Two Distinct Clinical Courses and Outcomes in T-Cell Prolymphocytic Leukemia

Abstract Introduction: T-cell prolymphocytic leukemia (T-PLL) is a rare type of mature T-cell neoplasm with a poor prognosis. Up to 30% of patients initially present with indolent disease course that may be observed until progression to T-PLL with aggressive behavior. We aimed to compare the clinicopathologic characteristics and outcomes of patients with initially indolent versus aggressive disease. We hypothesized that patients with indolent disease have less cytogenetic abnormalities and a favorable overall survival (OS). Methods: We identified 65 patients diagnosed with T-PLL between 2004 and 2020 who were treated at Moffitt Cancer Center. Clinical presentation, laboratory parameters, and bone marrow biopsy at the time of diagnosis were retrospectively reviewed. Patients were categorized into two groups: indolent or aggressive disease type. Patients were considered indolent if they did not have symptoms requiring immediate treatment such as B symptoms or fatigue, symptomatic lymphadenopathy, symptomatic organomegaly, hyperlymphocytosis, organ dysfunction, or cytopenias requiring transfusions. Patients with 3 or more chromosomal abnormalities were considered to have complex cytogenetics. Clinicopathologic characteristics were compared using Chi-square test. OS and factors that are potential influencers of survival were compared using the Kaplan Meier curve as well as Cox Proportional Hazards regression. Results: Of the 65 patients with T-PLL, 32 (49%) presented with indolent disease and 33 (51%) presented with aggressive disease. The median age at diagnosis was 68 years (range 43-88 years). Patients with aggressive disease presented with a higher WBC compared to those with indolent disease, with median WBC 79.7 x 10 9/L and 22.9 x 10 9/L, respectively (p=<0.001). Patients with aggressive disease also presented with a higher absolute lymphocyte count (ALC), with median ALC 47.8 x 10 9/L and 15.4 x 10 9/L (p=<0.001) (Table 1). Extra-nodal, skin, and CNS involvement was not significantly different between disease types. Flow cytometry was similar between indolent and aggressive disease with the exception with the exception of CD56 and CD57 which were rare and only observed in aggressive disease. Patients with aggressive disease were more likely to have complex karyotype compared to patients with indolent disease (p=0.023). FISH results for inversion 14 and trisomy 8 were similar between disease types. Median time from diagnosis to initial treatment was 379 days for indolent and 44 days for those with aggressive disease. 36 (55%) patients were treated with Alemtuzumab as first line treatment. A total of 15 (23%) patients ultimately underwent allogeneic hematopoietic stem cell transplant (HSCT). The median OS for the entire cohort was 30 months. The median OS for indolent and aggressive disease was 44 and 24 months, respectively (p=0.015, Figure 1). The median OS for patients who underwent HSCT compared to those who did not was 99 and 24 months, respectively (p=0.002). Among patients with indolent disease, those who underwent HSCT had a significantly longer median OS of 153 compared to 34 months for those who did not (p=0.022). There was a trend toward improved OS in patients with aggressive disease who underwent HSCT compared to those that did not (35 vs 16 months; p=0.08). In addition, there was a trend toward improved OS with earlier treatment (<12 months) in the indolent group (383 versus 86 months, p= 0.155). On multivariate analysis (Table 2), factors that negatively affected overall survival were aggressive disease type (HR 3.0, p=0.018), presence of inversion 14 (HR 2.5, p=0.032), presence of B symptoms (HR 2.4, p=0.036), and absence of HSCT (HR 0.2, p=0.001). Conclusion: Patients with T-PLL who present with aggressive disease, inversion 14, B symptoms, and those who are unable to undergo bone marrow transplant have lower overall survival. Characteristics that predict a more aggressive disease phenotype at diagnosis are high WBC, high ALC, presence of B symptoms, and complex karyotype. Figure 1 Figure 1. Disclosures Saeed: Kite Pharma: Consultancy, Other: investigator; Other-TG therapeutics: Consultancy, Other: investigator; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Epizyme, Inc.: Consultancy; Bristol-Myers Squibb Company: Consultancy; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; Nektar Therapeutics: Consultancy, Other: research investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees.

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Preliminary Study of Ruxolitinib and Venetoclax for Treatment of Patients with T-Cell Prolymphocytic Leukemia Refractory to, or Ineligible for Alemtuzumab

Blood ◽

10.1182/blood-2021-149228 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1201-1201

Author(s):

Charles Herbaux ◽

Stéphanie Poulain ◽

Damien Roos-Weil ◽

Jacques-Olivier Bay ◽

Yann Guillermin ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Advisory Committees ◽

Prolymphocytic Leukemia ◽

Oncology Research ◽

Grade 3 ◽

Stat Pathway

Abstract Background: Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are 2 drug candidates recently identified as promising candidate for the treatment of T-Cell prolymphocytic leukemia (T-PLL). We recently reported that JAK/STAT pathway inhibition with RUX enhances BCL-2 dependence, thereby sensitizing T-PLL cells to VEN (Herbaux et al., Blood, 2021). We also showed that JAK/STAT pathway mutational status could impact RUX activity. Here, we report results on the 15 first patients who were treated with RUX and VEN oral combination for T-PLL. All patients were refractory to, or ineligible for alemtuzumab, the principal therapeutic option to date. Methods: In this multicenter retrospective study from the French Innovative Leukemia Organization, 15 patients with T-PLL (according to consensus criteria) were included. All patients were informed about the off-label use of this combination and provided informed consent. Patients received a maximum dose of RUX 15 mg twice daily, and VEN 800 mg daily. VEN was started with daily ramp-up from 20 mg to 800 mg over 6 days, with TLS prophylaxis (rasburicase and IV hydration). Responses were assessed by consensus criteria. Next generation sequencing (NGS) was performed using a custom-designed panel of 33 genes, including among others: ATM, TP53, IL2R, JAK1, JAK3, and STAT5B. CytoScan HD microarray (Affymetrix) were used to study copy number variation and or uniparental disomy. In vivo dynamic BH3 profiling (DBP) was performed on samples obtained from two patients on treatment. Results: All 15 patients were refractory or relapsing after chemotherapy (mostly bendamustine and pentostatin), except one. They were either refractory to (n=10) or ineligible (n=5) for alemtuzumab (ineligibility was decided by the treating physician based on age and comorbidities). The median age was 70 years (48-88). Within a week of starting RUX, a transient increase of the absolute lymphocyte count was observed in 66.6% of the patients. Based on the molecular status of the JAK/STAT pathway, we established 2 groups of patients. One with samples where no mutations were found (WT, n=3), and one with at least one mutation in the JAK/STAT pathway (MUT, n=12). The overall response rate (ORR) was 73.3%, with only partial responses. Five patients nearly fulfilled CR criteria except that they had persistent lymphocytosis (over 4 x 10 9/L), all of them were in the MUT group. ORR was 83.3% in the MUT group, and only one patient of the WT group obtained a PR. With a median follow-up of 73 days (22 to 368), the median progression free survival was significantly shorter in the WT group in comparison to the MUT group (1.8 months versus 5.6 months, p=0.04, Figure). Of note, four patients were treated with VEN monotherapy before the start of the combination with RUX. With that treatment, 3 of these patients achieved stable disease followed by progression within 2 to 3 months, while 1 was primary refractory to VEN monotherapy. The most frequent reported adverse events (AEs) of the RUX plus VEN combination were cytopenias, with 46.6% grade 3 or 4 thrombocytopenia and 40% grade 3 or 4 neutropenia. DBP showed that overall priming and BCL2 dependence increased in vivo (n=2) during the treatment with RUX and VEN. Finally, SNP arrays identified clonal evolution in the 3 patients evaluated sequentially (before treatment versus at progression). In one case, emergence of EZH2 and JAK1 mutation was also observed at progression using NGS. Conclusions: These preliminary results suggest promising activity of RUX plus VEN in T-PLL, and justify the development of a prospective clinical trial of this combination. Our data seem to show that this combination may be especially active for patients with JAK/STAT pathway activating mutations and that disease progression is associated with clonal evolution. Updated results will be presented at the meeting. Figure 1 Figure 1. Disclosures Herbaux: Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Lemonnier: Gilead: Other: travel grant; Institut Roche: Research Funding. Laribi: Jansen: Research Funding; AstraZeneca: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; BeiGene: Other: Personal Fees. Moreaux: Diag2Tec: Consultancy. Morschhauser: Janssen: Honoraria; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Davids: Ascentage Pharma: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Eli Lilly and Company: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Research to Practice: Consultancy; BeiGene: Consultancy; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Takeda: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. OffLabel Disclosure: Ruxolitinib and venetoclax are used offlabel for patients refractory to current therapeutic options, based on preclinical data.

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Influence of Karyotype On Overall Survival in Patients with Higher-Risk Myelodysplastic Syndrome Treated with Azacitidine or a Conventional Care Regimen.

Blood ◽

10.1182/blood.v114.22.1755.1755 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1755-1755 ◽

Cited By ~ 5

Author(s):

Ghulam J Mufti ◽

Steven D. Gore ◽

Valeria Santini ◽

Pierre Fenaux ◽

Lewis R. Silverman ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Conventional Care ◽

Complex Karyotype ◽

Trisomy 8 ◽

Employment Equity ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Equity Ownership

Abstract Abstract 1755 Poster Board I-781 Background Karyotypic abnormalities are common in myelodysplastic syndromes (MDS), and specific chromosomal abnormalities are associated with poor prognosis. The phase III AZA-001 study (Lancet Oncol, 2009) showed azacitidine (AZA) prolonged overall survival (OS) regardless of IPSS cytogenetic risk category. This analysis assessed the effects of specific cytogenetic abnormalities on OS in patient (pt) subgroups treated with AZA or a conventional care regimen (CCR). Methods Pts with higher-risk MDS (FAB RAEB, RAEB-t, or CMML and IPSS Int-2 or High) were enrolled and randomized to receive AZA or CCR. CCR comprised 3 treatments: best supportive care only, low-dose ara-C, or induction chemotherapy. Erythropoietins were prohibited. OS was determined in subgroups of pts with del 5/5q-, del 7/7q-, or trisomy 8, each as part of a non-complex karyotype (<3 cytogenetic abnormalities) or as part of a complex karyotype (≥3 cytogenetic abnormalities). OS was also analyzed in pts with combinations of del 5/5q- and/or del 7/7q- as part of non-complex or complex karyotypes (Table). Pt karyotype was determined at baseline. OS was assessed using Kaplan-Meier methods. A stratified Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and associated 95% confidence intervals (CI). Results A total of 358 pts were enrolled (AZA 179, CCR 179). Of them, 153 had normal karyotypes (AZA 77, CCR 76). Median OS in pts with normal karyotypes was not reached at 21.1 months with AZA vs 17.2 months (95%CI: 15.2 – 24.1 months) with CCR; HR = 0.63 (95%CI: 0.39 – 1.03). Of remaining pts, 136 had del 5/5q-, del 7/7q-, and/or trisomy 8 as part of a non-complex or complex karyotype. AZA was associated with longer OS vs CCR in all subgroups of pts with non-complex cytogenetics, with HRs ranging from 0.20 (95%CI: 0.06 – 0.65) to 0.51 (95%CI: 0.05 – 4.74) (Table). In both the AZA and CCR treatment groups, pts in all subgroups with non-complex karyotypes had substantially longer OS than pts with complex karyotypes. Pts with complex karyotypes in some subgroups had longer OS with AZA vs CCR: median OS in pts with del 5/5q-, del 5/5q- WITHOUT del 7/7q-, or trisomy 8 as part of a complex karyotype treated with AZA survived 5.1, 8.0, and 12.4 months longer, respectively, than their counterparts who received CCR. HRs with AZA vs CCR in pts with complex cytogenetics ranged from 0.42 (95%CI: 0.10 – 1.69) to 0.55 (95%CI: 0.29 – 1.05). Conclusions These findings support earlier data showing effectiveness of AZA in higher-risk MDS pts with complex or non-complex karyotypes. Major gains in OS were obtained with AZA vs CCR (12-18 months longer OS with AZA) for the following categories: del 7/7q- (non-complex), del 7/7q- WITHOUT del 5/5q- (non-complex), and trisomy 8 (non-complex and complex). Pts with trisomy 8 treated with AZA experienced a 3-fold increase in median OS compared with similar pts who received CCR. Longer OS (AZA 15.3 vs CCR 7.3 months) was also obtained for pts with del5/5q- WITHOUT del7/7q- as part of a complex karyotype. The worse cytogenetic categories, del 7/7q- and del 5/5q- AND del 7/7q-, both with complex karyotype, were associated with the poorest OS regardless of treatment. Pt subgroups in this post hoc analysis were small and heterogeneous; confirmation of these findings in larger pt samples is warranted. Disclosures Mufti: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Santini:Celgene: Honoraria. Fenaux:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Epicept: Honoraria, Research Funding. Skikne:Celgene: Employment, Equity Ownership. Hellstrom-Lindberg:Celgene: Research Funding. Seymour:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Beach:Celgene: Employment, Equity Ownership. Backstrom:Celgene: Employment, Equity Ownership. Fernando:Celgene: Employment, Equity Ownership.

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Adult T-Cell Leukemia/Lymphoma: A Cohort of 41 Cases Recorded in the Brazilian T-Cell Project

Blood ◽

10.1182/blood-2020-142818 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Daniel Silva Nogueira ◽

Marcia Torresan Delamain ◽

Eliana Cristina Miranda ◽

Yung Bruno de Melo Gonzaga ◽

Juliana Pereira ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Line Treatment ◽

Cell Leukemia ◽

Advisory Committees ◽

Stage Disease ◽

Ann Arbor

Introduction:Adult T cell Leukemia/Lymphoma (ATLL) is a mature T-Cell-neoplasm related to human T-cell lymphotropic virus type 1 (HTLV-1) infection that shows variable clinical presentation and adverse prognosis with shorter overall survival (OS) when compared to other peripheral T-cell lymphomas (PTCL). Previous epidemiological studies estimated cumulative incidence in endemic regions around the world. In Brazil, mainly due to its vast dimension, data collection has limitations and is subject to bias. In April 2015 theBrazilianT-cell longitudinal project initiative was launched. One of the primary purposes was the collection of epidemiological and clinical data from the most frequent subtypes of newly diagnosed PTCL. Among them, 41 cases of ATLL were recorded. Objectives:The aim of this study is to describe clinical features, frequency and overall survival (OS) of 41 cases of ATLL registered in the ongoingBrazilianT-Cell Project. Methods:This is an ambispective observational study design collecting baseline characteristics, clinical features including date of diagnosis, clinical subtypes, B symptoms, performance status, Ann-Arbor staging, HTLV-1 status, number of sites, nodal and extra nodal presentation and types of skin lesions, peripheral blood counts and biochemical tests, front-line treatment and best response after first-line treatment. REDcap Platform has been used to collect and store data and for descriptive analysis the IBM-SPSS version 24 was applied. Kaplan-Meier method estimated the OS, whereas Log-Rank tests to compare its curves. OS period was calculated from diagnosis date until death or last seen date, and event was death by any cause. Results:Out of 281 cases of PTCL registered so far, 41 were ATLL cases. The median age was 50 years (34-88), 25 (64%) female; a higher incidence of lymphoma subtype was observed (46%), followed by acute (29%), chronic (17%) and smoldering (8%). Most of the patients (85%) had advanced-stage disease (III-IV, Ann-Arbor) and 56% had B symptoms (Table 1); 73% received chemotherapy with anthracycline-based regimens (46.5% CHOEP; 33.5% CHOP; 20% others) whereas 17% were managed with immunotherapy and antiviral therapy. The overall response rate was 30%; no response or progression 46%; stable disease 9% and 15% no data available yet (Table 2). Median follow-up was 13 months and 25 months for 41% of alive patients. Two year OS was 39% (95%CI: 23-55%) (Figure 1). Smoldering and Chronic subtypes showed better OS when compared with acute and lymphoma (100% smoldering, 86% chronic; 30% lymphoma type and 13% acuteP=0.04) (Figure 2). The multivariate Cox Regression analysis found male gender (HR 10.9 95%CI: 3.0-39.7, P<0.0001) and albumin (HR 0.23 Beta -1.45 95%CI: 0.10-0.55, P=0.001) as significant prognostic factors for OS. Discussion:ATLL prognosis remains poor regardless of the type of treatment regimen and may be associated with the high incidence of lymphoma and acute subtypes, as well as advanced stage disease presentation. Despite the high number of cases seen in southeastern region of Brazil, it is important to emphasize there are still limited data from other regions. Albeit the sample size is small, these findings confirmed literature review data so far, with poor overall survival in a short time and gender and albumin as predictors of OS in the multivariate analysis. Conclusion:This study highlights the poor prognosis associated with ATLL. Moreover, it seems relevant to expand this study to all Brazilian regions. Hence, the need for early diagnosis and new treatment strategies, able to reduce mortality is warranted, that could possibly change the nature and spectrum of disease. Disclosures Federico: Spectrum:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sandoz:Consultancy, Membership on an entity's Board of Directors or advisory committees;Cephalon/Teva:Research Funding;Mundipharma s.r.l.:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Millennium/Takeda:Research Funding;Roche:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Azacitidine (AZA) Prolongs Overall Survival in Older Patients with Acute Myeloid Leukemia (AML) with Poor Prognostic Karyotypes Compared with Conventional Care Regimens (CCR)

Blood ◽

10.1182/blood.v128.22.1638.1638 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1638-1638 ◽

Cited By ~ 2

Author(s):

Hartmut Döhner ◽

Paresh Vyas ◽

John F. Seymour ◽

Valeria Santini ◽

Richard M. Stone ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Complex Karyotype ◽

Employment Equity ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Poor Risk ◽

Equity Ownership

Abstract Background: Karyotype is the strongest independent prognostic factor for survival in AML. The randomized phase 3 AZA-AML-001 study of older patients with AML showed AZA prolonged overall survival (OS) compared with CCR (10.4 vs 6.5 months, respectively; P=0.101) (Dombret et al, Blood, 2015). In a prospective subanalysis of the study, AZA was shown to meaningfully prolong OS by 3.2 months compared with CCR (P=0.0185) in the subgroup of patients with NCCN-defined poor-risk cytogenetics (Döhner et al, Blood, 2014: Abstract 621). Aim: This analysis evaluates treatment effects of AZA vs CCR on OS in subgroups of patients with specific cytogenetic abnormalities as well as in patient subgroups defined by cytogenetic risk per modified European LeukemiaNet (ELN) recommendations (not considering molecular markers) (Döhner et al, Blood, 2010). Methods: Patients aged ≥65 years with newly diagnosed AML (>30% bone marrow [BM] blasts), ECOG performance status score ≤2, intermediate- or poor-risk cytogenetics per NCCN 2009 criteria, and WBC count ≤15x109/L were randomized to receive AZA (75 mg/m2/day [d] x7d/28d) or CCR: intensive chemotherapy (cytarabine 100-200mg/m2IV x7d + anthracycline IV x3d induction), low-dose ara-C (20mg SC BID x10d/28d), or best supportive care only. Karyotypes obtained from BM were reviewed centrally by an independent cytogeneticist. OS was evaluated in subgroups of patients with frequent specific abnormalities, including -5/del(5q), -7, -7/del(7q), abnormal (17p) or complex karyotype (based on specific abnormalities, patients may have been evaluated in more than one category). OS was also assessed for patients in ELN-defined karyotype risk subgroups: Intermediate (Int)-I (normal karyotype), Int-II (all abnormalities not classified as Favorable or Adverse), and Adverse karyotype. OS was assessed using Kaplan-Meier methods and compared using a weighted log-rank test. Results: Centrally reviewed cytogenetic data were available for 485/488 patients (99.4%). In all, 220 patients (45.4%; AZA n=114, CCR n=106) had Int-I karyotype, 111 patients (22.9%; AZA n=53, CCR n=58) had Int-II karyotype, and 154 patients (31.8%, AZA n=73, CCR n=81) had Adverse karyotype (Figure 1). OS was comparable between AZA and CCR in patients with Int-I karyotype (14.1 vs 10.1 months, respectively; hazard ratio [HR] 0.83, 95%CI 0.60, 1.1; P=0.44) and patients with Int-II karyotype (8.9 vs 9.6 months; HR 1.19, 95%CI 0.79, 1.8; P=0.78). There was a significant 2.4-month median OS difference in favor of AZA in patients with Adverse karyotype (5.3 vs 2.9 months with CCR; HR 0.71, 95%CI 0.51, 0.99; P=0.046; Figure 2), with 1-year survival rates of 29.1% vs 14.7% for AZA and CCR, respectively. AZA was associated with longer median OS and higher 1-year survival compared with CCR for all subgroups of patients with the specific cytogenetic abnormalities under study: -5/del(5q), -7, -7/del(7q), abnormal (17p), and complex karyotype, with HRs ranging from 0.54 to 0.69(Table). Median OS in the CCR arm was less than 3 months for each of these subgroups. Similar to what has been reported in MDS (Ravandi et al, Cancer, 2009), AML patients with chromosome 7 abnormalities responded particularly well to AZA, with an improvement in median OS of 4.1 months over CCR. Patients with complex karyotypes also had meaningful improvements in OS, with ~15% more AZA-treated patients alive at 1 year than CCR patients. Conclusions: Prognosis is dismal for older AML patients with adverse karyotypes, and is especially poor for patients with complex karyotypes. Median OS and 1-year survival in patients with ELN-defined Adverse karyotype treated with AZA were almost double those of patients treated with CCR. AZA-treated patients with the specific cytogenetic abnormalities and/or complex karyotype in this analysis had a 31-46% reduction in risk of death vs CCR, and proportions of patients alive at 1 year were 11-22% greater with AZA. These data suggest AZA should be the preferred treatment for older patients with AML and adverse karyotypes. Disclosures Seymour: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Santini:Astex: Consultancy; Amgen: Consultancy; Onconova: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Stone:Celator: Consultancy; Novartis: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Morrill:Celgene: Employment, Equity Ownership. Songer:Celgene: Employment, Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Dombret:Agios: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Menarini: Honoraria; Menarini: Honoraria; Servier: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding.

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Favorable Outcomes of Acute Leukemia of Ambiguous Lineage Treated with Hypercvad: A Multi-Center Retrospective Study

Blood ◽

10.1182/blood-2018-99-115448 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2658-2658

Author(s):

Vu H. Duong ◽

Kebede H. Begna ◽

Kendra L. Sweet ◽

Eunice S. Wang ◽

Ryan James Caddell ◽

...

Keyword(s):

Overall Survival ◽

Acute Leukemia ◽

Board Of Directors ◽

Median Overall Survival ◽

Median Number ◽

World Health ◽

Additional Patient ◽

Complex Karyotype ◽

Advisory Committees ◽

Number Of Cycles

Abstract Background: Acute leukemias of ambiguous lineage (ALAL), including acute undifferentiated leukemia and mixed phenotype acute leukemia (MPAL), are rare hematologic malignancies, accounting for only 2-5% of cases of acute leukemia. Outcomes are generally poor, and retrospective studies have suggested that patients have better outcomes when treated with regimens used for acute lymphoblastic leukemia (ALL) rather than acute myeloid leukemia (AML). Due to heterogeneous definitions and rarity of these leukemias, no single ALL regimen has been studied extensively. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) is one of the most widely used adult ALL regimens in the United States. We retrospectively examined the effectiveness of this regimen as initial therapy in patients with ALAL. Methods: We retrospectively reviewed records from adult patients treated initially with hyperCVAD-based chemotherapy for ALAL as defined by the World Health Organization at five academic institutions. Only patients whose diagnosis was verified at a participating institution were examined. Philadelphia (Ph) chromosome-positive ALAL patients treated concurrently with tyrosine kinase inhibitors were included. The primary objective of the study was to determine the overall response rate (ORR) and median overall survival (OS). Descriptive statistics were used for baseline characteristics and responses, and Kaplan-Meier estimates were used to calculate all time-to-event outcomes. Results: Twenty-two patients were identified, and pre-treatment characteristics are shown in the Table. Median age was 50 years (range, 22-69), with an even distribution of male and female patients (50% each). The majority (77%) were Caucasian. Two patients (9%) had acute undifferentiated leukemia, 11 (50%) T/myeloid MPAL, 8 (36%) B/myeloid MPAL, and 1 (5%) B/T MPAL. Seven (32%) had a complex karyotype (at least 3 abnormalities), 6 (27%) had a normal karyotype, 3 (14%) were Ph-positive and were treated concurrently with dasatinib, and 1 (5%) had an 11q23 rearrangement. FLT3-ITD was detected in 5 of 8 patients (63%) with an available mutation panel. Three (15%) had central nervous system (CNS) involvement at presentation, and one additional patient developed CNS disease during the course of therapy. There were no deaths within the first 30 days, and the median number of cycles given was 4 (range, 1-8). The CR rate was 73% (n=16) and an additional 14% (n=3) had CR with incomplete count recovery (CRi), for an ORR rate of 86%. One patient had a partial response, and 2 patients had no response. Of the 19 patients achieving CR or CRi, median number of cycles to CR was 1.5, and 12 (63%) proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT). Of the 7 responders who did not receive alloHSCT, 3 relapsed shortly after initial CR and 4 are alive and in remission 77, 39, 37 and 10 months from treatment initiation. All 3 patients with Ph-positive disease achieved CR. Only 1 proceeded with alloHSCT and all 3 patients are alive and in remission at 51, 39, and 10 months. With a median follow up of 37 months, 14 (64%) patients were alive and in remission, including 11 who had undergone alloHSCT. Four of the 6 patients who died had a complex karyotype. Median overall survival for the entire cohort was not reached (Figure). Conclusions: HyperCVAD results in high remission rates in patients with ALAL, with low incidence of early mortality and high ability to proceed to allogeneic transplantation following response. HyperCVAD can be considered an effective front-line therapy for patients with ALAL. Additionally, hyperCVAD may be a backbone for incorporation of novel immunotherapies and targeted therapies, which may improve results in patients with appropriate targets. Disclosures Sweet: Astellas: Consultancy; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria; Phizer: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; BMS: Honoraria. Wang:Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy. Al-Kali:Novartis: Research Funding.

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Hematopoietic Stem Cell Transplant in Novel Agent Era Is Associated with Improved Survival in Relapsed and Refractory Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-111476 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1640-1640

Author(s):

Madhav Seshadri ◽

Zhengming Chen ◽

Peter Martin ◽

John P. Leonard ◽

Tsiporah B. Shore ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Board Of Directors ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Cell Lymphoma ◽

Novel Agents ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Novel Agent

Abstract Background Conventional salvage chemotherapy has limited efficacy in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL). In the last decade, several novel agents, including pralatrexate, an antifolate, brentuximab vedotin (BV), a CD30-directed antibody-drug conjugate, and romidepsin, a histone deacetylase inhibitor, have been introduced into clinical practice based on phase 2 data demonstrating efficacy in relapsed/refractory (R/R) diseases. Their impact on real world survival remains to be defined. In this single-center retrospective cohort study we assessed survival including outcomes after hematopoietic stem cell transplant (HSCT) with respect to novel agent exposure. Methods Patients diagnosed with PTCL from 2012-2017 who consented for inclusion in the Weill Cornell lymphoma and bone marrow transplant databases with adequate treatment records were included. Medical records were reviewed for baseline characteristics, treatment course, and outcomes including overall survival and HSCT. Median follow-up time was estimated on overall survival by reverse Kaplan-Meier method. Overall Survival (OS) time was calculated from date of diagnosis to date of death or last follow-up. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test and Cox regression analysis for statistical significance. Results A total of 123 cases were reviewed with median follow-up of 34 months. The major PTCL subtypes were PTCL NOS (N=34, 27.6%), angioimmunoblastic T-cell lymphoma (N=21, 17%), adult T-cell leukemia/lymphoma (N=19, 15.4%), and anaplastic large cell lymphoma (N=14, 11.4%). The most common 1st line chemotherapy regimens were CHOP (N=34, 31.5%), EPOCH (N=21, 19.4%), or CHOEP (N=10, 9.3%). Ninety-two patients had relapsed or refractory disease, and the most common 2nd line therapies were DICE/ICE (N=17, 18.4%), gemcitabine-based regimens (N=6, 7.5%), bendamustine (N=5, 5.4%), hyperCVAD (N=5, 5.4%), or combinations of novel agents. Thirty-three R/R patients received a novel agent, including pralatrexate alone (N=3), BV (N=13), or romidepsin (N=17). Thirty-six R/R patients underwent HSCT, including 26 allogeneic and 10 autologous. Baseline characteristics at diagnosis including age, gender, Ann Arbor stage, ECOG status, and IPI were similar between R/R patients who received a novel agent and those who did not. Although no differences in OS were seen with novel agent use among patients with R/R disease, there was a significant difference in OS among patients who received HSCT and those who did not (p=0.012 by log-rank test). Compared to no HSCT, significantly improved survival was observed in patients receiving allogeneic HSCT (HR = 0.47, p = 0.03) as well as autologous HSCT (HR = 0.27, p= 0.03) by Cox regression survival analysis, both univariate and multivariate when adjusting for interaction with novel agents. Conclusion Data from this single-center retrospective cohort study suggest that hematopoietic stem cell transplant, both autologous and allogeneic, was associated with overall survival benefit in R/R diseases in the novel agent era. The real world impact of novel agents use in PTCL subtypes warrants further study, preferably in a prospectively designed multicenter population study with larger sample size where disease subtypes, therapeutic targets of novel agents, and line of therapies can be sufficiently delineated for response and survival analysis. Disclosures Martin: AstraZeneca: Consultancy; Gilead: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy. Allan:Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Furman:TG Therapeutics: Consultancy; Sunesis: Consultancy; Loxo Oncology: Consultancy; Incyte: Consultancy, Other: DSMB; Gilead: Consultancy; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Verastem: Consultancy; Janssen: Consultancy; AbbVie: Consultancy.

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Characteristics and Outcome of Patients with Core Binding Factor Acute Myeloid Leukemia and FLT3-ITD: Results from an International Collaboration

Blood ◽

10.1182/blood-2019-125317 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2693-2693

Author(s):

Sabine Kayser ◽

Michelle A Elliott ◽

Marlise Luskin ◽

Andrew M. Brunner ◽

Michael Kramer ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Complex Karyotype ◽

Core Binding Factor ◽

Advisory Committees ◽

Allelic Ratio ◽

Binding Factor ◽

Acute Myeloid

Background: Core binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22) and is associated with a favorable outcome, particularly if treated with repetitive cycles of high-dose cytarabine as post-remission therapy. Long-time 10-year overall survival (OS) rate was reported of 58% in FLT3-ITD negative patients (pts; Allen et al. Leukemia 2013). Nevertheless, 30-40% CBF-AML pts experience relapse. FLT3-ITD mutations occur in roughly 5-10% of adult CBF-AML. However, their prognostic relevance is still controversial. Aims: To characterize CBF-AML with FLT3-ITD and compare outcomes according to their genetic background. Methods: We retrospectively studied 65 AML pts with CBF-AML and FLT3-ITD (median age at diagnosis, 54 years; range, 22-81 years) diagnosed between 1996 and 2018 within seven study groups/institutions of the US and Europe. Results: Thirty-two (49%) of the 65 pts harbored t(8;21). Median white blood cell and platelet counts at diagnosis of patients with t(8;21) and inv(16) were 18.3/nl (range, 1.8-202/nl) and 31/nl (range, 7-372/nl), respectively. AML diagnoses were de novo in 61 (94%) and therapy-related in 4 (6%) of the pts. Thirty (46%) pts were female. Cytogenetic analysis revealed additional abnormalities (abn) in 38 (58%) pts, most frequently loss of X or Y (n=13; n=12 associated with t(8;21)), complex karyotype (≥3 abn; n=12; n=7 occurring in t(8;21)), trisomy 22 (n=7, all associated with inv(16)) or trisomy 8 (overall n=6, n=5 occurring in inv(16)). Four pts were positive for both mutations, FLT3-ITD as well as FLT3-TKD. Median ITD allelic ratio were 0.44 (range, 0.003-50) and median ITD size 60 bp (range, 3-120 bp). Three older pts (median age, 75.5 years) were treated with either azacitidine + sorafenib, azacitidine + venetoclax or with etoposide + tipifarnib. All three patients receiving non-intensive therapy died within one year and were excluded from further analysis. Complete remission (CR) after anthracycline-based induction therapy was achieved in 98% (n=61/62) of patients fit for intensive treatment including two pts treated with 7+3 ± midostaurin within the RATIFY trial. One patient died during induction. Fifteen (24%) pts underwent allogeneic hematopoietic cell transplantation. Of those, 10 pts were transplanted in 1st and 5 pts in 2nd CR. Median follow-up for the entire cohort was 4.43 years (95%-CI, 3.35-8.97 years). Median and 4-year relapse-free survival (RFS) rates were 3.41 years (95%-CI, 1.26 years - not reached) and 44.9% (95%-CI, 32.9-61.4%). Median and 4-year overall survival rates (OS) were 4.48 years (95%-CI, 2.26 years - not reached) and 51.8% (95%-CI, 39.6.2-67.9%). Neither type of CBF-AML (p=0.60), nor additional chromosomal abn (p=0.80), nor presence of a complex karyotype (p=0.50) had a prognostic impact on OS. Higher age (≥60 years) was an in trend negative prognostic factor on RFS and OS (p=0.07, each). High allelic ratio (≥0.5) had no impact on RFS (p=0.3), but in trend on OS (p=0.10). Conclusions: Despite a high remission rate pts with FLT3-ITD had an inferior outcome as compared to previously published data on CBF-AML without FLT3-ITD. Thus, CBF-AML with FLT3-ITD should not be classified within the low-risk category. CBF pts with FLT3-ITD warrants further study and should be included in FLT3-inhibitor trials. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Novak:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stoelzel:Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding; JAZZ Pharmaceuticals: Consultancy. Thiede:Daiichi Sankyo: Honoraria; AgenDix GmbH: Employment, Equity Ownership; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Diaceutics: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Levis:Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

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Combinatorial Antigen Targeting Strategy for Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-141540 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Pinar Ataca Atilla ◽

Mary K McKenna ◽

Norihiro Watanabe ◽

Maksim Mamonkin ◽

Malcolm K. Brenner ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Tumor Control ◽

Publicly Traded ◽

Advisory Committees ◽

Car T Cells ◽

Car T Cell ◽

Car T

Introduction: Efforts to safely and effectively treat acute myeloid leukemia (AML) by targeting a single leukemia associated antigen with chimeric antigen receptor T (CAR T) cells have had limited success. We determined whether combinatorial expression of chimeric antigen receptors directed to two different AML associated antigens would augment tumor eradication and prevent relapse in targets with heterogeneous expression of myeloid antigens. Methods: We generated CD123 and CD33 targeting CARs; each containing a 4-1BBz or CD28z endodomain. We analyzed the anti-tumor activity of T cells expressing each CAR alone or in co-transduction with a CLL-1 CAR with CD28z endodomain and CD8 hinge previously optimized for use in our open CAR-T cell trial for AML (NCT04219163). We analyzed CAR-T cell phenotype, expansion and transduction efficacy by flow cytometry and assessed function by in vitro and in vivo activity against AML cell lines expressing high, intermediate or low levels of the target antigens (Molm 13= CD123 high, CD33 high, CLL-1 intermediate, KG1a= CD123 low, CD33 low, CLL-1 low and HL60= CD123 low, CD33 intermediate, CLL-1 intermediate/high) For in vivo studies we used NOD.SCID IL-2Rg-/-3/GM/SF (NSGS) mice with established leukemia, determining antitumor activity by bioluminescence imaging. Results: We obtained high levels of gene transfer and expression with both single (CD33.4-1BBʓ, CD123.4-1BBʓ, CD33.CD28ʓ, CD123.CD28ʓ, CLL-1 CAR) and double transduction CD33/CD123.4-1BBʓ or CD33/CD123.CD28ʓ) although single-transductants had marginally higher total CAR expression of 70%-80% versus 60-70% after co-transduction. Constructs containing CD28 co-stimulatory domain exhibited rapid expansion with elevated peak levels compared to 41BB co-stim domain irrespective of the CAR specificity. (p<0.001) (Fig 1a). In 72h co-culture assays, we found consistently improved anti-tumor activity by CAR Ts expressing CLL-1 in combination either with CD33 or with CD123 compared to T cells expressing CLL-1 CAR alone. The benefit of dual expression was most evident when the target cell line expressed low levels of one or both target antigens (e.g. KG1a) (Fig 1b) (P<0.001). No antigen escape was detected in residual tumor. Mechanistically, dual expression was associated with higher pCD3ʓ levels compared to single CAR T cells on exposure to any given tumor (Fig 1c). Increased pCD3ʓ levels were in turn associated with augmented CAR-T degranulation (assessed by CD107a expression) in both CD4 and CD8 T cell populations and with increased TNFα and IFNɣ production (p<0.001 Fig 1d). In vivo, combinatorial targeting with CD123/CD33.CD28ʓ and CLL-1 CAR T cells improved tumor control and animal survival in lines (KG1a, MOLM13 and HL60) expressing diverse levels of the target antigens (Fig 2). Conclusion: Combinatorial targeting of T cells with CD33 or CD123.CD28z CARs and CLL-1-CAR improves CAR T cell activation associated with superior recruitment/phosphorylation of CD3ʓ, producing enhanced effector function and tumor control. The events that lead to increased pCD3ʓ after antigen engagement in the dual transduced cells may in part be due to an overall increase in CAR expression but may also reflect superior CAR recruitment after antigen engagement. We are now comparing the formation, structure, and stability of immune synapses in single and dual targeting CARs for AML. Disclosures Brenner: Walking Fish: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Tumstone: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Founder; Maker Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Memmgen: Membership on an entity's Board of Directors or advisory committees; Allogene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Atilla:Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Tumstone: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: founder; Marker Therapeuticsa: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties; Allogene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Walking Fish: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Memgen: Membership on an entity's Board of Directors or advisory committees; KUUR: Membership on an entity's Board of Directors or advisory committees.

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T Cell Immunity Toward Viral- and Tumor-Antigens Is Preserved in MDS Patients

Blood ◽

10.1182/blood-2019-126792 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4225-4225

Author(s):

Hussein Hamad ◽

Wingchi K Leung ◽

Spyridoula Vasileiou ◽

Shivani Mukhi ◽

Quillan Huang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Healthy Donor ◽

Tumor Antigens ◽

Ex Vivo ◽

Advisory Committees ◽

Cell Immunity ◽

Healthy Donors ◽

T Cell Lines

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by bone marrow failure and a propensity to progress to acute myeloid leukemia (AML). A core component of the underlying pathogenesis in MDS is deregulation of inflammatory cytokines, such as tumor growth factor-β (TGFβ), which impact the function of immune cells and hence their capacity to mount anti-infective or anti-tumor responses. However, little is known about antigen-specific T cell function in patients with MDS. We hypothesized that virus-specific T cell (VST) function might be preserved in patients with MDS, and that the functional capacity of T cells reactive against tumor-associated antigens aberrantly overexpressed by clonal MDS cells such as Cyclin A1 (CCNA1) and Proteinase (PR3) might also be preserved and exploited for immunotherapeutic purposes. Following informed consent, we collected peripheral blood samples from 10 patients (pts) with MDS and 17 healthy donors. Most pts (9 out of 10) were transfusion dependent and 3 subsequently underwent an allogeneic HSCT. Table 1 summarizes the other clinical characteristics, karyotypic and mutational profile at the time of blood collection. Compared with T cells isolated from healthy donors, MDS patient-derived T cells had a similar CD4 to CD8 ratio (1.5-2.5:1 for healthy donors and 3:1 for MDS pts), but displayed a more exhausted profile at baseline (CD3+TIM3+: 1% in healthy donors and 5% in MDS pts) and produced higher levels of inflammatory cytokines [IFNγ (18±3pg/ml vs 36±16pg/ml, healthy donor vs MDS; p=0.12), and IL-8 (56±32 vs 704±446 pg/ml, p=0.01)]. Next, to assess the capacity of MDS pts to mount ex vivo functional virus-directed responses, we stimulated patient-derived PBMCs (n=5) with overlapping peptide libraries (pepmixes) spanning immunogenic AdV, CMV, EBV, BK and HHV-6 antigens. Similar to healthy donor-derived T cell lines (n=5, 3 specific for 4 viruses and 2 for 5 viruses), all 5 MDS patient-derived lines demonstrated specificity for one or more of the target viruses (1 for 5 viruses, 1 for 4, 2 for 3 and 1 for 1 virus) as observed by IFNγ ELISpot assay with comparable magnitude (range Adv: 43-730 vs 384-941 in healthy donors, CMV: 0-1599 vs 0-3002, EBV: 0-1486 vs 0-541, BK: 0-839 vs 38-275 and HHV6: 0-794 vs 5-407 SFU/2x105 cells, respectively). We next examined the feasibility of expanding autologous MDS-antigen directed T cell products (n=10) to determine whether an adoptive immunotherapeutic approach might be applicable for MDS treatment. Thus, we exposed patient-derived PBMCs to autologous dendritic cells (DC) loaded with pepmixes spanning 6 MDS-associated antigens (CCNA1, survivin, WT1, PRAME, PR3 and NYESO1). After 3 rounds of stimulation, the products obtained were predominantly CD3+ T cells (mean 88±1.3%) that were polyclonal (CD4: 46±5% and CD8: 41±4%) containing predominantly memory T cells (TEM: 36±6% TCM: 37±5% and Tnaïve =13±3%). Six lines (60%) showed specific recognition to at least one of the target antigens: 4 lines specific for PRAME, 1 for CCNA1, 1 for WT1 and 1 for NYESO1 (range 0-40, 0-184, 0-1386 and 0-179 SFU/2x105 cells, respectively by IFNγ ELIspot). T cell lines were capable of specifically secreting multiple effector cytokines in response to targets (TNFα: 12% and IFNγ: 16% in response to PRAME in a representative patient-derived T cell line). Furthermore, this line was capable of killing PRAME+ targets in a 4hr 51Cr release assay [60% specific lysis, E:T 20:1]. In conclusion, functional virus-directed T cell immunity in patients with MDS is preserved, potentially explaining the lower rates of viral reactivation seen in these patients compared with other infections. Moreover, T cells specific for MDS-expressed tumor antigens can also be successfully expanded ex vivo from patients. Taken together this raises the possibility of applying an adoptive immunotherapeutic approach for the treatment of MDS. Disclosures Ramos: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding. Leen:Allovir: Consultancy, Other: Cofounder, Ownership Interest; Marker Therapeutics: Consultancy, Other: Cofounder, Ownership Interest.

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Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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