our experience in 24 pts with MCL treated with venetoclax and report their mutation profiles associated with progression on venetoclax. Methods: We collected data from 24 pts with MCL who were treated with venetoclax (off clinical trial) as a salvage measure after failing multiple lines of prior therapies. Pt characteristics were collected from the time of initiating venetoclax. Progression free survival (PFS) was calculated from the time of initiating venetoclax to the date of progression or to last follow up date/date of death while overall survival (OS) was calculated from the time of initiating venetoclax to the date of last follow up date/date of death. Post venetoclax survival was calculated from the date of discontinuing venetoclax to the date of last follow up/death. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from evaluable biopsy samples from 7 pts (5 pts at/before starting venetoclax and 6 pts after progression of venetoclax), this included 5 pts who have pairs available for analysis (pre and post venetoclax). Results: Twenty four pts were treated with venetoclax (12 started as single agent and 8 started with combination with obinutuzumab and 3 with BTK inhibitors with/without obinutuzumab). Four pts had initial single agent venetoclax and later were rechallenged with combinations. Initial dose of venetoclax was dose escalation from 20 mg, then 50 mg then 100 mg PO daily up to 400 mg daily in 18/24 pts while in 3 pts it was 100 mg daily and in another 3 it was 400 mg daily. Median age at venetoclax start was 69 years (58-82). Median number of prior lines of therapy was 5 (range 1-11; including 17 pts who progressed on ibrutinib or other BTK inhibitors, 5 had exposure to ibrutinib and discontinued for intolerance, 4 had prior SCT and 2 had prior anti CD19 cellular therapy). At the baseline (pre/at-venetoclax start), 13 pts (54%) had blastoid/pleomorphic histology and 11 (46%) had classic variant morphology, the median Ki-67% was 60% (5-90%) and pts with Ki-67% ≥ 50 were 11 (55%), 4 pts did not have available Ki-67% values. Overall response rate (ORR) was 65% (13/20) - complete remission 25% (5/20) and partial remission 40% (8/20). Stable disease was observed in 10% (2/10), primary refractory were 25% (5/20). Four pts were not evaluable for response assessment. The median follow up after starting venetoclax was 17.5 months (1-27). The median PFS was 7.7 months (2 year 20%) and the median OS was 13.5 months (2 year 30%) Figure-1A-B. Pts in CR had a PFS of 15 months vs no CR 10 months (p=0.29). At the last follow up, 11 pts remained on venetoclax therapy (4 alive and 7 dead). Overall, 15 pts progressed and 14 pts were alive. The median post venetoclax survival was 6 months. Among 20 pts who discontinued venetoclax, 1 achieved CR and 3 PR on subsequent therapies. Among the 20 pts who discontinued venetoclax, 6 discontinued due to intolerance. In addition, we evaluated the somatic mutation profile in pts who progressed on venetoclax using WES. Figure-1C shows mutation spectrum. In our cohort, pts with MCL who progressed on venetoclax exhibited infrequent Bcl2 mutations (one pt at progression; 14 %; p.H3D) while the mutation frequency of other genes such as TP53 (71% vs. 40%), ATM (43% vs. 20%), KMT2D (57% vs. 20%), CELSR3 (57% vs. 20%), and KMT2C (43% vs. 20%) increased by 〉 2-fold at progression (compared to pretreatment samples, p=N.S due to small cohort size). The mutation of CARD11 (14%) and SMARCA4 (14%) was only observed at progression. Further details on copy number abnormalities will be presented. Conclusions: Venetoclax has promising results in refractory pts with MCL. Combination clinical trials with obinutuzumab, acalabrutinib are ongoing in MCL. We have characterized mutations and aneuploidy abnormalities in venetoclax resistant MCL pts and shown that unlike CLL, Bcl2 mutations are infrequent in venetoclax resistant MCL. Disclosures Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Fowler:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Aviara: Research Funding; Dava Oncology: Honoraria; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; VelosBio: Research Funding.

Description: Abstract 1529 The interim PET scan has prognostic value in pts with cHL. Because the outcome of ptswho have positive interim PET scans was dismal in previous reports, multiple clinical trials are ongoing using the interim PET to guide treatment decisions, but these are mostly non-randomized studies. We performed a retrospective study analyzing the prognostic role of the interim PET scan for predicting event free survival (EFS) for early stage (I and II non-bulky) and advanced stage (II-bulky, III and IV) cHL treated with standard ABVD with or without radiation therapy. This study was approved by the institutional review board. Interim PET results (positive or negative) were collected from the clinical reports of PET scans which were based on visual interpretation. A total of 327 pts diagnosed between 01/2001 and 05/2011, and had interim PET scan after 2 (PET2; n=231) or 3 (PET3; n=96) cycles were reviewed. The median follow up duration of surviving pts was 45 months (range 2–130 months). For pts with advanced stage disease, 5-year EFS rates in PET2-negative (n=79) and PET2-positive (n=20) groups were 75% and 54%, respectively (p=0.027). For pts with low IPS scores (0–2), 5-year EFS rates in PET2-negative (n=60) and PET2-positive (n=15) groups were 77% and 53%, respectively (p=0.02). For pts with high IPS scores (3–7), 5-year EFS rates in PET2-negative (n=19) and PET2-positive (n=5) groups were 69% and 50%, respectively (p=0.76). In pts with early stage disease, 5-year EFS rates in PET2-negative (n=107) and PET2-positive (n=25) groups were 98% and 65%, respectively (p

Description: Background - Mantle cell lymphoma (MCL) generally affects patients with a median age of 71 years. Majority of elderly MCL patients are transplant ineligible and are not suitable for intensive chemoimmunotherapy. Considering these limitations, our efforts are focused on developing "chemotherapy-free" modalities to treat these patients. We have previously reported high efficacy from a combination of ibrutinib with rituximab (IR) in relapsed MCL (Wang M et al Lancet Oncology 2015). We will now present the efficacy/safety analysis of our single center, phase II clinical trial using IR in previously untreated elderly (age ≥65 years) patients (pts) with MCL. Methods - We enrolled previously untreated elderly (≥65 years) MCL pts (n=50) in this study (NCT01880567). Pts with Ki-67% ≥ 50%, blastoid/pleomorphic histology and those with clinically uncontrolled co-morbidities (including atrial fibrillation) were excluded from this study. Pts received IR combination - ibrutinib 560 mg orally daily for 28 days (one cycle) continued until disease progression or discontinued for any reason. Rituximab was given on days 1, 8, 15 and 22 +/- 1 day by intravenous infusion (IV) at a fixed dose of 375 mg/m2 (Cycle 1, followed by rituximab on day 1 of every cycle starting in Cycles 3 - 8. Following cycle 8, rituximab was given on day 1 of every other cycle for up to 2 years. The primary objective was to assess the response rate and safety of IR in elderly MCL. Among evaluable samples, minimal residual disease (MRD) by flow cytometry at best response and whole exome sequencing (WES) from baseline tissue samples was performed. Results - Forty nine pts were included in this analysis. Median age was 71 years (range 65-84), 75% were males, ECOG PS was (0/1) in 48 (98%) pts, 16% had high risk simplified MIPI score and 28% had high risk biologic MIPI score. Forty seven patients (96%) had initial bone marrow involvement by MCL. The Ki-67% was low (

Description: Introduction: Patients (pts) with histologically aggressive MCL (HA-MCL; blastoid or pleomorphic) including [de novo (dnMCL) or those transformed from classic morphology (t-MCL)], exhibit a poor prognosis. This analysis provides a comprehensive assessment of so far the largest patient cohort with HA-MCL treated with various modalities. Methods: We included all HA-MCL pts [blastoid (n=142) or pleomorphic morphology (n=26)] at MD Anderson Cancer Center from 12/1997 to 07/2018. Among the 168 pts, 99 were dn-MCL and 69 were t-MCL. Pt characteristics were collected at the time of initial diagnosis in dnMCL and at transformation in t-MCL. Overall survival (OS) was defined from the time of initial diagnosis of HA-MCL to death/last follow-up and failure free survival (FFS) - time of starting first-line treatment after diagnosis of HA-MCL to treatment failure. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on specimens from 100 pts (among them, 27 tumor-normal pairs and 73 tumors without matched germline), this included CNT (classic never transformed=52), dnMCL=27, t-MCL=21. Two t-MCL pts had tumors sequenced at both classic and HA-MCL phase. Results: Median age for all 168 pts was 65 years (range, 39 to 95). Median time from initial diagnosis of classic t-MCL to HA t-MCL was 39 months (5 to 240 months). The median follow up after the diagnosis of HA-MCL was 19 months (0.1-168). Main clinical features of HA-MCL were - 72% pts had stage IV disease, 67% with marrow involvement, 27% leukemic phase, 20% with B symptoms, 6% had ECOG PS (3-4) and central nervous system involvement in 9% pts. Other features were, median Ki-67% 70% (10-100%), complex karyotype 11%, LDH 〉 upper limit of normal 44%, Sox-11 positive in 82%, median β2M of 2.9 mg/dL. In pt subsets, t-MCL were distinct from dnMCL in having significantly higher median age, higher Ki-67% and lower proportion of marrow involvement at diagnosis. All pts with t-MCL had prior treatment for MCL before transformation. Overall, the median OS after diagnosis of HA-MCL was 32.5 months (45 and 13 months for dnMCL and t-MCL respectively; p=0.001) and the median FFS was 12.5 months (22 and 5 months for dnMCL and t-MCL respectively; p=0.001). In univariate analysis, factors significantly associated with inferior OS in HA-MCL were older age, high Ki-67%, higher LDH, elevated WBC count, higher β2M, lower hemoglobin, lower platelet counts and advanced ECOG-PS, presence of B symptoms, CNS involvement, complex karyotype and t-MCL. Recursive partitioning analysis revealed that Ki-67% ≥50%, LDH ≥1282, β2M ≥ 4, hemoglobin