ALBERT

Description: The reported incidence of t-MDS/t-AML following traditional ASCT for lymphoma ranges between 0–12%. Previously identified risk factors include older age, prior alkylator therapy and use of radiation either prior to ASCT or as part of the preparative regimen. It is unclear whether novel conditioning regimens for ASCT that utilize targeted RIT with the potential to deliver higher radiation doses to the marrow are associated with a higher risk of t-MDS/t-AML. We identified a case-series of 83 pts who underwent RIT based ASCT between 06/00 and 01/06 to evaluate the incidence of t-MDS/t-AML; Forty-one pts received standard dose 90Y ibritumomab tiuxetan (0.4mci/kg: median dose 32.9 mci (range 20–40)) in combination with high dose BEAM (BCNU 450mg/m2, etoposide 800mg/m2, cytarabine 800mg/m2, melphalan 140mg/m2) and 42 pts received high dose 90Y based on dosimetry (median 70.8 mci range 36–105) in combination with etoposide 60mg/kg plus cyclophosphamide 100mg/kg. Pts were followed prospectively post ASCT with serial bone marrow biopsies approximately annually. The median age at ASCT was 54 years (range 19–78). Disease histology included diffuse large cell n=40, follicular NHL n=17, mantle cell n=21, transformed n=4, SLL n=1. Disease status at ASCT was 1st CR n=17, 1stPR n=14, induction failure n=14, 1st relapse or greater n=38. With a median follow-up of 39 months (range, 1.4–83), three patients (3.61%) have developed t-MDS/t-AML. The three pts also had associated complex chromosomal abnormalities including de1(13q), del(5q), del (20q). The median time to t-MDS/t-AML was 2.63 years (range, 1.51 – 8.41) post NHL diagnosis and 1.99 years (range, 0.56 – 5.10) post ASCT. The cumulative incidences of t-MDS/t-AML at 1 and 2 years were 1.20% (95%CI, 0.17– 8.1%) and 2.60% (95%CI 0.64–9.9%). None of the potential risk factors including age(〉50 at ASCT) (p=0.33), prior radiotherapy (p=0.99), number of prior regimens (p=0.5) and 90Y dose (p=0.99) were statistically significant by univariate analysis. As 82/83 pts had received prior alkylator therapy this was not analyzed as a separate risk factor. Two year overall survival for the entire cohort is 90% (95%CI 83–95). Although the follow up is relatively short, the incidence of t-MDS/t-AML is consistent with our previous institutional experience in ASCT patients who received non-RIT based conditioning (Krishnan et al. Blood 2000) and with the 2.5% incidence of t-MDS/t-AML observed in pts receiving 90Y in registration and compassionate use trials (Czuczman et al JCO 2007 in press). In conclusion RIT based conditioning does not appear to confer an increased risk of t-MDS/t-AML above what has been previously reported with traditional ASCT preparative regimens. Incidence of t-MDS/t-AML Incidence of t-MDS/t-AML

Description: Brentuximab vedotin induces an overall response rate of 75% in patients with relapsed/refractory Hodgkin lymphoma, but its impact on future allogeneic transplantation (allo-HCT) is not known. We retrospectively examined the records of 18 patients with relapsed/refractory Hodgkin lymphoma who were treated on brentuximab vedotin clinical trials to evaluate the efficacy and safety of subsequent reduced-intensity allo-HCT. Seventeen patients had previous autologous transplant; 6 were in complete remission, and 8 were in partial remission before allo-HCT with 12 grafts from unrelated or mismatched donors. The 1-year overall survival was 100%, progression-free survival was 92.3%, and nonrelapse mortality was 0% (median follow-up, 14 months). The incidence of acute GVHD was 27.8% and chronic GVHD was 56.3%. Brentuximab vedotin before reduced-intensity allo-HCT does not appear to adversely affect engraftment, GVHD, or survival and may provide sufficient disease control to enable reduced-intensity allo-HCT.

Description: Background: High risk AML patients (pts) have poor outcome with low complete remission (CR) rate and long term survival despite intensive chemotherapy. Tyrosine kinases play an important role in AML pathogenesis. Pre-clinical studies performed in our center (Blood. 2013 122:1900) have shown that Src family tyrosine kinases (SFK) including Lyn, Hck and Fgr are abnormally activated in AML compared to normal hematopoietic stem cell and progenitor cells. Other studies have shown that the c-Kit receptor is over-activated in a subset of AML pts and contributes to abnormal leukemia cell growth. We further show that the small molecule SFK and c-Kit inhibitor dasatinib reduces proliferation and survival of AML stem and progenitor cells. Importantly, dasatinib enhances the sensitivity of AML stem and progenitor cells to chemotherapeutic agents by inhibiting Akt signaling, increasing mdm2 phosphorylation and enhancing p53 activity in AML cells. Based on this data we conducted a phase I/II clinical study of the combination of dasatinib with conventional cytarabine-idarubicin ("7+3")-based induction chemotherapy in high-risk AML. Methods: Between September 20013 and July 2015, 18 adult AML pts were enrolled in the study. Eligibility criteria were high-risk AML, age 〉18 years, and suitability for intensive therapy. High risk AML was defined by one of the following criteria: older age (〉 60 yrs), poor-risk cytogenetic and molecular abnormalities (ELN criteria), secondary disease (AML evolving from myelodysplasia or myeloproliferative neoplasm), therapy related (t-AML), or relapsed/refractory. This Phase I study used a 3 + 3 dose escalation design for dasatinib while keeping a fixed dose of cytarabine and idarubicin (cytarabine 200 mg/m2 CIV days 1-7, idarubicin 12 mg/m2 IV days 1-3). Dasatinib was started at a dose of 70 mg (dose level 1; DL-1) days 1-7, and escalated to 100 mg orally days 1-7 (DL 1). Pts who failed to achieve CR received second re-induction with the same regimen. Pts who achieved CR received consolidation high dose cytarabine and/or allogeneic stem cell transplantation (SCT) based on donor availability. Results: Of the 18 pts enrolled on the study, 7 pts (39%) had secondary AML, 5 pts (28%) relapsed AML, 2 pts (11%) t-AML, and 4 (22%) were newly diagnosed older AML pts (one with complex karyotype, one with trisomy 8 and one cytogenetically normal with FTL3-ITD). The median age of all pts was 62 yrs (range 27-73). Of the 18 pts, 13 pts are currently evaluable for response; of which 10 (77%) achieved CR/Cri. Of the 5 non-evaluable pts, one pt withdrew from study after 2 days of therapy, one pt was taken off study after 3 days due to cytarabine neurotoxicity, one pt died of intracranial hemorrhage before the day 14 bone marrow biopsy, one pt had therapy interrupted secondary to pneumonia and sepsis, and one is still receiving therapy. None of the pts required more than one induction to achieve CR. Of the 10 pts who achieved CR/Cri, 8 patients went on to receive allogeneic SCT. As expected, the most commonly reported grade 3 and 4 adverse events (AE) were anemia 50%, thrombocytopenia 44%, neutropenia 38%, and fatigue 27%. The most common grade 1-2 AE were GI toxicities 61% and rash 33%. Correlative studies performed on blood samples obtained from pts on day 3 after initiation of treatment (n=9) demonstrated significant decrease in of SRC activity (as indicated by reduction in phospho-SRC levels on immunoblotting, 0.52±0.11 of control, p=0.01), and increased expression of p53-target genes as evaluated by Q-RT-PCT [including Puma (16.2±6.9 fold, p=0.015), P21 (4.9±1.1 fold, p=0.004), DR5 (3.4±0.9, p=0.004), Bax (3.7±0.9 fold, p=0.001) and HDM2 (2.1±0.5, p=0.02)]. Conclusion: Combination of dasatinib with conventional "7+3" induction chemotherapy is feasible in high-risk AML and leads to higher CR rate compared to historical data without increase in toxicity rate, allowing more pts to receive allogeneic transplantation. Correlative laboratory studies are consistent with pre-clinical studies suggesting that this combination is associated with significant inhibition of SRC activity and enhanced activation of p53-target genes. Disclosures Dos Santos: Amgen: Employment. Stein:Amgen: Speakers Bureau. Chen:Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; genentech: Consultancy, Speakers Bureau. Khaled:Sequenom: Research Funding.

Description: Reconstitution of cytomegalovirus (CMV)–specific CD8+ T cells is essential to the control of CMV infection in CMV-positive recipients (R+) after allogeneic hematopoietic stem cell transplantation (HCT). Six-color flow cytometry was used to assess the functional profile of CMV-specific CD8+ T cells in 62 of 178 R+ HCT recipients followed virologically for CMV reactivation. R+ recipients receiving grafts from CMV-negative donors (D−; D−/R+) reconstituted fewer multifunctional CD8+ T cells expressing tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1β (MIP-1β), and CD107 in addition to interferon-γ (IFN-γ), compared with D+/R+ recipients. Unlike monofunctional CD8+ T cells secreting IFN-γ, which were abundantly generated during CMV reactivation in D−/R+ recipients, the relative lack of multifunctional CD8+ T cells persisted until at least 1 year post-HCT. D−/R+ recipients were more likely to require recurrent and prolonged use of antivirals. These findings were robust to statistical adjustment for pretransplant factors, as well as for posttransplant factors including graft-versus-host disease (GVHD) and its treatment by steroids. These analyses suggest that D+/R+ transplants, on average, generate higher levels of multifunctional CMV-specific T cells and require less antiviral therapy compared with D−/R+ HCT recipients. These results highlight the benefit of D+ donors in improving outcomes of R+ HCT recipients by reducing the duration and recurrent need of antiviral treatment, aided by increased levels of multifunctional CMV-specific T cells.

Description: Combination tacrolimus and sirolimus graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant in patients conditioned with a fractionated total body irradiation–based regimen has shown encouraging results. We studied this prophylaxis combination in 85 patients receiving a matched-sibling transplant conditioned with 3 different regimens:fludarabine-melphalan (n = 46); total body irradiation–etoposide (n = 28), and busulfan-cyclophosphamide (n = 11). The conditioning regimens were completed on day −4. Sirolimus and tacrolimus were started on day −3 to avoid overlap with conditioning therapy. All patients engrafted, with a median time to neutrophil engraftment of 15 days. The cumulative incidence of acute GVHD grades II to IV and III to IV was 43% and 19%, respectively, with no significant difference by conditioning regimen. The 2-year cumulative incidence of chronic GVHD was 46%. With a median follow-up of 26 months, disease-free survival was 58% and overall survival, 66%. The day-100 and 2-year nonrelapse mortality was 4.8% and 10.2%, respectively. The overall incidence of thrombotic microangiopathy was 19%, and it was significantly higher with busulfan/cyclophosphamide (55%, P = .005). Tacrolimus plus sirolimus is an effective combination for acute GVHD prophylaxis and is associated with very low nonrelapse mortality. Thrombotic microangiopathy is a significant complication with this regimen, particularly in patients receiving busulfan/cyclophosphamide.

Description: Background: Double-hit lymphomas (DHL) - diffuse large B-cell lymphomas (DLBCL) with concurrent rearrangements of MYC and BCL2 and/or BCL6, and double-expressor lymphomas (DEL) - DLBCL with co-expression of MYC and BCL2 by immunohistochemistry (IHC), are associated with poor outcomes after standard chemoimmunotherapy. We have previously demonstrated that patients with relapsed or refractory (rel/ref) DHL and DEL have inferior outcomes after autologous stem cell transplantation (autoSCT) compared to patients with neither DEL nor DHL [Herrera et al, ASH 2015]. Although patients with DEL and DHL have inferior outcomes after chemotherapy-based treatment modalities, we hypothesized that allogeneic SCT (alloSCT) could potentially abrogate that negative prognostic impact. Data are extremely limited regarding the outcome of patients with DHL who undergo alloSCT, and no study has examined alloSCT outcomes in patients with DEL. We studied alloSCT outcomes in a multicenter cohort of rel/ref DLBCL patients and evaluated the prognostic impact of DEL and DHL status. Methods: We retrospectively studied patients with rel/ref DLBCL, transformed indolent lymphoma (TIL), or high-grade B-cell lymphoma unclassified (BCLU) who had available tumor tissue and underwent alloSCT at Dana-Farber Cancer Institute, Massachusetts General Hospital, or City of Hope between 1/2000 and 5/2014. IHC for MYC, BCL2, and BCL6 were performed. DEL was defined as MYC expression in ≥ 40% tumor cells and BCL2 expression in ≥ 50% tumor cells. FISH for MYC was performed using dual-color break-apart probes. Cases with MYC-rearrangement had FISH performed for BCL2 and BCL6 using break-apart probes. Rearrangement was defined as ≥ 10% nuclei with break-apart signals. DHL was defined as concurrent rearrangement of MYC and BCL2 and/or BCL6. Results: Tumor tissue was available in 103 patients, among whom we could obtain complete IHC and FISH data in 74. In these 74 patients, the median age was 54 years (range 24-69); 69% had DLBCL/BCLU whereas 31% had TIL; the median number of prior therapies was 4 (range 2-9); 58% had prior autoSCT; 73% were in complete or partial remission (CR/PR) at alloSCT; 77% had reduced intensity conditioning (RIC); 78% had a matched related or unrelated donor. 4y progression-free survival (PFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) in the overall cohort were 34%, 40%, 44% and 22%, respectively, with a median follow-up of 46 months for survivors. 47% of patients had DEL and 14% had DHL. The proportion of patients with a history of primary refractory disease was higher among DHL (60%) and DEL (52%) patients compared to nonDHL/nonDEL patients (37%), although the difference was not significant (p=0.3). Overall, there were no significant differences in clinical characteristics between patients with DHL, DEL, and nonDHL/nonDEL. Neither DEL nor DHL were significantly associated with outcome (Figure). The 4y PFS in DEL v non-DEL patients was 29% v 39% (p=0.2), 4y OS 30% v 49% (p=0.11), 4y CIR 50% v 40% (p=0.3), and 4y NRM 21% v 22% (p=1.0). The 4y PFS in DHL v non-DHL patients was 40% v 33% (p=0.6), OS 50% v 37% (p=0.4), CIR 40% v 45% (p=0.9), and NRM 20% v 22% (p=0.8). In multivariable Cox models for PFS and OS, age ≥ 55 (PFS: HR 0.4, p=0.002; OS: HR 0.4, p=0.005), refractory disease (not CR/PR) at alloSCT (PFS: HR 2.4, p=0.009; OS HR 2.6, p=0.007), and TIL (PFS HR 0.4, p=0.018; OS HR 0.4, p=0.028) were associated with PFS and OS, but DEL (PFS HR 1.2, p=0.5; OS HR 1.6, p=0.12) and DHL (PFS HR 0.8, p=0.7; OS HR 0.8, p=0.7) were not. We also constructed multivariable competing risk regression models for CIR and NRM. Age, remission status, histology, and conditioning intensity were associated with relapse, while no factor was significantly associated with NRM. Neither DEL (CIR HR 1.2, p=0.7, NRM HR 0.8, p=0.7) nor DHL (CIR HR 1.1, p=0.9, NRM HR 0.8, p=0.8) were associated with either outcome in those models. Conclusions: AlloSCT produced durable remissions in heavily treated rel/ref DLBCL patients, regardless of DEL and DHL status. In our cohort, DEL and DHL status did not have a significant prognostic impact. Although patients with DEL or DHL have poorer outcomes after chemoimmunotherapy and autoSCT, our results suggest that alloSCT may overcome the chemoresistance of double-hit/double-expressor tumors. Figure Progression-Free Survival After AlloSCT in DEL, DHL, and nonDEL/nonDHL Patients Figure. Progression-Free Survival After AlloSCT in DEL, DHL, and nonDEL/nonDHL Patients Disclosures Herrera: Adaptive Biotechnologies: Research Funding; Genentech: Research Funding; Immune Design: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding. Song:Seattle Genetics: Consultancy. Chen:Genentech: Consultancy, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Koreth:LLS: Research Funding; amgen inc: Consultancy; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; kadmon corp: Membership on an entity's Board of Directors or advisory committees; prometheus labs inc: Research Funding; millennium pharmaceuticals: Research Funding. Pillai:Trillium Therapeutics: Research Funding. Siddiqi:Janssen Biotech: Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Juno Therapeutics: Research Funding; Kite Pharma: Research Funding; Acerta Pharma: Research Funding; MedImmune: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding. Zain:Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Kwak:XEME BioPharma: Consultancy, Equity Ownership; Antigenics: Equity Ownership; Celltrion: Consultancy; Sella Life Sciences: Consultancy. Nademanee:Celgene: Consultancy; Seattle Genetics: Consultancy, Research Funding. Weinstock:Novartis: Consultancy, Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Armand:Roche: Research Funding; Pfizer: Research Funding; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

Description: Philadelphia (Ph) chromosome [t(9;22)] was reported as a rare recurrent balanced translocation among therapy-related acute leukemia (N=10, 2%) [Gene Chromosomes Cancer. 2002]. Here, we conducted a retrospective analysis of therapy-related acute leukemia with Ph chromosome (Ph+ t-AL) to better understand this entity. We included cases diagnosed at our institution between 2000 and 2016, excluding patients with CML in blastic phase. We defined Ph+ t-AL as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) harboring Ph chromosome that developed after prior exposure to cytotoxic therapy (chemotherapy, radiation or both). Of the 330 patients with Ph+ AL, 28 cases (8.4%) met our definition of Ph+ t-AL, including 25 (89%) B-cell ALL, 1 case of T-cell ALL, and 2 cases of AML. The median age at diagnosis was 56 years (range: 29-79), and 64% (N=18) of them were female. Breast cancer was the most common prior malignancy [N=8, 29%], followed by lymphoma [N=6, 21%] and sarcoma [N=4, 14%]. Prior cytotoxic therapy consisted of chemotherapy (32%), radiotherapy (29%) and chemoradiation (39%). Among 20 patients who had prior chemotherapy, 70% had received alkylating agents (i.e., cyclophosphamide, temozolomide), 70% had received topoisomerase II inhibitors (i.e., etoposide, anthracycline), 40% had received antimetabolites, (i.e., methotrexate) and 50% both alkylators and topoisomeraseII inhibitor. The median interval between prior malignancy and Ph+ t-AL diagnosis was 6.8 years (range: 2.5-19.6) and was not different according to prior cytotoxic therapy modality [chemotherapy/radiotherapy vs. either chemotherapy or radiotherapy alone (P = 0.66)]. The median white blood cells count at presentation was 20 x103/µL (range: 1.4-230). Myelodysplastic syndrome preceded one case of AML. Among 22 patients with available standard cytogenetics, 7 (32%) had Ph chromosome as the sole abnormality, while 15 (68%) had an additional cytogenetic abnormality (ACA). Complex (≥ 3 abnormalities) or monosomal karyotypes were observed respectively in 12 and 9 cases. Chromosome 7 abnormality was observed in 6 (27%) cases, including 5 of them with monosomy 7. In 18 patients (ALL = 17; AML = 1) with available molecular study for BCR/ABL1, all were positive for p190 fusion transcript, including 3 patients who carried both p210 and p190 (ALL =2; AML =1). The median time from prior diagnosis to AL onset was not different according to cytogenetics (isolated Ph chromosome vs. complex/monosomy karyotype) (P〉 0.99). However, prior exposure to topoisomeraseII inhibitor was more common among patients with isolated Ph chromosome compared to patients with complex/monosomy karyotype (86% vs. 33%, P= 0.02). Tyrosine-kinase inhibitor (TKI) was administered as part of initial induction regimen to all patients except 4 (N= 24, 86%), who received TKI only upon leukemia relapse/progression. Of the 28 patients, 25 (89%) achieved complete remission (CR) with induction, and 17 (61%) patients subsequently underwent alloHCT; of them, 13 (76%) were in CR1. The 2-year overall survival and event-free survival were respectively 48% and 36% for all patients, and 63% and 41% for those who underwent alloHCT, respectively. The 2-year cumulative incidence rates of relapse and non-relapse mortality for transplanted patients were 19% and 25%, respectively. In conclusion, Ph+ chromosome is a recurrent therapy-related chromosomal aberration presenting most often as a B-cell ALL phenotype, and only rarely as T-cell ALL or AML. Ph+ t-AL is associated with high incidence of ACA, including complex and monosomal karyotype as well as chromosome 7 abnormalities, similar to therapy-related myeloid neoplasms. Similar to de novo Ph+ ALL, a high response rate to TKI-based regimen was observed among Ph+ t-AL. Given its therapeutic implication, presence of Ph chromosome should be excluded in all cases of t-AL. Disclosures Song: Seattle Genetics: Consultancy. Ali:Incyte Corporation: Research Funding. Salhotra:Alexion: Consultancy. Snyder:Ariad: Consultancy; Novartis: Consultancy. Stein:Amgen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.

Description: Allogeneic hematopoietic cell transplantation (HCT) is the only known curative modality for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). Sixty-seven patients with HLA-matched sibling donors received fractionated total body irradiation (FTBI) and high-dose VP16, whereas 11 patients received FTBI/VP16/cyclophosphamide, and 1 patient received FTBI/VP16/busulfan. The median age was 36 years. At the time of HCT, 49 patients (62%) were in first complete remission (CR1) and 30 patients (38%) were beyond CR1 (〉 CR1). The median follow-up was 75 months (range, 14-245 months). The 10-year overall survival for the CR1 and beyond CR1 patients was 54% and 29% (P = .01), respectively, and event-free survival was 48% and 26% (P = .02), respectively. There was no significant difference in relapse incidence (28% vs 41%, P = .28), but nonrelapse mortality was significantly higher in the beyond CR1 patients, (31% vs 54%, P = .03, respectively). By univariate analysis, factors affecting event-free and overall survival were white blood cell count at diagnosis (〈 30 × 109/L vs 〉 30 × 109/L) and disease status (CR1 vs 〉 CR1). The median time to relapse for CR1 and for beyond CR1 patients was 12 months and 9 months, respectively. Our results indicate that FTBI/VP16 with or without cyclophosphamide confers long-term survival in Ph+ ALL patients and that disease status at the time of HCT is an important predictor of outcome.

Description: Key Points Daratumumab conjugated with 64Cu efficiently binds to CD38 on myeloma cells and was mainly detected in the bones of mice. PET/CT based on 64Cu-radiolabeled daratumumab displays a higher resolution and specificity for detecting myeloma than does 18F-FDG PET/CT.

Description: Cutaneous T cell lymphoma (CTCL) is thought to originate from clonally expanded, effector/central memory CD4+ T-cells in a background of chronic inflammation. Our recent investigations have provided evidence for T-cell exhaustion in CTCL with high levels of PD1 and other immune checkpoints (1. Gonzalez BR, Zain J, Rosen ST, Querfeld C. Current Opinion in Oncology. 2016; 28(1): 88-96. 2. Querfeld C, Curran SA, Leung S, Myskowski PL, Horwitz SM, Halpern AC, Young JW. Blood. 2014;124[21, abstract #1695). One potential mechanism by which immune checkpoint protein synthesis can be modulated is by the induction of miRNAs. A subset of miRNAs contributes to the pathogenesis and progression of mycosis fungoides/Sézary syndrome (MF/SS)), but no experimental research has evaluated the effects of miRNAs on immune checkpoints and T-cell exhaustion in CTCL. To address whether miRNA expression correlates with disease and is involved in regulating key immune checkpoint molecules linked to T cell exhaustion, we performed miRNA and gene expression profiling on 50 MF/SS patient samples using high-throughput sequencing, to achieve further insight into the molecular pathogenesis of CTCL disease. Total RNA, which includes miRNA, was extracted from CTCL (MF and SS) samples. Library preparation and high-throughput next generation small RNA sequencing were performed by the City of Hope Integrative Genomics Core. Reads were aligned to human genome assembly hg19, and miRNA expression levels were counted based on miRBase mature miRNA sequences. Differences in miRNA and gene expression between MF and SS patients were measured. Aberrantly expressed miRNAs specific for infiltrated plaques and tumor stage MF were compared. Our preliminary results have identified molecular signatures in CTCL that are linked to disease progression and key immunomodulatory molecules. Unsupervised cluster analysis of skin samples from patients using a heat map was performed (Fig 1). Patients were subdivided into 2 distinct clusters. The top cluster contains all tumor samples with few plaques, while the bottom cluster contains all patch/plaque samples. The clusters also correlated with clinical stage (top cluster = advanced stage ≥IIB; bottom cluster = early stage IA-IIA). Comparison analysis between the top and bottom cluster identified the 20 most significant up-regulated miRNAs that correlate with immune checkpoint (PD1, PD-L1, CTLA4, LAG3, TIM3, and ICOS) expression. For one, miR-146 showed the highest correlation (Table 1). The 20 most significant down-regulated miRNAs were also identified by class comparison analysis performed between top and bottom clusters and correlated with immune checkpoint expression. In conclusion, CTCL develops in a complex microenvironment. The expression of both miRNA and immune checkpoint proteins suggest patterns that provide insight into pathogenesis and potential therapeutic options. Disclosures Querfeld: Celgene: Consultancy, Research Funding; Actelion: Consultancy; Miragen: Consultancy. Zain:Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.