Kyowa Hakko Kirin Pharma Research Articles

Chemotherapy-Related Mutational Signatures Reveal the Origins of Therapy-Related Myeloid Neoplasms

Chemotherapy-Related Mutational Signatures Reveal the Origins of Therapy-Related Myeloid Neoplasms

Machine Learning of Genomic Factors in 1,961 Patients with Acute Myeloid Leukemia Identifies Patients with Very Good or Very Poor Prognosis Who Do Not Benefit from Allogeneic Hematopoietic Cell Transplant in First Remission

Genomic profiling contributes to assessment of suitability for allogeneic hematopoietic cell transplant (alloHCT) in Acute Myeloid Leukaemia (AML). The ELN 2017 AML risk classification identifies patients with favorable, intermediate and adverse risk (Döhner 2017). We have used supervised machine learning (ML) to prognostically risk stratify patients with AML and explore whether prognostic groups benefit from alloHCT in first complete remission (CR1) based on pre-treatment stratification.1961 patients were identified across the German Acute Myeloid Leukemia Study Group (AMLSG, n=1315) and National Taiwan University Hospital (NTUH, n=646) who had sufficient cytogenetic and genomic information available including the ELN 2017 cytogenetic and genomic abnormalities, spliceosome, cohesin complex and the fifteen most common genomic alterations from the Cancer Genome Atlas dataset (Ley 2013). A supervised machine learning model within R (version 4.1.0) employed a combination of random forest analysis (utilising the RandomForestSRC module version 2.11.0) and recursive partitioning (utilising the Rpart module version 4.1-15) to identify prognostic groups categorised into quintiles based upon 4-year overall survival (OS) into very poor, poor, intermediate, good and very good prognostic groups (A). Outcome according to alloHCT in CR1 was then determined by a time-dependent analysis comparing patients who in CR1 who did/or did not receive an alloHCT and were alive at 147 days (median time to transplant in the cohort). The prognostic groups were then validated against a separate AML cohort (Montreal Leucegene cohort)Patients defined by ML classification (figure 1A) to have very poor risk included patients with complex karyotype and either -7, del(7q), -17, del(17p), abn(17p) or TP53 mutations; EVI1 abnormalities (inv(3)/t(3;3)) and combined spliceosome and ASXL1 mutations. These patients had a very poor outcome irrespective of alloHCT in CR1 with a 4yr OS of 13% vs 15% (p=0.24) (alloHCT vs no-alloHCT). Patients with the combination of bi-allelic CEBPA and NRAS mutations, or the combination of NPM1, NRAS and Cohesin mutations had very good prognosis and failed to derive survival benefit from alloHCT in CR1 (4yr OS 80% vs 96% (p<0.05)) (figure 1B). Patients with either good, intermediate and poor prognosis all demonstrated improvement in OS with alloHCT in CR1 (good prognosis 90% vs 74% (p<0.05), intermediate 65% vs 50%mo (p<0.05) and poor 50% vs 31% (p<0.05)(figure 1B).ML AML classification defines two groups of patients who may not benefit from an alloHCT in CR1. Patients with very good prognosis may avoid the toxicity associated with transplantation with expectation of equivalent outcomes to those in receipt of alloHCT. Patients with very poor prognosis also fail to derive survival benefit from transplantation and represent candidates for novel post-remission strategies to improve the natural history of their disease. As this data predates the usage of FLT3 inhibitors and other novel therapies such as liposomal cytarabine/daunorubicin the impact of these therapies on patient outcome will warrant future consideration. [Display omitted] DisclosuresFleming: Amgen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Servier: Honoraria. Döhner: AstraZeneca: Honoraria; GEMoaB: Honoraria; Novartis: Honoraria, Research Funding; Helsinn: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Agios: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding. Döhner: Abbvie: Consultancy, Honoraria; Jazz Roche: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Astellas: Research Funding; Agios and Astex: Research Funding; Daiichi Sankyo: Honoraria, Other: Advisory Board; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Tien: AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Reynolds: Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company; Novartis AG: Current equity holder in publicly-traded company. Wei: Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy.

Whole Transcriptome Analysis Identifies Distinct Gene Expression Profiles between SF3B1mut and SF3B1 wt Myelodysplastic Syndrome with Ring Sideroblasts

Background and aims - The 2016 revised WHO classification incorporated somatic mutation in SF3B1 spliceosome gene within the diagnostic criteria of myelodysplastic syndrome (MDS) with ring sideroblasts (RS). However, SF3B1wt MDS-RS display significantly different clinical features and outcome from those of SF3B1mut MDS-RS. Recently, the recognition of SF3B1-mutant MDS as a distinct nosologic entity has been proposed to overcome this limitation.Methods - To evaluate the biological relevance of this proposal, we studied a consecutive cohort of 132 MDS with RS >5% using a pangenomic approach (targeted-DNA sequencing, genome-wide copy number variation analysis and bulk RNA-sequencing of CD34+ bone marrow mononuclear cells). 16 age-matched healthy individuals and 43 MDS-SLD/MLD negative for both splicing mutation and RS were included in this study as controls.Results - Unsupervised clustering analysis based on mutation profiles identified two major clusters predicted by SF3B1 mutation (87 MDS-RS-SF3B1mut and 45 MDS-RS-SF3B1wt). The most recurrently mutated genes in MDS-RS-SF3B1wt were TP53(40%), SRSF2(38%), TET2 (33%), ASXL1 (21%) and DNMT3A (12%). SRSF2 and TP53 mutations were found to be mutually exclusive with SF3B1 (p-value <0.05), whereas no difference was found in TET2, DNMT3A and ASXL1 frequencies between MDS-RS-SF3B1 mutand MDS-RS-SF3B1wt subgroups. TP53-mutated MDS-RS exhibited shorter overall survival (median 1.3 years, log-rank p-value<0.0001) compared to SF3B1mut (median 7.6 years), SRSF2mut (median 3.4 years) and MDS-RS without the abovementioned aberrations (median 4.4 years). Notably, allelic imbalances analysis of oncogenic variants identified a significant enrichment of TP53 biallelic inactivation in MDS-RS-SF3B1wt (64% vs 0, p<0.01).Differential gene expression analysis results were incorporated into a specific expression signature highly predictive of MDS-RS-SF3B1 mutand MDS-RS-SF3B1wt subgroups (Figure 1). The resulting gene clusters were classified in RS-specific genes (cluster 1 and 2) and SF3B1-specific genes (cluster 3 and 4). RS-specific genes comprising heme and hypoxia genes were enriched (Figure 2AB) and correlated with RS percentage (p<0.01). Pathway analysis revealed a specific downregulation of adhesion molecules and an upregulation of G-protein coupled receptor signaling molecules in MDS-RS-SF3B1mut. Among SF3B1-specific genes (Figure 2CD), we confirmed ABCB7 downregulation and identified new molecular targets that may concur to the pathophysiology of SF3B1-driven myeloid neoplasms.Conclusions - This study contributes to unveil molecular features of SF3B1-mutant MDS and provides further evidence to support recognition of somatic SF3B1 mutation as a disease-defining genetic lesion. DisclosuresPapaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy.

The Genomic Landscape of Waldenström Macroglobulinemia Reveals Sustained Germinal Center Activity and Late-Developing Copy Number Aberrations

The Genomic Landscape of Waldenström Macroglobulinemia Reveals Sustained Germinal Center Activity and Late-Developing Copy Number Aberrations

Isogenic MDS-RS Patient-Derived iPSCs Define the Mis-Spliced Transcript Repertoire and Chromatin Landscape of SF3B1-Mutant Hematopoietic Stem/Progenitor Cells

▪The somatic hotspot mutation SF3B1K700E is characteristically found in myelodysplastic syndrome with ring sideroblasts (MDS-RS) and frequently occurs as an isolated mutation. However, our understanding of how this mutation drives MDS pathogenesis remains limited. To explore the downstream consequences of the SF3B1K700E mutation and its role in disease pathogenesis, we generated a panel of isogenic SF3B1K700E and SF3B1WT induced pluripotent stem cell (iPSC) lines from 3 MDS-RS patients with isolated SF3B1K700E mutation (3 SF3B1K700E and 3 SF3B1WT lines per patient, total 18). Upon hematopoietic differentiation, SF3B1K700E cells exhibited lower growth and colony-forming ability, compared to SF3B1WT cells, recapitulating hallmark phenotypes of MDS cells.To investigate the effects of the SF3B1K700E mutation on the transcriptome and chromatin landscape, we performed RNA- and ATAC- sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from the panel of the 18 isogenic SF3B1K700E and SF3B1WT iPSC lines. Principal component analysis (PCA) and hierarchical clustering based on gene expression grouped the iPSC lines primarily by genotype (SF3B1K700E vs SF3B1WT) and secondarily by genetic background. To assess the impact of the SF3B1K700E mutation at the exon, transcript and gene level, we developed an analytical framework integrating differential splicing with differential transcript usage and differential gene expression analyses. We thus discovered 59 splicing events linked to 34 genes (most statistically significant events that also mapped to differentially used transcripts and differentially expressed genes). This SF3B1K700E splicing signature includes genes previously reported as mis-spliced in SF3B1K700E cells (e.g BRD9, ABCB7), as well as novel genes. We tested this signature against a published dataset of primary MDS patient samples (Pellagatti et al.). PCA based on the inclusion level of the splicing events of our signature separated SF3B1-mutated MDS patients from patients without splicing factor mutations (SF-WT) or healthy individuals. Furthermore, it identified one patient erroneously annotated as SF-WT that clustered together with the SF3B1-mutated patients, who had a, previously overlooked, 6bp in-frame deletion spanning the K700E hotspot.By comparing the chromatin accessibility profiles of SF3B1K700E and SF3B1WT iPSC-HSPCs to those defined in primary human cell types along the hematopoietic hierarchy (Corces et al.), we found that the chromatin landscape of SF3B1K700E HSPCs resembled more this of megakaryocyte-erythroid progenitor cells (MEPs) and erythroid cells, whereas that of SF3B1WT HSPCs resembled more granulocyte-monocyte progenitors (GMPs) and monocytes. This finding may underlie the more prominent involvement of the erythroid lineage in the pathology and clinical presentation of MDS-RS. To interrogate transcriptional programs in SF3B1K700E mutant cells, we performed transcription factor (TF) motif enrichment analysis. Motifs enriched in ATAC-Seq peaks more accessible in SF3B1K700E cells that were linked to genes upregulated in SF3B1K700E cells, included motifs of several TFs with known roles in hematopoiesis (GATA, ETS, STAT, AP-1). Unexpectedly, motifs of the TEAD TFs were also enriched. The TEAD family of TFs are best known as effectors of the Hippo signaling pathway, with important roles in various biological processes and malignancies, albeit no clear links to adult hematopoiesis or hematologic disease. TEAD2 and TEAD4 were upregulated in SF3B1-mutant, compared to the WT, iPSC-HSPCs and TEAD transcriptional activity, measured with a luciferase reporter construct, was higher in SF3B1K700E, compared to SF3B1WT iPSC-HSPCs. We did not find expression or activation of YAP or TAZ, which bind to DNA as a complex with TEAD upon Hippo pathway activation. These results support a Hippo-independent increase of TEAD expression and activity in SF3B1K700E cells.In summary, we generated a panel of isogenic patient-derived iPSCs that allowed us to comprehensively characterize the transcriptome and chromatin landscape of SF3B1K700E HSPCs in an isogenic system, derive a splicing signature of SF3B1K700E and identify the TEAD TF as a new transcriptional regulator of SF3B1K700E mutant HSPCs.G. Asimomitis, A.G. Deslauriers: shared 1 st authorshipE. Papaemmanuil, E.P. Papapetrou: shared senior authorship DisclosuresDeslauriers: Novo Nordisk A/S: Current Employment. Hellström-Lindberg: Celgene: Research Funding. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy.

PET-Based Staging Reduces the Prognostic Impact of Early Disease Progression in Patients with Follicular Lymphoma

Background: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods: In this retrospective study, we identified 1,088 patients with grade 1-3A FL of whom 238 patients with stage II-IV disease were initially treated with R-CHOP and 346 patients treated with R-chemotherapy. Patients (N=484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (PET, vs. CT) and early POD status using event defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Findings: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had 5-year OS of 57·6% for CT-staged patients compared with 70·6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53·9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients compared with PET-staged patients (16·7% vs. 6·3%), which was associated with a 9.7 fold higher risk for death. Interpretation: In FL, pre-treatment PET-staging reduced the prognostic impact of early POD compared with CT-staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy. Funding: NCI Cancer Center Support Grant (P30 CA008748). Declaration of Interest: 1) Connie L. Batlevi: Research Support: Janssen, Novartis, Epizyme, Xynomics; Honorarium: Dava Oncology. 2) Fushen Sha: None 3) Anna Alperovich: None. 4) Andy Ni: None. 5) Katy Smith: None 6) Zhitao Ying: None. 7) John F. Gerecitano: Currently employed by Janssen. Honoraria: Bayer, Epizyme, Roche, Genentech, Abbvie. 8) Paul A. Hamlin: consultancy at Portola Pharmaceutics, Celgene, Karyopharm, Juno Therapeutics; research funding from Portola, Molecular Templates, Incyte, JJ research funding from ADCT therapeutics, Aileron,Celgene, Forty-Seven, Infinity/Verastem, Kyowa-Hakka-Kirin, Millenium/Takeda, Seattle Genetics, Trillium. 10) Anita Kumar: Research Support: Abbvie, Adaptive Biotechnologies, Celgene, Pharmacyclics, Seattle Genetics; Scientific Advisory Board: Celgene. 11) Matthew J. Matasar: Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle Genetics, GlaxoSmithKline. Consulting: Genentech, Bayer, Merck, Juno, Roche, Teva, Rocket Medical, Seattle Genetics. Research: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics. Travel: Genentech, Roche, Seattle Genetics, Bayer. 12) Alison J. Moskowitz: consultancy at Kyowa Hakko Kirin Pharma, Miragen Therapeutics, Takeda Pharmaceuticals, ADC therapeutics, Seattle Genetics, Cell Medica, Bristol-Myers Squibb, Erytech Pharma; research funding from Incyte, Seattle Genetics, BMS, and Merck. 13) Craig H. Moskowitz: Consulting: Astra Zeneca, BMS, Karyopharm Therapeutics, Merck, Seatle Genetics, Takeda, Vaniam Group; Scientific Advisory Board: Astra-Zeneca, Karyopharm Therapeutics, Merck, Seattle Genetics, Takeda, Vaniam Group; Research support: BMS, Merck, Seattle Genetics. 14) Ariela Noy: Research funding from Pharmacyclics, NIH, Raphael Pharma; consulting for: Janssen, Pharmacyclics, Medscape, Targeted Oncology. 15) Maria Lia M. Palomba: Honoraria from Merck, Celgene, Juno and Pharmacyclics. 16) Carol Portlock: None 17) David Straus: Advisory Board and research support: Seattle Genetics. 18) Andrew D. Zelenetz: consultancy at Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotechnology; research funding MEI Pharma, MorphoSys, Sandoz, Celgene, Roche, Gilead; Board of Directors (DMC Chair) Beigene. 19) Venkatraman E Seshan: None. 20) Stefano Luminari: Consulting/Advisory boards: Roche, Celgene, Sandoz, Gilead 21) Luigi Marcheselli: None. 22) Massimo Federico: Research support: Mundipharma s.r.l., Chephalon/Teva, Celgene, Millennium/Takeda, and Roche. Consulting/Advisory boards: Takeda, Roche, Celgene, Sandoz, and Spectrum. 23) Anas Younes: Research Support: Janssen, Curis, Merck, BMS, Syndax, and Roche; Honorarium: Janssen, AbbVie, Merck, Curis, Epizyme, Roche, Takeda; Consulting: Biopath, Xynomics, Epizyme, Roche. Ethical Approval: This is a retrospective study of adult patients (≥18 years old) diagnosed between the years of 1998 to 2009 with FL managed at Memorial Sloan Kettering Cancer Center (MSKCC). The institutional review board approved this study.

Clinical Benefit of Adalimumab Dose Adjustment for Patients With Moderately to Severely Active Crohn’s Disease in EXTEND

Clinical Benefit of Adalimumab Dose Adjustment for Patients With Moderately to Severely Active Crohn’s Disease in EXTEND

Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia

X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.

HLA Haplo-Identical Peripheral Blood Stem Cell Transplantation Using High-Dose Cyclophosphamide Post-Transplantation For Poor Prognosis Or Refractory Acute Leukemia and Myelodysplastic Syndrome: A Prospective Pilot Study At a Single Center

Recently nonmyeloablative, haplo-identical T-cell replete bone marrow transplantation using high-dose cyclophosphamide (CY) post-BMT to control GVHD and prevent graft rejection by inducing bi-directional tolerance was reported. This strategy resulted in promising outcomes with low transplantation-related mortality (TRM) due to a low incidence of GVHD and infectious disease. However, the high relapse rate remained a major problem in high-risk hematological disease. We therefore planned a prospective pilot study of myeloablative or reduced intensity HLA haplo-identical allogeneic hematopoietic cell transplantation (HCT) using reduced doses of CY post-transplantation, followed by administration of peripheral blood stem cells (PBSC) instead of bone marrow, for those with a poor-prognosis or refractory leukemia and MDS.As of 30 June 2013, 17 patients had been enrolled in this prospective pilot study. Patients with a poor prognosis or refractory leukemia and MDS requiring prompt HCT were eligible for this study if they lacked a donor who was serologically HLA-identical or had a single antigen mismatch.The conditioning regimen consisted of fludarabine 15 mg/m2 and cytarabine 2.0 g/ m2 twice a day on days -11 and -10, thymoglobulin 2.0 mg/kg on days -8 and -7, and fludarabine 30 mg/ m2/day with intravenous busulfan 3.2 mg/kg/day on days -6 to -3 (n=11) or melphalan 100 mg (n=6) on day -2. Nine patients received a single dose of 25 mg/kg CY on day 3 and eight patients, double doses of 25 mg/kg CY on days 3 and 4 post-peripheral blood stem cell transplantation (PBSCT). Tacrolimus and oral mycophenolate mofetil was started after the completion of high-dose CY post-HCT.The median age of patients was 42 years (range 18–65). Disease diagnoses included AML (n=14), ALL (n=2) and MDS (n=1). In 12 (71%) of 17 patients, disease status was non-remission, with active disease at the time of PBSCT. Eight (47%) of 17 patients had a history of prior HCT. Donors were partially HLA-mismatched (haplo-identical) first degree relatives of the patients and differed from the patients at a median of 3/8 HLA loci in both the HVG and GVH directions. All patients received G-CSF-mobilized, unmanipulated PBSC containing a median of 3.0 x 106 CD34+cells/kg and 1.4 x 108CD3+T-cells/kg.Non-infectious fever due to PBSC infusion occurred in 14 (82%) patients and persisted until day 2 in most patients. Except for one patient who died soon after PBSCT due to disease progression, full donor T-cell chimerism was achieved at day 30 following PBSCT in all patients. Nine of 17 developed grade II-III acute GVHD. None developed grade IV acute GVHD. Three of nine patients receiving a single dose of CY, but only one of eight patients receiving double doses of CY developed grade III acute GVHD. In 12 of 16 evaluable patients, CMV reactivation was observed by day 100. Three patients developed CMV disease. BK virus cystitis occurred in four of eight patients receiving double doses of CY, however, none receiving a single dose of CY post-PBSCT developed BK virus cystitis. The cumulative incidence of TRM at one year was 13%. At one year, the overall survival of all patients, and the percentages of patients in remission and those with active disease were 43%, 75% and 31%, respectively.The results of our study demonstrated that our HLA haplo-identical transplantation using high-dose CY post-PBSCT resulted in a low incidence of TRM and was feasible even in patients with high-risk acute leukemia and MDS as an alternative stem cell source. Of note, the dose of CY post-PBSCT affected the incidence of both BKV cystitis and severe GVHD. The optimal dose of CY following HLA haplo-identical PBSCT and preparative regimen should be further explored to establish a standard regimen. Disclosures:Nakamae:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Off Label Use: Mycophenolate mofetil was used as one of drugs for acute GVHD prophylaxis. Koh:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nishimoto:Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakashima:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nagasaki:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakane:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Speakers Bureau, Travel/accommodations/meeting expenses Other. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Travel/accommodations/meeting expenses Other. Hino:Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.

Romidepsin Is Effective and Well-Tolerated In Patients ≥ 60 Years Old With Relapsed Or Refractory Peripheral T-Cell Lymphoma (PTCL): Analysis From Phase 2 Trials

BackgroundPTCL is a heterogeneous group of mature, post-thymic, T- and natural killer–cell disorders associated with a poor prognosis in most subtypes. Anthracycline-based therapies (eg, CHOP) are most often used in the frontline treatment of PTCL, although they do not typically lead to durable remissions. Older patients may not be eligible for additional chemotherapeutic regimens due to comorbidities and/or poor performance status. Thus, it is important to identify appropriate treatment strategies for older patients with PTCL, particularly in the salvage setting. Romidepsin is a potent class I histone deacetylase inhibitor approved by the FDA for the treatment of patients with PTCL who have received ≥ 1 prior therapy and patients with cutaneous T-cell lymphoma who have received ≥ 1 prior systemic therapy. Approval of PTCL was based on results from the pivotal study of romidepsin for the treatment of relapsed/refractory PTCL (N = 131) that demonstrated durable clinical benefit and tolerability and was supported by a similar study from the National Cancer Institute (N = 47). The objective herein is to present efficacy and safety data for romidepsin specific to older patients (≥ 60 years) with relapsed/refractory PTCL in the pivotal and supportive trials. MethodsIn both trials, patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles. For the pivotal trial, the primary endpoint was confirmed/unconfirmed complete response (CR/CRu) determined by an independent review committee. For the supportive trial, the primary endpoints were objective response rate (ORR) and rate of CR by investigator assessment. In this analysis, efficacy and safety data for patients ≥ 60 years old were examined and compared with those for the overall study population. ResultsIn the pivotal study, the overall median age was 61 years (range, 20-83); 71/130 patients (55%) were ≥ 60 years old (median 67 years [range, 60-83]) with a median of 2 prior systemic therapies (range, 1-8), including prior stem cell transplant in 7 patients. Response rates in the older population were similar to those seen overall: 25% ORR for both populations, including 14% and 15% with CR/CRu for older vs overall populations, respectively. Also, in both the older and overall populations, the median DOR was 28 months, with the longest response ongoing at 48 months (median follow-up 22.3 months). Of the 10 older patients who achieved CR/CRu, 6 had a DOR of ≥ 12 months. Survival was also similar, with 5 and 4 months PFS and 12 and 11 months OS for the older vs overall populations, respectively. In the supportive trial, the overall median age was 60 (range, 27-84); 23/47 patients (49%) were ≥ 60 years old (median 68 years [range, 61-84]) with a median of 2 prior regimens (range, 1-8), including prior stem cell transplant in 7 patients. Response rates in the older population were similar to those seen overall: 32% and 38% ORR, including 14% and 18% with CR, respectively. The median DOR was 5 months (range, 3-49) and 9 months (range, 2-74+) for the older vs overall populations, respectively. One 79-year-old patient with 6 prior systemic therapies achieved CR on romidepsin and stopped therapy after 6 cycles in consideration of his age. Off therapy, disease progression was observed; romidepsin was restarted per protocol and patient achieved a second CR, receiving an additional 22 cycles of therapy. In both the pivotal and supportive trials, rates of grade ≥ 3 adverse events were similar for the overall vs older patient populations (Table). ConclusionsIn phase 2 trials of romidepsin for the treatment of relapsed/refractory PTCL, patients aged ≥ 60 years comprised approximately half of patients. Both efficacy and safety were similar for the older vs overall populations. Thus, data were not skewed due to age, and romidepsin is suitable for use in elderly patients with relapsed/refractory PTCL. Disclosures:Shustov:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Coiffier:Celgene Corporation: Consultancy; Spectrum Pharmaceuticals: Consultancy. Horwitz:Celgene Corporation: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; Seattle Gen: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Kyowa Hakko Kirin Pharma: Research Funding; Millenium: Consultancy, Research Funding; Genzyme: Consultancy; Janssen: Consultancy. Sokol:Celgene Corporation: Consultancy, Speakers Bureau; Gloucester: Research Funding. Pro:Celgene Corporation: Honoraria. Nielsen:Celgene Corporation: Employment, Equity Ownership. Balser:Celgene Corporation: Consultancy. Prince:Celgene Corporation: Honoraria, Research Funding. Allen:Celgene Corporation: Honoraria. Bates:Celgene Corporation: Research Funding.

Cytomegalovirus Reactivation After Allogeneic Stem Cell Transplantation Is Associated With a Reduced Risk Of Relapse In Patients With Acute Myeloid Leukemia: The Japan Society For Hematopoietic Cell Transplantation (JSHCT) Transplantation-Related Complication Working Group

▪ BackgroundCytomegalovirus (CMV) infection is still a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Recently, it is reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study is to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSC in a large cohort of patients. Patients and MethodsThe Transplantation-related Complication Working Group of JSHCT retrospectively surveyed the database of the Transplant Registry Unified Management Program (TRUMP) at the JSHCT. Patients with AML (n=1836), acute lymphoblastic leukemia (ALL) (n=911), chronic myeloid leukemia (CML) (n=223) and myelodysplastic syndrome (MDS) (n=569) who underwent their first allo-HCT from HLA matched related or unrelated donors between 2000 and 2009, and who survived without disease relapse until day 100 after transplantation were analyzed. Patient who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment and the start of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, non-relapse and overall mortality. CMV reactivation and acute/chronic GVHD were evaluated as time-dependent covariates. ResultsCMV reactivation was associated with a decreased cumulative incidence of relapse among patients with AML (20.3% versus 26.4%, p=0.027), but not in patients with ALL, CML or MDS by Gray's test. Among 1836 AML patients, CMV reactivation occurred in 795 patients (43.3%) at median 42 days (-8 - 407 days), and 436 patients (23.7%) relapsed at median 221 days (101-2057 days) after allo-HCT. Grades II to IV acute GVHD developed in 630 patients (34.3%). On multivariate analysis taking competing risk factors into account, three factors significantly associated with a decreased risk of AML relapse: CMV reactivation (HR 0.765, 95%CI 0.59-0.99), unrelated donor compared to related donor (HR 0.593, 95%CI 0.42-0.84) and development of chronic GVHD (HR 0.773, 95% CI 0.60-0.99). However, no benefit in relapse-free survival associated with CMV reactivation was observed (HR 1.025, 95%CI 0.85-1.24). CMV reactivation was associated with increased non-relapse mortality (HR 1.160, 95%CI 1.02-1.32) and overall mortality (HR 1.370, 95%CI 1.11-1.69). Pre-transplant CMV serostatus was not extracted as a risk factor for relapse, non-relapse and overall mortality. ConclusionsA beneficial effect of CMV reactivation on the subsequent relapse risk was observed in patients with AML but no other hematological malignancies in our large cohort study. However, this benefit was canceled out by the increased non-relapse mortality. The underlying mechanism is unclear, but the immunological activation against CMV reactivation plays an essential role in this association. Thus, the immune augmentation treatment options including vaccination and adoptive T-cell transfer might be useful to take advantage of the efficacy of CMV reactivation with minimal increase of non-relapse mortality. Disclosures:Miyamura:Novartis: Speakers Bureau; JRC Nagoya 1st Hospital: Employment. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other. Fukuda:the Japanese Ministry of Health, Labour, and Welfare: Research Funding.

Clinical and Economic Burden Of Peripheral T-Cell Lymphoma In The United States

BackgroundPeripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma (NHL). PTCL has a poor prognosis due to advanced stage at presentation, and generally poor response to standard chemotherapy. According to recent SEER estimates, PTCL accounts for about 4% of all NHL cases in the United States each year. To date, few studies have assessed the clinical and economic burden of PTCL. MethodsMarketScan data for commercially insured and Medicare supplemental patients were used to retrospectively identify unique PTCL patients. Patients were identified by ICD-9-CM diagnosis codes between October 1, 2007 and June 30, 2011. The time of first PTCL diagnosis code served as the index date, and a second PTCL diagnosis date was used for confirmation. All patients were required to have at least 6 months of continuous enrollment before and 12 months of continuous enrollment after their index date. Patients were excluded if aged <18 years, date of birth or gender were missing, or if they had received a stem cell transplant (SCT) prior to PTCL diagnosis. The control group includes patients that may have any other malignant (excluding PTCL) or non-malignant condition and are considered to represent an average insured patient population from the payer perspective. The control group was matched based on age, sex, region, plan type, payer type, and length of enrollment. Mean cost per month was measured and annualized to provide average yearly costs. Healthcare costs included hospitalizations, pharmacy services, office visits, emergency room visits, hospice stays, SCT, and other patient-related costs (lab procedures, radiology procedures, blood transfusions, and other ancillary procedures). ResultsOf 2820 patients with ≥1 PTCL diagnosis, 1000 patients were identified that met all inclusion criteria (mean age 56 years, 58% male), and were matched to the control group. On an average annual basis, PTCL patients were hospitalized more often (0.9 vs 0.1 hospitalizations), and experienced a longer length of stay (6.4 vs 4 days) compared with matched controls. In addition, PTCL patients had a higher utilization of office visits (16.2 vs 4.1 visits), pharmacy services (34.2 vs 11.6 prescriptions), emergency room visits (0.8 vs 0.2 visits), and hospice care (0.6 vs 0.1 stays). PTCL patients also experienced higher comorbidities (mean Charlson Comorbidity Index of 1.72 vs 0.39, as determined at index date). Overall, PTCL patients incurred much higher average annual costs compared with matched patients ($75,934.08 vs $4660.64; Table), driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). ConclusionsPTCL is associated with high resource utilization rates and high overall costs. The development of efficacious treatments for PTCL may offer better disease management and may reduce the clinical and economic burden of PTCL. Disclosures:Potashman:Millennium: The Takeda Oncology Company: Employment. Burudpakdee:Millennium: The Takeda Oncology Company: Consulting researcher Other. Wang:Millennium: The Takeda Oncology Company: Consulting researcher Other, Research Funding. Zhu:Millennium: The Takeda Oncology Company: Employment. Carson:Millennium: The Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Research Funding.

Correlation of Target Molecule Expression and Overall Response in Refractory Cutaneous T-Cell Lymphoma Patients Dosed with Mogamulizumab (KW-0761), a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4)

AbstractAbstract 3697 Introduction:The CC chemokine receptor 4 (CCR4) is over expressed in most cutaneous T-cell lymphomas (CTCL), and is a potential target for anti-neoplastic therapy in these disorders. Mogamulizumab (KW-0761), a humanized monoclonal antibody with enhanced antibody dependent cellular cytotoxicity has shown promising activity in a Phase 1/2 study in refractory CTCL. Study Design:This study assessed the relationship between baseline CCR4 expression levels and tumor response to mogamulizumab in a phase 1/2 study in refractory CTCL. Patients were dosed with mogamulizumab iv as monotherapy, once weekly for four weeks in the first cycle, then every two weeks on subsequent cycles. A global response score was assigned, as a composite of the response in all compartments (skin, lymph nodes, viscera) with response in blood also considered for subjects with significant blood involvement. CCR4 expression levels were determined by both immunohistochemistry (IHC%) on skin biopsy samples and flow cytometric (FC%) analysis of peripheral blood (PB) specimens using the murine parent antibody for mogamulizumab. Logistic regression models were used to assess response as a function of both IHC% and FC%, on IHC% and FC% separately, and with disease type [Mycosis fungoides (MF) or Sezary Syndrome (SS)] in the model. Results:Patients were treated with mogamulizumab at 0.1 mg/kg (n=3), 0.3 mg/kg (n=3), or 1.0 mg/kg (n=36). Thirty eight patients (21MF and 17 SS) were evaluable for tumor response and the overall response rate was 37% (29% in MF and 47% in SS). Thirty (30) patients had IHC evaluable skin biopsy specimens at baseline and 28 patients had identifiable PB lymphoma cells by FC in pre-treatment specimens. In all, 35 patient samples were evaluated for CCR4 expression by at least one method. All 28 patients with identifiable PB lymphoma cells were confirmed to be CCR4-positive by FC, and 73% (22/30) of skin biopsy samples showed staining by IHC above background (>5% lymphocytes in skin lesions positive for CCR4). 89% (31/35) of patient samples were positive by at least one method. Logistic regression analyses found no statistical evidence that IHC% or FC% are significant predictors of response, either independently or when disease type is included in the model (p-values >.05 in all cases). Plots of response to mogamulizumab versus CCR4 expression are given below: [Display omitted] Conclusions:CCR4 was confirmed to be expressed in most of the CTCL patients. Its expression levels had no correlation to response to mogamulizumab in this phase 1/2 study. Further studies with larger sample size are warranted to determine whether measurement of CCR4 expression in diagnostic biopsies may provide clinical utility in predicting mogamulizumab response. Disclosures:Duvic:Allos: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Biocryst: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Research Funding; Eisai Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Eli Lilly and Company: Research Funding; Galderma: Research Funding; Hana Biosciences, Inc.: Research Funding; Hoffman-La Roche, Ltd.: Consultancy; Infinity Pharma: Consultancy; Kyowa Hakko Kirin Pharma, Inc. : Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; NAAF: Research Funding; NIH: Research Funding; Novartis Pharma: Consultancy, Research Funding; Pfizer Inc.: Research Funding; Quintiles Pharma: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shape: Consultancy, Research Funding; Sloan-Kettering: Research Funding; Spectrum: Research Funding; Therakos, Inc.: Research Funding; Topotarget: Research Funding; Yaupon Therapeutics, Inc.: Research Funding. Pinter-Brown:Allos Therapeutics: Consultancy; Millenium/Seattle Genetics: Consultancy. Foss:Allos: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Eisai: Consultancy; Merck: Study Grants Other; Celgene: Study Grants, Study Grants Other. Sokol:Celgene: Honoraria, Speakers Bureau. Ni:Kyowa Hakko Kirin Pharma, Inc: Research Funding. Dwyer:Kyowa Hakko Kirin Pharma, Inc. : Employment. Mohamed:Kyowa Hakko Kirin Pharma, Inc. : Employment. Kim:Allos: Consultancy, Research Funding; Kyowa Kirin Pharma, Inc.: Compensated, Compensated Other, Consultancy, Research Funding; Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Emergent: Consultancy; Merck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celegene: Membership on an entity’s Board of Directors or advisory committees; Shape: Research Funding; Yaupon: Research Funding.

A Targeted Mutational Landscape of Angioimmunoblastic T-Cell Lymphoma: Association Between Advanced Age and Mutations in TET2 and DNMT3A

Abstract 299Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of T-cell lymphoma that manifests with a broad array of neoplastic and paraneoplastic manifestations, including generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, rash and hypergammaglobulinemia. AITL accounts for approximately 20% of T-cell lymphomas and 1–2% of all non-Hodgkin lymphomas (NHL). Median survival among patients with AITL is less than 3 years, although the course of illness varies widely. Histologic examination of AITL characteristically demonstrates proliferation of high endothelial venules and a polymorphic infiltrate, malignant cells that resemble CD4+ follicular helper T-cells and occasional EBV-positive lymphoid cells. The genetics of AITL remain almost completely undefined, in part because of the low tumor cell fraction and the abundance of non-malignant bystander cells. We reasoned that targeted sequencing of selected genes of interest would increase coverage and thereby enable the detection of low frequency variants present with malignant AITL cells.To define a targeted mutational landscape of AITL, we performed exon capture and next-generation sequencing of all coding exons of 197 genes known to be recurrently altered in cases of NHL. Single nucleotide variants (SNVs) and insertions/deletions were confirmed by manual review of sequencing reads and a subset was validated by Sanger sequencing of tumor and germline tissue. Twenty-six cases collected from three sites in the USA had adequate tumor specimens available and resulted in high-quality reads (median depth of coverage∼300). Median age among the 26 cases was 66.5 years (range 30–89). Twelve (46%) patients were male. Among 21 cases with adequate clinical annotation, all 21 had advanced stage disease (11 stage 3, 10 stage 4), 13 (62%) had B-symptoms and 19 (90%) had an ECOG performance score of 0–2. Ten patients received CHOP-like regimens, 4 received non-anthracycline containing chemotherapy regimens, 5 received prednisone monotherapy, 2 received cyclosporine monotherapy, and one patient underwent allogeneic stem cell transplantation after cytoreduction with alemtuzumab. Among the 17 patients with staging after first-line treatment, 8 (47%) achieved a complete response, 3 (18%) achieved a partial response, 1 (6%) had stable disease and 5 (29%) had progression of disease. Median overall survival among the 26 patients was 420 days with a median follow-up of 426 days (range 21–3532).Recent studies have identified both TET2 and DNMT3A mutations in a small number of AITL samples as well as hematopoietic stem cells from the same patients. From the 26 cases, we identified 28 TET2 mutations (13 frameshift, 8 nonsense, 5 missense, 2 splice site) in 17 (65.4%) cases, including 5 cases with 2 TET2 mutations and 2 cases with 3 TET2 mutations. Among the latter, the fractions of mutant reads suggested that one mutation was present within all tumor cells and the other 2 mutations were present in subclones. Six of 17 cases with TET2 mutations also harbored mutations in DNMT3A, compared with 0 of 9 cases that lacked TET2 mutations (p=0.06). Median age for patients with wild-type TET2 was 56 years (range 30–83), 68 years for patients with one TET2 mutation (range 55–89), and 77 years for patients with 2 or 3 TET2 mutations (range 59–84; p<10−4). Median age for patients with wild-type DNMT3A was 64 years (range 30–84) and 75.5 years for patients with mutated DNMT3A (range 64–89; p=0.03).Known gain-of-function mutations were identified at JAK3 V722I (n=2) and IDH2 R172K (n=1). Frame-shift mutations were recovered in ABCA7 (n=1), ARID1B (n=1), CREBBP (n=2), GNAS (n=1), IKZF2 (n=2), PRDM1 (n=2), SMARCA2 (n=1), and TNFRSF14 (n=1). Nonsense mutations were recovered in ALPK2 (n=1), CCND3 (n=2), and CHD8 (n=2). Only 2 cases harbored TP53 mutations (M133R, S261_splice). Additional missense variants were identified across a large number of genes, including several previously described in the COSMIC database.In conclusion, the genetics of AITL vary broadly across cases, with a small number of genes previously associated with NHL harboring recurrent mutations. Mutations of DNMT3A commonly occur in combination with one or more mutations in TET2. Mutation of either locus is associated with advanced age, supporting the hypothesis that the mutations are acquired over time within hematopoietic stem cells. Disclosures:Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Weinstock:Novartis: Consultancy, Research Funding.

Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Advanced Hematologic Malignancies

AbstractAbstract 3663 Introduction:Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. Impaired development and function of B and T lymphocytes has been demonstrated in PI3K-δ and PI3K-γ isoform knockout mice, supporting the development of PI3K-δ,γ specific inhibitors for B- and T-cell lymphoid malignancies. IPI-145 is a potent PI3K-δ,γ inhibitor in clinical development for patients (pts) with hematologic malignancies. The activity of IPI-145 via PI3K-δ and PI3K-γ isoform inhibition has been characterized in biochemical and cellular assays and demonstrated in preclinical models of B- and T-cell mediated disease. Early results of the Phase 1 study in pts with advanced hematologic malignancies are reported here. Methods and Patients:This Phase 1 dose-escalation study is designed to evaluate the safety, pharmacokinetics (PK) and activity of orally administered IPI-145 in pts with advanced hematologic malignancies, including T-cell lymphomas/leukemias. Sequential cohorts of pts are enrolled at progressively higher dose levels with expansion cohorts of pts with select hematologic malignancies. IPI-145 is administered orally 2 times per day (BID) continuously in 28-day cycles. Tumor response is evaluated based on disease-specific standard criteria. Results:As of 16 July 2012, the study had enrolled 20 pts; 5 pts with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), 4 with indolent non-Hodgkin’s lymphoma (iNHL), 3 with aggressive B-cell NHL [including diffuse large B-cell lymphoma (DLBCL) n=2 and Richter’s transformation n=1], 3 with multiple myeloma (MM), 2 with Hodgkin’s lymphoma (HL), 2 with T-cell lymphoma [anaplastic large-cell lymphoma (ALCL) n=2] and 1 with mantle cell lymphoma (MCL). Of these pts, 11 are male and 9 female, with a median [range] age of 63 years [30–81], with 36% <6 month from most recent prior systemic therapy. The median [range] number of prior therapies was 3 [1–8]. IPI-145 doses administered include 8 mg BID (n=1), 15 mg BID (n=6), 25 mg BID (n=7), 35 mg BID (n=3), and 50 mg BID (n=3). The median [range] number of treatment cycles was 2 [1–8], with 12 (60%) pts continuing on treatment. Adverse events (AEs) have occurred in 13 (65%) pts, including 7 (35%) pts with AEs Grade ≥3. Treatment-related AEs occurred in 11 pts (55%) with Grade ≥3 occurring in 5 pts (25%). Grade 4 neutropenia was the one dose limiting toxicity observed to date (15 mg dose cohort). New Grade ≥3 hematological laboratory abnormalities included neutropenia [n= 6 (30%)] and thrombocytopenia [n= 1 (5%)]. Grade 3 ALT/AST elevations occurred in 1 (5%) MM pt with onset 6 weeks after IPI-145 initiation.Preliminary PK show dose-proportional increases in plasma Cmax and AUC over the dose range studied. Further, the PK and initial pharmacodynamic (PD) data from the first 3 cohorts (8–25 mg BID) predict continuous suppression of the PI3K-δ pathway with increasing inhibition of the PI3K-γ pathway with a 25 mg BID dose or greater.In the evaluable pts (n=11), responses were observed at the 8, 15, and 25 mg BID dose levels including 2/3 CLL/SLL pts (0 CR/2 PR/1 SD), 1/2 iNHL pts (1 CR/0 PR/1 SD), and 1/1 in MCL (1 PR). No responses have been observed to date in evaluable pts with MM (0/3) or aggressive NHL (0/2). All pts with at least SD after 2 cycles (n=6) remain on treatment including the first pt dosed.Based on the PK/PD and the preliminary activity observed in pts with CLL, iNHL and MCL, an expansion cohort is enrolling pts in these select hematologic diseases dosed at 25 mg BID to further evaluate the safety and preliminary activity of IPI-145. Dose escalation continues with a focus on pts with T-cell malignancies and DLBCL where increasing suppression of the PI3K-γ isoform may improve the efficacy profile. Additional expansion cohorts in T-cell lymphoma, DLBCL, myeloproliferative neoplasms and the acute leukemias will better define disease specific activity. Conclusions:IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears to be well tolerated and has shown initial clinical activity in pts with iNHL, MCL, and CLL. A dose of 25 mg BID effectively inhibits PI3K-δ, providing a rationale for expansion in CLL/iNHL/MCL. Additional safety and efficacy data from the ongoing dose escalation evaluation in T-cell/aggressive NHL and the CLL/iNHL/MCL expansion cohort will be presented. Disclosures:Flinn:Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc. : Research Funding. Patel:Infinity Pharmaceuticals, Inc. : Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc. : Research Funding; Gilead: Research Funding. Porter:Infinity Pharmaceuticals, Inc. : Employment. Sweeney:Infinity Pharmaceuticals, Inc. : Employment. Allen:Infinity Pharmaceuticals, Inc. : Employment. Kelly:Infinity Pharmaceuticals, Inc. : Employment. Kahl:Infinity Pharmaceuticals, Inc. : Research Funding.

Pralatrexate in Relapsed/Refractory HTLV-1 Associated Adult T-Cell Lymphoma/Leukemia: A New York City Multi-Institutional Experience.

Abstract 2735 Introduction:Adult T-cell lymphoma/leukemia (ATLL) is a mature T-cell malignancy associated with human T-cell lymphotropic virus -1 (HTLV-1) infection, which presents as aggressive (acute/lymphomatous) or indolent (chronic/smouldering) subtypes. The aggressive subtypes have a median survival of 6 months. Further, there is no established therapy for patients with relapsed/refractory disease. Pralatrexate is a dihydro-folate reductase inhibitor with high affinity for the reduced folate carrier type 1, a protein involved in trafficking of native folates. Pralatrexate given weekly at 30 mg/m2 for six of seven weeks was the first drug approved for use in relapsed/refractory peripheral T-cell lymphoma (PTCL) after demonstrating an overall response rate (ORR) of 29%. However, only one patient in the pivotal PROPEL study had ATLL. Approaches for relapsed/refractory PTCL are often applied to ATLL, as there is little data for this subtype. Here, we report a multi-institutional retrospective experience of pralatrexate in relapsed/refractory ATLL focusing on efficacy, durability, and toxicity. Methods:To investigate the therapeutic benefit and toxicity profile of pralatrexate we reviewed all patients with relapsed/refractory ATLL treated with pralatrexate on published trials or treated off study between 2005 and 2012 at three New York City institutions. Individual chart review was performed to report clinicopathologic features, treatment outcomes, and toxicity assessments. An event was defined as toxicity from pralatrexate resulting in discontinuation, progression, or death. Results:We identified 21 patients with relapsed/refractory ATLL treated with pralatrexate. Patient characteristics were: median age 52 (range 37–74); male:female 9:12; Region of origin was Caribbean-18, non-Caribean-3. Subtype at diagnosis of ATLL was: Acute/Lymphomatous-17 and Smouldering/Chronic-4. The median number prior treatments were 1 (range 0–5). Seven patients were treated on pralatrexate developmental clinical trials with one patient on the pivotal phase II PROPEL study. The median dose and number of treatments administered were 30 mg/m2 (range 15–45) and 4 (range 1–53) respectively. The ORR in patients evaluable for response (N=16) was 19% (2:PR; 1:CR) with an intent-to-treat (N=20) ORR was12% in patients with any exposure to pralatrexate. The median duration of response was 15 weeks (range 11–83). The median event free survival (EFS) was 6 weeks (range 1 to 90). One patient continues on pralatrexate without toxicity and has yet to be evaluated for response. Four patients (19%) developed findings consistent with Stevens-Johnson Syndrome (SJS) after 1 (N=2) or 2 (N=2) doses of pralatrexate. One additional patient developed a papular rash after pralatrexate; no biopsy was obtained. In the four patients with SJS, one had skin involvement of ATLL at diagnosis and at the time of pralatrexate, two had cutaneous ATLL lesions at the time of pralatrexate, and one did not have any cutaneous ATLL. Dermal apoptosis of tumor was not assessed in any of the cases. Seven patients (33%) developed clinically significant mucositis with two cases in patients with SJS. Conclusion:ATLL is a rare and difficult disease to manage. In our retrospective experience in relapsed/refractory ATLL, pralatrexate appears to have inferior ORR and much shorter EFS when compared to other PTCL subtypes. Notably, the risk of SJS, even without cutaneous involvement by lymphoma, may be higher in ATLL. In early phase studies of pralatrexate skin erosions were also seen in patients with PTCL with cutaneous involvement, including one cases of an ATLL patient with in vivo evidence of apoptosis of cutaneous tumor cells, but no cases of SJS were reported. A dedicated phase II study of pralatrexate in relapsed/refractory ATLL is planned by the Japan Clinical Oncology Group. Disclosures:Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding.

Romidepsin Induces Durable Responses in Patients with Peripheral T-Cell Lymphoma: GPI-06–0002 Study Update

AbstractAbstract 3641 Background:Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative disorders, and most subtypes have a poor prognosis even with aggressive chemotherapy. Romidepsin is a potent class 1 histone deacetylase inhibitor approved by the US Food and Drug Administration for treatment of patients with PTCL who have received at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. A phase 2, single-arm, open-label registration study (GPI-06–0002) demonstrated the clinical benefit and tolerability of romidepsin in patients with relapsed or refractory PTCL (data cutoff: Oct 2010). Here, we present an update of the efficacy of GPI-06–0002 and characterize patients who achieved long-term responses (≥ 12 months) as of Dec 2011 (median follow-up: 22.3 months). Methods:Patients with histologically confirmed PTCL (N = 130) who failed or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for responding patients. The primary endpoint was confirmed/unconfirmed complete response (CR/CRu) determined by an independent review committee (IRC) based on the International Workshop Response Criteria. Secondary endpoints included objective response rate (ORR: CR/CRu + partial response), duration of response (DOR), and time to progression. Disease response was assessed every 2 treatment cycles. Baseline patient characteristics by DOR (≥ 12 months vs < 12 months) were examined. Results:The majority of the 130 patients had stage III or IV disease (70%); 28% had bone marrow involvement. PTCL not otherwise specified (53%) and angioimmunoblastic T-cell lymphoma (21%) were the most common subtypes. Patients received a median of 2 prior systemic therapies (range, 1–8); 38% of patients were refractory to their last line of therapy. The ORR was 25% (33 of 130 patients), including CR/CRu in 15% (19 of 130) of patients. The median duration of objective response was 28 months, with the longest response ongoing at 48 months (Figure). Of the 19 patients who achieved CR/CRu, 13 (68%) had not experienced disease progression per the IRC at a median follow-up of 25.8 months. The median duration of CR had not yet been reached (range, 1–48+ months; Figure). Of the 19 patients who achieved CR/CRu, 10 were long-term responders (responses ≥ 12 months). Interestingly, heavy pretreatment (≥ 4 prior systemic therapies) did not preclude patients from achieving long-term CR/CRu: 5 of 10 patients (50%) who maintained CR/CRu for ≥ 12 months were heavily pretreated vs 1 of 9 (11%) patients with CR/CRu maintained for < 12 months. Long-term CR/CRu was achieved regardless of response to last prior therapy; only 2 of 10 (20%) long-term responders had an objective response on their last treatment. In contrast, 6 of 9 (67%) patients with CR/CRu for < 12 months responded to their last prior therapy. Furthermore, advanced disease did not preclude long-term response to romidepsin: all 10 patients (100%) who maintained CR/CRu for ≥ 12 months had stage III/IV disease vs 55.5% of those who maintained CR/CRu for < 12 months. Other characteristics, such as Eastern Cooperative Oncology Group performance status, International Prognostic Index score, age, sex, and race, were similar among patients achieving CR/CRu for ≥ 12 months or < 12 months. Conclusions:Single-agent romidepsin induced durable responses in patients with relapsed/refractory PTCL, with responses ongoing at 48 months. None of the examined patient and disease characteristics predicted failure to achieve long-term remissions. These results support the use of romidepsin in relapsed/refractory PTCL. [Display omitted] Disclosures:Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Pro:Allos: Honoraria; Spectrum : Honoraria; Seattle Genetics : Research Funding; Celgene: Honoraria, Research Funding. Prince:Celgene : Consultancy, Honoraria, Research Funding. Foss:Celgene : Consultancy. Sokol:Celgene : Honoraria, Speakers Bureau. Morschhauser:Celgene : Consultancy, Honoraria. Pinter-Brown:Celgene : Consultancy; Allos : Consultancy. Shustov:Celgene : Honoraria, Research Funding, Speakers Bureau. Nielsen:Celgene: Employment, Equity Ownership. Nichols:Celgene: Consultancy, Employment, Equity Ownership. Horwitz:Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy; Bristol-Myers Squibb: Consultancy; Allos: Consultancy, Research Funding; Genzyme: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding.

CD30 Is a Potential Therapeutic Target in Patients with HTLV-1 Associated Adult T-Cell Leukemia/Lymphoma Presenting Outside of Japan.

AbstractAbstract 2706 Objective:Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell malignancy associated with human T-cell lymphotropic virus -1 (HTLV-1) infection. Four clinical subtypes are recognized including acute/lymphomatous (aggressive) or chronic/smouldering (indolent). For the aggressive subtypes the median overall survival is 6 months despite aggressive combination chemotherapy. Novel therapeutic targets against CD25, CD52, and NF μB have shown preliminary activity in ATLL. Recently, the chemokine receptor 4 (CCR4) antibody (KW-0761) was approved in Japan based on a phase II overall response rate of 50% and median overall survival of 13.7 months in 28 patients with relapsed/refractory ATLL. CD30 (Ki-1) is a marker of immune activation expressed on lymphocytes, and is an emerging target in lymphoma. The novel antibody-drug conjugate brentuximab vedotin targets CD30 and has shown efficacy in Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL). While CD30 positive ATLL is infrequent in Japanese ATLL patients, ranging from 12.1% to 19.4%, the prevalence of CD30 positive ATLL outside of Japan has not been extensively studied. Patients and Methods:To investigate the prevalence of CD30 expression and its importance in ATLL outside of Japan we conducted a retrospective review of all patients who underwent treatment or consultation for ATLL at our institution between 1998 and 2012. Individual chart review was performed to report the clinical presentation, pathological features, and outcomes. Pathology review of CD30 expression status was conducted if specimens were available. The CD30 (Ber-H2) antibody from Ventana was used on automated platforms per manufacturer’s instructions. Specimens were determined to be positive if the CD30 expression was >20% by an expert hematopathologist (AC). Results:We identified 50 patients with ATLL. Patient characteristics were: median age 54 (range 30–82); male:female 19:31; Caribbean-39, American-6, Western African-2, Peruvian-2, and Greek-1. Subtype of disease at diagnosis was: Acute/Lymphomatous—41 and Chronic/Smouldering—9. Thirty-six of 50 (72%) patients’ samples had been tested at least once for CD30. Eighteen patients (50%) were reported positive. Of all cases reviewed (N=50), eight had pathology available for confirmatory review. Of those, five patients remained positive, 1 patient was reclassified as positive after initially being reported as negative, and two remained negative. The median overall survival of all patients was 13 months. In the subset who had CD30 status assessed the median overall survival for CD30 negative and positive ATLL was 18 and 45 months respectively (p=0.116). Conclusions:CD30 expression on normal lymphocytes is rare. Our retrospective data suggests that ATLL patients presenting outside of Japan may demonstrate CD30 positivity at a higher prevalence compared to Japanese reports. In pre-clinical studies of CD30 positive ATLL, SGN-35 has been shown in vitro and in vivo to demonstrate similar cytotoxicity compared to ALCL (Maeda et al. Cancer Sci 2010). Novel strategies are clearly needed to improve the outcome of ATLL despite recent advances. Therefore, CD30 testing may be considered in ATLL as a novel target for future research strategies. [Display omitted] Disclosures:Matasar:GSK: Research Funding; Genentech: Consultancy. Straus:Seattle Genetics: Consultancy. Zelenetz:GSK: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Gilead: Consultancy; Sanofi Aventis: Consultancy; Cephalon: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Amgen: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding.

Pharmacokinetics and Pharmacodynamics of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, Following Single- and Multiple-Dose Administration in Healthy Subjects and Patients with Advanced Hematologic Malignancies

AbstractAbstract 4853 Introduction:Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions. PI3K-δ and PI3K-γ isoforms are necessary for adaptive and innate immunity and contribute to the development and maintenance of inflammatory and autoimmune diseases and hematologic malignancies. IPI-145 is a potent inhibitor of PI3K- δ,γ isoforms (Ki = 23 pM and 243 pM, respectively) in clinical development for patients with advanced hematologic malignancies and inflammatory/autoimmune disorders. The pharmacokinetics (PK) and pharmacodynamics (PD) of IPI-145 were evaluated in a Phase 1 clinical study in healthy subjects and are being characterized in patients with advanced hematologic malignancies. Methods:In a healthy subject study, IPI-145 was administered orally as a single dose and as multiple doses once daily (QD) or twice daily (BID) for 14 days. In a Phase 1 oncology study, IPI-145 was administered orally starting at a dose of 8 mg BID. PK and PD markers were evaluated after the first dose and at steady state. PD activity (PI3K inhibition) in whole blood was evaluated using a basophil activation assay which measured reduction in CD63 expression on the surface of basophils following ex vivo stimulation. Results:IPI-145 was well tolerated in healthy subjects at single doses up to 30 mg (highest dose tested) and up to 10 mg total daily dose (highest dose tested; 5 mg BID or 10 mg QD) for 14 days. In healthy subjects, the PK profile of IPI-145 is characterized by rapid absorption (peak plasma concentrations reached within 0.5–1 hour), moderately rapid elimination (half-life 3.5 to 9.5 hours following a single dose and 6.5 to 11.7 hours following repeat dosing) and dose proportional increases in systemic exposure (Cmax and AUC). Minimal accumulation was observed after multiple dose administration (accumulation ratio 1.65–1.83 for BID dosing and 1.54 for QD dosing). Following single oral dose administration, clearance ranged from 6.7 L/h to 11.1 L/h and the volume of distribution ranged from 38.8 L to 147 L. Excretion of unchanged IPI-145 in urine was <2% of the administered dose, indicating minimal renal elimination of parent drug. CD63 expression on the surface of activated CCR3+ basophils was reduced in a dose-dependent manner at all single and multiple dose levels, with a maximum reduction at 1 hour post dose, corresponding to the time of maximum IPI-145 plasma concentrations. Inhibition of basophil activation mirrored the IPI-145 concentration-time profile, with CD63 expression returning to baseline levels as plasma concentrations declined. Administration of 5 mg BID maintained PI3K-δ inhibition (EC50 = 48 ng/mL) throughout the 12 hour dosing interval. Concomitant administration of a high-fat, high-calorie meal decreased Cmax approximately 10%, shifted median Tmaxfrom 1 to 3 hours, and increased overall exposure (AUC) approximately 8–9%. These data suggest IPI-145 may be administered without regard to meals. Emerging data from a Phase 1, dose escalation study in subjects with hematologic malignancies demonstrate rapid drug absorption and dose-proportional PK. As in healthy subjects, maximum inhibition of basophil activation was observed 1 hour post dose. Prior to dose administration at the beginning of Cycle 2 (i.e. after 28 days of BID dosing), CD63 expression was reduced 45% or more relative to the start of treatment. Mean steady-state trough concentrations were maintained above levels sufficient for PI3K-δ inhibition following doses ≥15 mg BID. Early signs of clinical response have been observed. Conclusions:Across both Phase 1 studies, IPI-145 drug absorption was rapid and exposure was proportional to dose. CD63 expression on the surface of activated basophils was reduced in the presence of IPI-145 in both healthy and oncology subjects, an observation consistent with PI3K-δ inhibition. An exposure-response relationship was evident, suggesting a concentration-dependent pharmacological response to IPI-145. Preliminary PK/PD data from the oncology study demonstrate inhibition of PI3K-δ activity and suggest higher doses may increasingly suppress PI3K-γ activity. Dose escalation and PK/PD monitoring are ongoing. Collectively, the data available support the clinical development of IPI-145 as a potential therapeutic in hematologic malignancies and inflammatory diseases. Disclosures:Dunbar:Infinity Pharmaceuticals, Inc.: Employment. Nevejans:Infinity Pharmaceuticals, Inc.: Employment. McKee:Infinity Pharmaceuticals, Inc.: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Zhao:ApoCell: Employment. Kahl:Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Patel:Infinity Pharmaceuticals, Inc.: Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc.: Research Funding; Gilead: Research Funding. Flinn:Infinity Pharmaceuticals, Inc.: Research Funding.