ALBERT

Description: Introduction: Mantle cell lymphoma (MCL) is a rare and incurable subtype of B-cell lymphoma. Intense chemo-immunotherapy with 8 cycles of Rituximab-HyperCVAD alternating with Rituximab-Methotrexate-Ara C is associated with an overall survival of 10.7 years but the 10-year cumulative incidence of therapy-related myeloid neoplasm was 6.2%. The ibrutinib-rituximab combination has produced durable responses in 88% of patients with relapsed and refractory MCL with acceptable toxicity. This gives rise to a "Window" of opportunity to use chemotherapy-free induction with ibrutinib plus rituximab followed by fewer cycles of chemo-immunotherapy consolidation in young and fit patients with newly-diagnosed, untreated MCL. Methods: Enrolment began in June 2015 for a Phase II single-center clinical trial consisting of an initial chemotherapy-free phase (window) of ibrutinib and rituximab combination treatment in Part 1 until best response, followed by a shortened course of intense chemo-immunotherapy in Part 2 among young newly diagnosed MCL patients of ≤65 years. The primary objective was to evaluate the response rate of ibrutinib plus rituximab. The secondary objectives were to evaluate the progression free survival (PFS) of ibrutinib plus rituximab after consolidation with a shortened number of cycles of intense chemo-immunotherapy, and to further evaluate the toxicity profile. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m2 IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3-12. Intense chemo-immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); alternating every 28 days with rituximab plus high-dose methotrexate-Ara C. If in complete remission (CR) after initial ibrutinib and rituximab treatment, a total of 4 additional treatments of intense chemo-immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo-immunotherapy, a total of 2 cycles of chemo-immunotherapy therapy are administered beyond achievement of CR. Results: As of August 2, 2016, we have completed the target enrolment by accruing 50 out 50 patients with newly-diagnosed untreated MCL. Forty one (n=41) patients have begun treatment and 36 are evaluable for response. Of the 36 evaluable patients, overall response rate (ORR) to Part 1 alone (Ibrutinib plus rituximab) is 100% (n=36) with PR in 28% (n=10) and CR in 72% (n=20). Nineteen 19 patients have completed both Part 1 (ibrutinib and rituximab) and Part 2 (chemo-immunotherapy). The ORR to both Part 1 and Part 2 (n=19) was 100% and was equal to the CR rate (100%, n=19), i.e. all have achieved a CR to Part 1 and Part 2. Toxicities are recorded as the number of patients experiencing a certain adverse event. Regardless of their relation to study drug in Part 1, the most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=40), diarrhea (n=25), rash (n=24), myalgia (n=22), oral mucositis (n=17), peripheral neuropathy (n=15), nausea (n=14), blurred vision (n=14), edema (n=13), constipation (n=12), headache (n=11), dry eyes (n=9), dizziness (n=9) and watery eyes (n=6). Grade 3 non-heme AEs included fatigue (n=3), nausea (n=0), rash (n=1), pleural effusion (n=1), infection (n=2) and dyspnea (n=1). There was no grade 4 or grade 5 non-heme toxicities in Part 1. In part 2, common grade 1-2 hematological (heme) AEs was anemia (n=13). Grade 3-4 haematological AEs included neutropenia (n=2), ALT increase (n=1) and febrile neutropenia (n=1). In Part 2, there was no grade 5 hematologic toxicity. The toxicity after intensive immune-chemotherapy in shortened cycles are much improved compared to historical controls but longer follow-up is needed. Conclusions: Preliminary data indicate that the chemotherapy-free induction with ibrutinib and rituximab in newly diagnosed, young MCL patients was efficacious and well-tolerated. This unprecedented efficacy and safety may provide a window of opportunity for less chemo-immunotherapy needed for consolidation. Table Preliminary findings form the Window Study: a phase II clinical trial Table. Preliminary findings form the Window Study: a phase II clinical trial Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding.

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: Background - Combination of ibrutinib plus rituximab (IR) has generated significant efficacy and safety data in relapsed patients (pts) with MCL. In this single institution phase II trial, we investigated the efficacy and safety of using an IR combination followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years) pts with MCL. We hypothesized that using a chemo-free induction will mitigate the toxicities and risk of second cancers which are associated with the use of intensive chemoimmunotherapy regimen in these pts. Methods - We enrolled 131 previously untreated young (≤65 years) pts with MCL. This study is registered with a ClinicalTrials.gov identifier number NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. None of the patients received stem cell transplant or maintenance therapy. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. Among evaluable samples, minimal residual disease (MRD) by flow cytometry at best response, clonal evolution using circulating tumor DNA (ctDNA), baseline somatic mutations and baseline gene expression profile (GEP) are being evaluated. Results - Among the 131 pts, the median follow up was 22 months (1.4-48.70). Eighty percent were males. Median age was 56 yrs (range - 35-65). Forty nine percent had high Ki-67 (≥30%), 80% had low risk simplified MIPI score and 85% pts had initial marrow involvement. Fifteen pts had aggressive MCL (blastoid/pleomorphic), 17 pts had complex karyotype and 83% had positive SOX-11 expression. Median number of cycles on IR in part A was 7 (1-12). At week 16 on part A, the ORR was 95% (22% CR and 73% PR) and 5% pts had stable disease. Overall best response (ORR) on part A of therapy was 100% (88% CR and 12% PR) and at the time of last follow up after completion of part A and part B, ORR was 100% (94% CR). Among evaluable pts, MRD- negative CR rate assessed by bone marrow flow cytometry performed at best response at any phase of treatment was 78%. Among the 10 pts with TP53 mutations, 70% had a CR on part A alone. Overall, the median PFS and OS were not reached (3 year 85% and 97% respectively). Nine pts had relapsed after treatment, including 3 who transformed. Among these 9 pts, 7/9 pts had Ki-67% ≥ 30% and 3/9 pts had aggressive histology MCL. The PFS and OS were not significantly different among pts with high and low Ki-67% and among pts with/without achieving CR on part A and while PFS was significantly shorter in pts with aggressive MCL histology (p=0.005) but not the OS. Overall 3 pts died (one on study due to splenic hematoma, cardio-pulmonary arrest and was on IR for 1 month, one expired outside and was off study after discontinuation due to encephalitis and another expired outside and discontinued due to disease transformation). Twenty one pts came off study for various reasons [nine disease progression (including 3 transformation), 8 pt choice, 3 intolerance and one second cancer]. Grade 3-4 toxicities on part A were 4% myelosuppression and 8% each with fatigue, myalgia and rashes and 4% mucositis. None had grade 3-4 atrial fibrillation or bleeding. GEP was performed in 18 pts (2 PR, 16 CR on part A). Pts in PR had higher expression of HES1 while those in CR had significantly higher expression of CTLA4 and ITK genes compared with those in PR. Targeted DNA sequencing was done in 18 pts at baseline, one pt with PR had NSD2, KMT2C and another pt had TP53 mutations and had CR. Conclusions - Excellent responses were observed with IR combination which is a chemo-free induction treatment strategy for young pts with MCL. This treatment approach has a strong potential to change the treatment paradigm in MCL pts to minimize the toxicity from chemoimmunotherapy without compromising the treatment efficacy and safety. Disclosures Wang: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Acerta Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; Janssen: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Honoraria, Research Funding. Neelapu:Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Poseida: Research Funding; Cell Medica: Consultancy; Karus: Research Funding; Acerta: Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Cellectis: Research Funding; Incyte: Consultancy; Allogene: Consultancy; BMS: Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction: A fraction of pts with classic variant MCL can transform to an aggressive histology (blastoid/pleomorphic) MCL. Outcomes of transformed pts are inferior to that of denovo blastoid variant MCL and classic variant MCL who never transformed (CNT) Jain P et al ASH 2018. Application of routinely available clinical variables at initial diagnosis to predict the future risk for transformation or time to transformation is an unmet need in MCL. Methods: We analyzed charts from 369 pts with MCL (293 were CNT and 76 were transformed MCL). Statistical analysis was performed from baseline pt characteristics collected from the time of initial diagnosis in CNT group and at the time of initial diagnosis of classic variant MCL who later transformed (t-MCL). Time to transformation (TTT) was calculated from initial diagnosis to the date of transformation in those who transformed and last follow up in those who never transformed. Univariate and multivariate logistic regression modeled the risk of transformation. Classification and regression tree (CART) analysis was performed to identify optimal cut off in categorical variables predictive of TTT. Results: Among the 369 pts, the median age was 62 yrs (range 34-90), 79% were males. Ki-67% values were available in 133 pts (36% of total) and median Ki-67% was 25% (range 1-80). 84% had initial bone marrow involvement and 12% had leukemic phase at diagnosis. The median follow up was 58.5 months and the median overall survival (OS) was 94.8 months and 47% were alive at the time of this analysis. Compared to pts in the CNT group, pts in t-MCL group exhibited differences in following baseline characteristics - higher values of median Ki-67% (30% vs 20% in t-MCL; p=0.04), higher LDH levels, higher proportions of pts with high risk simplified MIPI risk score, leukemic phase at initial diagnosis, complex karyotype and lower hemoglobin and lower proportion of pts achieving complete remission (CR) after first line treatment (78% in t-MCL vs 86% in CNT). In addition, first line treatments received by both groups were similar - R-HCVAD based, R-chemo based, ibrutinib based, chemotherapy alone and miscellaneous. Logistic regression model showed factors associated with the risk of transformation. In univariate analysis, higher risk was significantly associated with Ki-67% as a continuous variable - OR 1.03 (95% CI 1.01-1.05; p=0.006), leukemic phase at diagnosis, high risk MIPI score, complex cytogenetics. First line treatment with ibrutinib compared to R-HCVAD, autologous stem cell transplant SCT at any time point and higher number of nodal sites were associated with decreased risk of transformation. In multivariate analysis (MVA), higher number of nodal sites and SCT were associated with decreased risk of transformation. The median time to transformation in months for those who transformed was 39 (range 5-240 months) while in CNT it was 51 months (1-257 months). We further identified that incremental Ki-67% was significantly associated with TTT and OS (Figure-1A-B). Using CART analysis we identified Ki-67% ≥60 is significantly associated with shorter TTT (HR, 6.26; 95% CI 2.58-15.21; p

Description: Introduction: Mantle cell lymphoma commonly presents as classic variant histology, however 10-30% patients (pts) can transform into an aggressive histology (blastoid and/or pleomorphic variants). We have previously reported that genomic profile and clinical outcomes of transformed MCL pts are distinct from classic variant pts who never transformed (CNT) and that transformed pts have poor clinical outcomes. In this study, we analyzed the factors at initial diagnosis which can predict the time to transformation and the risk for transformation in a cohort of 369 pts with MCL. Methods: We analyzed charts from 369 pts with MCL (293 were CNT and 76 were transformed MCL). Statistical analysis was performed from baseline pt characteristics collected from the time of initial diagnosis in CNT group and at the time of initial diagnosis of classic variant MCL who later transformed (t-MCL). Time to transformation (TTT) was calculated from initial diagnosis to the date of transformation in those who transformed and last follow up in those who never transformed. Univariate and multivariate (MVA) logistic regression modeled the risk of transformation. Classification and regression tree (CART) analysis was performed to identify optimal cut off in categorical variables predictive of TTT. Results: Among the 369 pts, the median age was 62 yrs (range 34-90). Ki-67% values were available in 133 pts (36% of total) and median Ki-67% was 25% (range 1-80). Three hundred eight pts (84%) had initial bone marrow involvement and 66 pts (18%) had leukemic phase at diagnosis. The median follow up was 133 months and the median overall survival (OS) was 95 months and 43% were alive at the time of this analysis. Discernible difference were noted in pts who belong to t-MCL group compared to pts in the CNT group, pts in t-MCL group exhibited - higher values of median Ki-67% (30% vs 20% in CNT; p=0.04), higher LDH levels, higher proportions of pts with high risk simplified MIPI risk score, leukemic phase at initial diagnosis, complex karyotype and lower hemoglobin. First line treatments received by both groups were similar. Eleven pts got anti-CD19 CART therapy at some point and 7 pts were t-MCL and 4 were CNT group. The median time to transformation in months for those who transformed was 39 (range 5-240 months) while in CNT it was 51 months (1-257 months). We further identified that incremental Ki-67% was significantly associated with TTT and OS (Figure-1A-B). Using CART analysis we identified Ki-67% ≥60 is significantly associated with shorter TTT (HR, 6.26; 95% CI 2.58-15.21; p 729 IU/L), higher platelet count 〉 180 and high absolute lymphocyte count 〉 5000 k/ul were predictive of shorter TTT. Logistic regression model showed factors associated with the risk of transformation. In univariate analysis, higher risk was significantly associated with Ki-67% as a continuous variable - OR 1.03 (95% CI 1.01-1.05; p=0.006), leukemic phase at diagnosis, high risk MIPI score and complex cytogenetics. First line treatment with ibrutinib compared to R-HCVAD, was associated with decreased risk of transformation. In MVA, ibrutinib/BTK inhibitor therapy (n=51) as first line therapy was associated with decreased risk of transformation while CNS involvement was associated with higher risk of transformation. Conclusions: Routinely available clinical variables can help determine the risk for transformation of MCL and time to transformation. Progressive increase in Ki-67 and high MIPI risk score is associated with shorter TTT and increases the risk for transformation. Earlier usage of BTK inhibitor therapy may reduce the risk of developing histologic transformation in MCL pts. Disclosures Lee: Seattle Genetics: Research Funding; Takeda: Research Funding; Aptitude Health: Speakers Bureau; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Vega:NCI: Research Funding. Flowers:Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; OptumRx: Consultancy; TG Therapeutics: Research Funding; BeiGene: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Kite: Research Funding; Bayer: Consultancy. Wang:Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Dava Oncology: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; InnoCare: Consultancy; Nobel Insights: Consultancy; OncLive: Honoraria; Loxo Oncology: Consultancy, Research Funding; MoreHealth: Consultancy; Oncternal: Consultancy, Research Funding; Targeted Oncology: Honoraria; Acerta Pharma: Research Funding; Guidepoint Global: Consultancy; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Lu Daopei Medical Group: Honoraria; Juno: Consultancy, Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding.

Description: Background - We investigated the efficacy and safety of using a combination of ibrutinib plus rituximab (IR) followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years) patients (pts) with mantle cell lymphoma (MCL). Using a chemo-free induction may reduce the toxicities, complications and the risk of second cancers which were observed with intensive chemoimmunotherapy regimen in MCL pts. Methods - We enrolled 131 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. None of the pts received stem cell transplant or maintenance therapy. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. Among evaluable samples, minimal residual disease (MRD) by flow cytometry at best response, clonal evolution and MRD using circulating tumor DNA (ctDNA), whole exome (WES) and bulk RNA sequencing from baseline tissue samples was performed. Results - Among the 131 pts, the median age was 56 yrs (range - 35-65). High Ki-67 (≥30%) in 58/117 (49.5%) pts, 10 pts (8%) had high risk simplified MIPI score, 15 pts (11%) had aggressive MCL (blastoid/pleomorphic) and 114 pts (87%) had initial bone marrow involvement. Seventeen pts (13%) had had complex karyotype and 83% had positive SOX-11 expression. Baseline PET scan was available in 101 pts and 97 pts had PET positive disease. Median number of cycles on IR in part A was 7 (1-12). At week 16 on part A, the ORR was 95% (15% CR and 80% PR) and 5% pts had stable disease. Overall best response (ORR) on part A of therapy was 100% (88% CR and 12% PR) and at the time of last follow up after completion of part A and part B, ORR was 100% (98% CR). Median time to CR was 5 months (range 1-16). Pts with CR within 6 months are "early" CR (n=66) and those with CR ≥ 6 months were "late" CR (n=49) while pts who never had CR were grouped as no CR (n=13). With a median follow up of 37 months, the median PFS and OS were not reached (3 year 82% and 95% respectively). Twenty two pts (17%) relapsed after treatment, including 6 who transformed to aggressive MCL. PFS among pts with high and low Ki-67% was 58 months vs not reached (P=0.03) while no difference was observed in OS. PFS was significantly shorter in pts with aggressive histology (p=0.003) but not the OS. Overall 6 pts died (2 with progression, 2 due to disease transformation, one on study due to multiple complications including splenic hematoma, cardio-pulmonary arrest and progression and the last one expired outside and came off study due to encephalitis). Forty two pts came off study for various reasons [16 disease progression (including 4 transformation), 20 pt choice, 3 intolerance, two second cancer and one lost to follow up]. Grade 3-4 toxicities on part A were 4% myelosuppression and 8% each with fatigue, myalgia and rashes and 4% mucositis. None had grade 3-4 atrial fibrillation or bleeding. WES in 76 pts revealed deletions of BANK1, CCND1, TP53, UBR5, ATM, RB1, CDKN2A and BCL2 in late CR (n=14) (≥ 6 months) and no CR (n=12) pt groups vs early CR (〈 6 months; n=30). KMT2C, NCOR2 SMARCA4 and NSD2 mutations were significantly different in late CR vs early CR groups. Furthermore, 68 pts had bulk RNA sequencing and a differential gene expression pattern was identified separating early vs late vs no CR groups. Immune response pathways were overexpressed in early CR pts while oncogenic signaling pathways were clustered in late CR and no CR groups. Conclusions - Chemo-free induction with IR induced durable and deep responses in young MCL pts in the frontline setting. Short course R-HCVAD chemotherapy minimized toxicities and consolidated responses. This combined modality treatment approach may significantly improve young MCL pts outcomes across all risk groups. Pathway analysis demonstrated immune response pathways to be associated with early CR on IR. Detailed analyses on MRD using ct-DNA will be reported. Disclosures Wang: Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; MoreHealth: Consultancy; Pulse Biosciences: Consultancy; Molecular Templates: Research Funding; OncLive: Honoraria; VelosBio: Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Lu Daopei Medical Group: Honoraria; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Verastem: Research Funding; Dava Oncology: Honoraria. Lee:Celgene: Research Funding; Guidepoint Blogal: Consultancy; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Aptitude Health: Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Research Funding. Westin:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding; Kite: Consultancy, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding; Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Gamida Cell: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Karus Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Gilead/KITE: Honoraria. Vega:NCI: Research Funding. Flowers:Millennium/Takeda: Consultancy, Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; TG Therapeutics: Research Funding; OptumRx: Consultancy; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Gilead: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Celgene: Consultancy, Research Funding.

Description: Introduction: Complex karyotype (Cx) refers to ≥3 unrelated cytogenetic abnormalities in addition to t(11;14) in MCL patients (pts). In limited pts treated with chemotherapy, pts with Cx exhibited poor outcomes compared to non-Cx group. Prognostic impact of Cx in pts treated with BTKi is unclear. We present the largest and most comprehensive analysis on the prognostic impact of Cx in MCL pts. Methods: We analyzed charts from 396 MCL pts with karyotype data. (271 were non-Cx and 125 were Cx). Karyotype status at initial MCL diagnosis was denovo (DN) while previously treated pts were secondary (S). Among Cx, n=80 pts were DN-Cx and 45 were S-Cx while in non-Cx group, 224 were DN-non-Cx and S-non-Cx were 47 pts. TP53 mutation/FISH data was available (n=134; 46 positive, 88 negative). Pt characteristics were obtained from the time of karyotype testing (at initial diagnosis in DN and at the time of testing in S group). Overall survival (OS) was calculated from test date to the last follow up and progression free survival (PFS) after first line therapy from treatment date to date of progression/death. Univariate and multivariate logistic regression modeled the risk of event and treatment response. Results: Cx pts had significant differences compared to non-Cx, including median Ki-67 (40 vs 20%), sMIPI (median 6 vs 4), poor performance status (p.s.), CNS involvement (7 vs 2%), blastoid (22 vs 7%), pleomorphic (12 vs 3%), higher LDH, WBC, ALC and β2M levels and low Hb and platelet counts, prior BTKi (35 vs 15%), TP53 positive (75 vs 17%), shorter median follow up from the test date (18 vs 33 months). Overall, 70 (56%) in Cx and 70 (26%) in non-Cx had died. Univariate analysis for OS showed, advanced age, higher values of Ki-67, WBC, LDH, β2M, MIPI scores, number of chromosomal aberrations, B symptoms, splenomegaly, CNS involvement, poor p.s., prior BTKi, blastoid/pleomorphic histology, TP53 positive status, non-responder to first line therapy and Cx (median 35 months vs 101 months in non-Cx respectively; p

Description: Background - Older patients (pts) with mantle cell lymphoma (MCL) may exhibit poor functional status and become ineligible for intensive chemo-immunotherapy or stem cell transplantation. The advent of chemotherapy-free therapies are a significant advance in MCL. We investigated the safety and efficacy of combining ibrutinib and rituximab (IR) in previously untreated older pts (age ≥65 years) with MCL in a single center, phase II clinical trial. Methods - We enrolled previously untreated pts with MCL ≥65 years (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 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 IV infusion at a fixed dose of 375 mg/m2 in cycle 1, followed by rituximab on day 1 of every cycle for cycles 3 - 8. Following cycle 8, rituximab was given on day 1 every 2 months for up to 2 years. The primary objective was to assess the safety and response of IR. For pts with evaluable samples, minimal residual disease (MRD) by flow cytometry at best response, whole exome (WES) and bulk RNA sequencing from baseline tissue samples was performed. Results - Among 50 pts enrolled, the median age was 71 years (range 65-84), 76% were males, ECOG PS was (0) in 42 (84%) pts, 16% had high risk MCL international prognostic index, 48 (96%) pts had initial bone marrow involvement, and 19 (79%) of 24 evaluable pts had baseline GI involvement by MCL. The Ki-67% was low (