Patnaik, Mrinal M.

Abstract Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is a rare and aggressive hematological malignancy. Unlike B-cell ALL, apart from age and presenting WBC, additional prognostic factors remain largely unknown. Additionally, the prognostic impact of a monosomal karyotype, which has a negative impact on survival in myeloid neoplasms, remains to be determined in T-ALL (Kenderian et al, BCJ 2013) Aim: To study predictors of survival including the role of a monosomal karyotype in T-ALL. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic Rochester were identified. All clinical and pathologic data including FISH studies and cytogenetics were retrospectively reviewed. Chi-square test was used to compare variables. Survival was estimated and compared using the Kaplan-Meier Method and log-rank test. Univariate and multivariate analysis was performed using the Cox regression model. Results: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified, 41 had acute lymphoblastic lymphoma (LBL), and 51 (55%) acute lymphoblastic leukemia (ALL). Median age at diagnosis was 33 years (range; 18-88 years) with 72%males. Median follow up of our cohort was 25 months (range; 0.9-260 months) during which time 42 deaths (45%) were documented. A. Baseline characteristics: Fifty six (67%) had constitutional symptoms, and 63 (77%) had lymphadenopathy at diagnosis. Mediastinal mass was identified in 49 (55%) pts with palpable splenomegaly in 16 (20%) pts. Fifty one (58%) pts had extranodal disease, and 17 (19%) pts had CNS involvement. Pleural and pericardial effusion were evident in 16 (19%), and 6 (7%) pts, respectively. Median laboratory values included; LDH 288 U/L (115-6590), hemoglobin (Hb) 12.8 g/dl (4.5-18.2), WBC 8.65 x109 (1.4-406), platelets 169 x109 (8-485), bone marrow blasts 29% (0-99). B. Treatments: Induction therapies were variable and included; 11 (12%) CHOP like regimens, 7 (8%) modified NHL regimens (Asparginase+CHOP), 54 (58%) ALL like regimens (CALGB 9111, E2993, or HyperCVAD), 13 (14%) Pediatric regimens (ALL 10403, CCG 1961, BFM, Augmented BFM, GRAALL 2003, or Hoelzer regimen), with 7 (8%) patients' receiving palliative care only. Seventy-one (77%) pts achieved complete remission (CR1) during induction therapy while eight pts had refractory disease (8%). Thirty-three (35%) pts underwent stem cell transplant; 7 (21%) autologous and 26 (79%) allogeneic. Forty one (44%) pts had disease relapse and median time to relapse was 10.8 months (range; 8.2-16 months) C. Predictors of survival: In univariate analysis, that included age > 60 years, leukocyte count Hb, Plt, Blast percentage, mediastinal mass, LDH and CNS involvement, only age >60 and CNS involvement were predictors of inferior survival and both retained significance in the multivariable analysis with HR 3.9 (CI 1.5 - 9; p=0.0055) and 2.8 (1.3 - 5.7; p =0.0085), respectively (Figure 1 and 2). In this cohort age >60 was a better stratification that the conventionally used age above 40 (p = 0.1). Among 56 pts with evaluable cytogenetics data, 7 (13%) pts had MK which did not have an impact on survival with HR 1.9 (CI 0.4-5.6; p=0.33). Conclusion: In this large cohort of adult T-ALL patients, we observed that age >60 years and CNS involvement were independent predictors of inferior survival. MK was infrequent, but unlike in myeloid neoplasms, does not seem to impact overall survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Spectrum: Research Funding; Valeant Pharma: Equity Ownership.

Abstract Introduction Midostaurin is an orally available multikinase inhibitor that blocks FLT3 kinase activity. FLT3 mutations are associated with more frequent and earlier relapses and worse survival. The phase 3 RATIFY trial showed that midostaurin compared with placebo improved overall and event-free survival in newly diagnosed pts with FLT3-mutated AML when administered in combination with standard chemotherapy and as single-agent maintenance (Stone et al, ASH 2015). The ongoing RADIUS trial (NCT01883362) is investigating whether adding midostaurin to SOC after alloHSCT reduces the risk of relapse in pts with FLT3-ITD-mutated AML. Here we report safety data from the first 56 enrolled pts. Methods RADIUS is a randomized, open-label, phase 2 study comparing SOC vs midostaurin + SOC after alloHSCT in adult pts with AML with FLT3-ITD mutations (planned enrollment, N = 60). Study treatment started 28-60 days after alloHSCT. SOC was dictated by the treating physician. Pts were randomized to either SOC or midostaurin 50 mg twice daily + SOC (hereafter called the midostaurin arm) continuously for ≤ 12 months and will be followed up for ≥ 24 months. The study was designed to look for any safety or efficacy signals and not powered to find differences between study treatments. The primary endpoint is relapse-free survival at 18 months after alloHSCT. Adverse events (AEs) were followed up for 30 days after treatment. Key inclusion criteria are documented FLT3-ITD mutation, age 18-70 years, and first complete remission status. Pts could enroll after the date of engraftment and hematologic recovery to an absolute neutrophil count > 1000/μL and platelet count ≥ 20,000/μL without requiring transfusion. Results Pts were randomized from Feb 5, 2014, to Jun 13, 2016. The 2 arms (n = 28 each) were balanced regarding age, sex, and race. Most pts (93%) had de novo AML. At data cutoff (Jun 3, 2016), data were not mature enough to evaluate efficacy. Median (range) follow-up in the SOC and midostaurin arms was 240 (3-786) and 234 (3-656) days, respectively. Overall, 18 pts (64%) in the SOC arm and 19 pts (68%) in the midostaurin arm stopped treatment. Of these, 10 (36%) and 8 (29%) in the SOC and midostaurin arms, respectively, completed 12 months of treatment. Other reasons for stopping treatment were relapse (2 [7%] and 2 [7%]), death (2 [7%] and 0 [0%]), administrative problems (2 [7%] and 1 [4%]), withdrawn consent (1 [4%] and 3 [11%]), abnormal test results (1 [4%] and 0 [0%]), and AEs (0 [0%] and 4 [14%]). In the 24 pts who received ≥ 1 dose in the midostaurin arm, the median midostaurin dose was 76.2 (range, 25-100) mg daily. In the 15 pts (54%) who required a dose change, the reasons for dose changes were AEs (13 [46%]), dosing error (3 [11%]), re-escalation (3 [11%]), abnormal test results (2 [7%]), per protocol (2 [7%]), use of concomitant strong CYP3A4 inhibitors (1 [4%]), and other reasons (4 [14%]). The most common any-grade (Gr) AEs were fatigue (29%) and AST, headache, nausea and vomiting (all 25%) in the SOC arm and nausea and vomiting (both 64%) and diarrhea (43%) in the midostaurin arm (Figure 1). The most common Gr 3/4 AEs were nausea and hypertension in the SOC arm (all 3 [11%] each) and diarrhea, increased ALT, neutrophil count decreased (all 3 [11%] each) and platelet count decreased (5 [18%]) in the midostaurin arm. No on-treatment deaths occurred in the midostaurin arm. AEs led to discontinuation of midostaurin in 4 pts and included Gr 1 nausea, Gr 2 nausea and vomiting, Gr 3 lung infection, and Gr 2 elevated liver enzymes (n = 1 each). All of these except the lung infection were considered related to midostaurin. Graft-vs-host disease (GVHD) occurred in 16 pts (57%) in the SOC arm and 18 pts (64%) in the midostaurin arm (Figure 2). No stage ≥ 3 organ involvement occurred. Most cases of GVHD (11 [39%] in the SOC arm and 17 [61%] in the midostaurin arm) were acute. The most commonly affected organ was the skin (11 [39%] and 13 [46%], respectively, of which 5 [18%] and 4 [14%], respectively, were stage 2). Conclusions The preliminary safety data in the post-alloHSCT setting was consistent with data from other studies. Rates of Gr 1/2 nausea, vomiting, and diarrhea were higher in the midostaurin arm. Midostaurin did not change rates of GVHD. Because of the limited duration of follow-up, effects on chronic GVHD are unknown. Follow-up is ongoing, with efficacy data anticipated in 2017. Disclosures Maziarz: Athersys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Deol:Jazz Pharmaceuticals: Consultancy. Haines:Novartis: Employment. Bonifacio:Novartis: Employment. Rine:Novartis: Employment. Fernandez:Fate Pharmaceuticals: Honoraria; Chimerix: Honoraria; Sanofi: Speakers Bureau.

Abstract Background : DNMT3A mutations result in epigenetic dysregulation and impart a negative prognostic impact in acute myeloid leukemia and myelodysplastic syndromes. In chronic myelomonocytic leukemia (CMML), DNMT3A mutations are seen in 2-5% of patients. In a large Groupe Français des Myélodysplasies (GFM) study (n=312), DNMT3A mutations were seen in 2% and were not included in further survival analyses (Itzykson JCO 2013). In a prior Mayo Clinic study (n=175), DNMT3A mutations were seen in 5% (n=9) and on univariate, but not multivariate analysis (Patnaik Blood C J 2016), were associated with shortened over-all survival (OS). We carried out this study on a larger CMML cohort (n=261), with more (n=15) informative cases to assess the impact of DNMT3A mutations. Methods : 261 patients with World Health Organization (WHO)-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. The 2016 WHO diagnostic criteria were used. Results: Among the 261 study patients, 65% were males and median age was 70 years (range, 28-91). 154 (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations (LT) were documented. Mutational frequencies ≥4% were encountered in; TET2 45%, ASXL1 45%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, DNMT3A 6%, U2AF1 6%, SF3B1 5%, ZRSR2 4%, Tp53 4%, and IDH2 4%. i) DNTM3A mutated CMML: phenotypic and molecular correlates DNMT3A mutations were seen in 15 (6%) patients; 64% male with a median age of 64 years. DNMT3A amino acid substitutions included; R882H 50%, R882C 29%, R910P 7%, R598* 7% and R320* 7%. The median variant allele frequency burden was 45%. Concurrent gene mutations were detected in; TET2 43%, ASXL1 21%, SF3B1 21%, U2AF1 14%, RUNX1 14%, SETBP1 14%, NRAS 14%, SRSF2 7%, JAK2 7% and Tp53 7%. There was no difference between DNMT3A mutated and wild-type patients in terms of age and gender distribution, hemoglobin level, leukocyte, monocyte (AMC), and platelet counts, peripheral blood (PB) or BM blast content. Concurrent gene mutations were equally distributed with the exception for a higher prevalence of SF3B1 (p=0.003) and a lower prevalence of SRSF2 (p=0.004) mutations in DNMT3A mutated CMML. Four (29%) patients underwent leukemic transformation. ii) Impact on OS and leukemia-free survival (LFS): Median survival for the entire cohort (n=261) was 24 months. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wild-type (median 27 months) patients (p=0.0007; HR 2.9, 95% CI 1.5-5.7; Figure 1A). Other variables of significance, in univariate analysis, included lower hemoglobin (p=0.002), higher leukocyte count (p=0.0009), higher AMC (p=0.0012), PB blast % (p=0.001), circulating immature myeloid cells (IMC, p=0.01), BM blast % (p=0.045), abnormal karyotype (p=0.02), and ASXL1 (p=0.01) mutations. Survival was also adversely affected by the presence of either (n=133) or both (n=3) ASXL1/DNMT3A mutations (0=0.007, Figure 1B). In multivariable analysis (MVA) excluding ASXL1 and DNMT3A mutations, hemoglobin (p=0.03), IMC (p=0.013) and AMC (p=0.02) retained significance. When ASXL1 mutations were added to the MVA, ASXL1 (p=0.01) mutations, AMC (p=0.012) and IMC (p=0.03) retained significance. Similarly, when only DNMT3A mutations were added to the MVA, DNMT3A (p=0.003) mutations, IMC (p=0.01) and AMC (p=0.02) retained significance. When both DNMT3A and ASXL1 mutations were added to the MVA, only DNMT3A (p<0.0001) and ASXL1 (p=0.004) mutations remained significant. DNMT3A mutations predicted shortened OS, independent of the ASXL1 inclusive GFM model (p<0.0001) and Mayo Molecular Model (p=0.002). DNMT3A mutations (p=0.0018), along with low hemoglobin levels (p=0.003) independently predicted for a shorter LFS. Conclusions: DNMT3A mutations are seen in ~5% of patients with CMML and impart a negative prognostic impact on both OS and LFS. This finding warrants inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models. Disclosures No relevant conflicts of interest to declare.

Abstract Background The impact of JAK inhibitor (JAKi) therapy on the natural history of myelofibrosis remains unclear. While a Phase 3 study showed that overall survival of ruxolitinib-treated intermediate-2 or high-risk myelofibrosis patients was superior as compared to placebo-treated patients, it remains unclear whether such an advantage would persist in patients receiving standard therapy, and whether this result is generalizable to other JAK inhibitors. We conducted a sponsor-independent, single-center retrospective analysis of overall and leukemia-free survival after long-term follow up in patients receiving JAKi treatment with comparison to two control populations: (i) a contemporaneously diagnosed (2005 onwards) primary myelofibrosis (PMF) patient cohort receiving standard therapy (JAKi and pomalidomide naïve); and (ii) a pomalidomide treated patient cohort (JAKi-naïve). Methods Baseline clinical, cytogenetic and molecular data were collected at the onset of study treatment with the first JAKi or pomalidomide, or at the time of first referral for patients receiving standard therapy. Information regarding bone marrow karyotype and DIPSS-plus risk status was available for all patients. Information on survival and leukemic transformation was updated in July 2013. Results The 3 patient groups were: (i) JAKi-treated: n=157, median age 65 years, range 34-89. DIPSS-plus risk: Low/Int-1 20 (13%), Int-2 66 (42%), and High 71 (45%). Median follow up from first JAKi treatment was 30 months (range 1-67 months); during this period, 72 deaths (46%) and 14 (9%) leukemic transformations were documented. The first JAKi was ruxolitinib in 51 patients (33%), momelotinib (CYT387) in 79 (50%), and fedratinib (SAR302503) in 27 (17%). The proportion of patient deaths and leukemic transformation (median follow up, range) per specific JAKi was: ruxolitinib 57% and 12% (40 months, 2-67), momelotinib 43% and 9% (29 months, 1-42), and fedratinib 33% and 4% (21 months, 2-53), respectively. (ii) Control#1 (Pomalidomide-treated): n=69, median age 67 years, range 36-87. DIPSS-plus risk: Low/Int-1 0 (0%), Int-2 28 (41%), and High 41 (59%). Median follow up was 25 months (range 2-70 months); during this period, 47 deaths (68%) and 7 (10%) leukemic transformations were documented. (iii) Control# 2 (Standard therapy): n=319, median age 66 years, range 22-90. DIPSS-plus risk: Low/Int-1 98 (31%), Int-2 122 (38%), and High 99 (31%). Median follow up from time of referral was 18 months (range 1-92 months); during this period, 101 deaths (32%) and 18 (6%) leukemic transformations were documented. For patients with Int-2 or high-risk disease (n=221), 92 deaths (42%) and 13 (6%) leukemic transformations were recorded (median follow up 16 months, range 1-92). The survival analysis focused on DIPSS-plus Int-2 and high-risk patients for all groups, reflecting the population predominantly selected for treatment on JAKi clinical trials. There was no significant difference in the median overall survival of myelofibrosis patients treated with JAKi (39 months) versus standard therapy (35 months) versus pomalidomide (26 months) (p=0.12) (Figure). The 5-year survival rates were 31%, 33% and 26%, respectively. Similarly, the median overall survival of patients treated with ruxolitinib (35 months), momelotinib (37 months) or fedratinib (42 months) was not significantly different (p=0.4). Baseline DIPSS-plus status (ie, Int-2 vs. high-risk) effectively stratified JAKi treated patients in terms of overall survival (median survival 31 vs. 60 months; p=0.0002). There was no significant difference in leukemia-free survival when comparing JAKi-treated patients versus standard therapy verus pomalidomide-treated patients (p=0.6) (Figure). The estimated 5-year risk of leukemic transformation was 17%, 12% and 13%, respectively. Conclusions With long-term follow up, myelofibrosis patients receiving JAKi therapy exhibited similar overall and leukemia-free survival as compared to two control populations (DIPSS-plus matched standard therapy and pomalidomide-treated patients). Baseline DIPSS-plus status was a powerful predictor of overall survival in JAKi treated patients. While underscoring the limitation of a non-head-to-head retrospective comparison, there was no significant difference in overall or leukemia-free survival when comparing individual JAKi drugs. Disclosures: Pardanani: Bristol Myers Squibb: Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; PharmaMar: Clinical trial support, Clinical trial support Other; JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other. Off Label Use: Use of Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting.

Abstract Background: Chronic GVHD contributes to morbidity and mortality after allogeneic transplantation. Several phase 2 and 3 open label studies suggested that ATLG (formerly referred to as ATG-F) reduces cGVHD without impacting relapse or survival. This report describes the first prospective randomized double blind phase 3 trial to assess the effect of ATLG (Neovii) when added to tacrolimus / methotrexate prophylaxis on cGVHD free survival. Patients and Methods: This study was conducted at 27 sites in the United States and Australia. 260 patients were randomized (132 placebo, 128 ATLG). 6 patients who were randomized never received ATLG/placebo (4 placebo and 2 ATLG). Data presented include the 128 placebo and 126 ATLG patients who underwent treatment and transplant. Patients were ages 18-65 years with a diagnosis of acute myeloid (AML, 64%) or lymphoblastic (ALL, 21%) leukemia in first or subsequent complete remission or myelodysplastic syndrome (MDS, 15%) with less than 10% marrow blasts. Median age was 48 years (18-65) with 55% males. All patients received 8/8 HLA (A, B, C, DR) allele matched unrelated products (80% mobilized peripheral blood, 20% bone marrow). Myeloablative conditioning was with cyclophosphamide and total body irradiation (Cy/TBI, 27%), busulfan and cyclophosphamide (Bu/Cy, 33%), or busulfan and fludarabine (Bu/Flu, 40%). All patients received tacrolimus starting on Day -1 and standard mtx on days 1, 3, 6, and 11 for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). The primary endpoint of the study was moderate/severe chronic GVHD free survival. cGVHD was scored by the investigator and then confirmed or overturned by an independent adjudication committee. Secondary endpoints included engraftment, acute GVHD , moderate/severe cGVHD, non-relapse mortality, GVHD and relapse free survival (GRFS), progression free (PFS) and overall survival (OS). The impact of ATLG on immune reconstitution was assessed in 91 patients. Results: Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), CMV serostatus and conditioning regimen. Median follow up of survivors was 745 days (61, 1425). Regarding the primary endpoint, there was no difference in 2 year moderate/severe cGVHD free survival between ATLG and placebo (48 vs 44%, p = 0.57), nor was there a difference in GRFS (Table 1). Neutrophil engraftment at Day 30 was less in the ATLG arm (85% vs 95%, p=0.00001). Grade 2 or higher infusion reactions were higher in the ATLG arm (16% vs 2.3%, p=0.0001). Reactivation of CMV was similar (27% vs 31%, p=0.58). The Day 180 cumulative incidence of grades 2-4 acute GVHD was lower in the ATLG arm (23 vs 40%, p = 0.003) as was the 2-year cumulative incidence of moderate/severe cGVHD (12 vs 33%, p = 0.000006). However, both 2-year OS and PFS were lower in ATLG treated patients (58 v 76% and 47 vs 67%, respectively) due in part to a higher incidence of relapse (32 vs 19%, p=0.068). Multivariable models confirmed that ATLG was associated with inferior OS, HR 1.85 (1.1-2.9, p=.0075) and PFS, HR 1.63 (1.1-2.41, p=0.015). We then conducted an unplanned post-hoc analysis and discovered a striking influence of conditioning regimen on outcomes. There were no differences in OS or PFS between ATLG and placebo arms in patients receiving Bu/Cy or Bu/Flu but a dramatic difference in patients receiving Cy/TBI conditioning (OS, 88% vs 48% p =0.006 and PFS, 75 vs 29%, p=0.007 in placebo and ATLG arms, respectively). 91 patients (44 ATLG, 47 placebo) participated in the immune reconstitution study. ATLG treatment was associated with lower CD3, CD4, and CD8 counts at Days 30, 100, and 360, respectively. In turn lower CD3, CD4, and CD8 counts assessed as time dependent variables were all associated with inferior OS and PFS as well as higher NRM (data not shown). Conclusion: In this first ever prospective, randomized, double blind trial of ATLG added to tacrolimus /methotrexate in recipients of matched unrelated donor grafts after myeloablative conditioning, there was no significant difference in 2 year moderate/severe cGVHD free survival or GRFS. ATLG did significantly reduce grades 2-4 acute and moderate/severe chronic GVHD. However, overall survival was higher in the placebo arm, driven mainly by patients who received Cy/TBI conditioning. Further analyses are needed to understand the proper role for ATLG in HCT. Disclosures Soiffer: Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Jagasia:Therakos: Consultancy. Szer:Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Glavin:Neovii Biotech: Employment. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Abstract Background : An increased incidence of second skin and visceral malignancies in comparison to the general population has been reported in patients with hematologic neoplasms such as, chronic lymhocytic leukemia (CLL) (~11-36%) (Tsimberidou, JCO, 2009),chronic myeloid leukemia (CML) (4-6%) (Miranda, Leukemia 2016)and multiple myeloma (MM) (3-4.3%) (Palumbo, Lancet Oncol 2014).Diverse etiologies exist for this association. We carried out this study to describe the spectrum of second malignancies in patients with chronic myelomonocytic leukemia (CMML). Methods : Patients with World Health Organization defined CMML were included in the study. All patients had bone marrow (BM) biopsies performed at diagnosis. We only included malignancies that were diagnosed at the time of CMML diagnosis or subsequent to it. Patients that had concomitant systemic mastocytosis (n=18), therapy related CMML (n=19) and those that underwent allogeneic stem cell transplantation (n=23) were excluded. Standard cancer specific diagnostic and staging methods were utilized. Results: The study included 378 patients (median age 71 years; 66% males). Seventy-one concomitant and/or subsequent second malignancies were identified in thirty-two (8%) patients. Age group distribution was; 50-59 years 1 (1%), 60-69 years 21 (30%), 70-79 years 30 (42%) and ≥ 80 years 19 (27%) second malignancies. 22 (69%) patients had 1 second malignancy, 4 (13%) had 2, 2 (6%) had 4 (skin neoplasms), while 4 (13%) patients had ≥ 5 second malignancies (Table one). At a median follow-up of 18 months, 284 (75%) deaths and 54 (14%) leukemic transformations were documented. i) Second hematological malignancies: Thirteen (18%) concomitant (n=7, 54%) and subsequent hematological malignancies (n=6, 46%) were observed in 13 (3.5%) patients. In addition, 10 (3%) pre malignant states including, 7 patients with MGUS and 3 with monoclonal B-cell lymphocytosis (MBL) were seen. In one case each, the MGUS and MBL evolved into multiple myeloma (after 16 months) and CLL (after 30 months), respectively. Concomitant malignancies included: polycythemia vera (n=2, 15%), MM (n=2, 15%), marginal zone B-cell lymphoma (n=1, 8%), splenic lymphoma (n=1, 8%), ALK-rearranged T-cell lymphoma (n=1, 8%), while subsequent malignancies included: MM (n=1, 8%), diffuse large B-cell lymphoma (n=1, 8%), Waldenström's macroglobulinemia (n=1, 8%), CLL (n=2, 15%) and acute lymphoblastic leukemia (n=1, 8%). Four (31%) patients needed chemotherapy, with outcomes including: complete remission in one case (multiple myeloma), progression of disease in 2 (multiple myeloma and diffuse large B cell-lymphoma) and partial response in 1 case (ALK rearranged T cell lymphoma). CMML related cytopenias did not preclude patients from getting chemotherapy. Three patients died from causes related to their second malignancies. ii) Cutaneous malignancies: Fifty-one (71%) concomitant (n=12, 24%) and subsequent cutaneous malignancies (n=39, 76%) were seen in 13 (3%) patients. The concomitant malignancies included: 7 (14%) basal cell carcinoma (BCC), 5 (10%) squamous cell carcinoma (SCC), while subsequent cancers included: 3 (6%) malignant melanoma, 7 (14%) BCC and 29 (57%) SCC. Four cases (8%) were locally advanced and four patients (8%) had recurrent lesions. A concomitant diagnosis of BCC and SCC was made in 8 patients (16%). All patients were treated surgically or with electrodesiccation and curettage. No deaths or metastases were reported. iii) Visceral malignancies: Seven (10%) subsequent visceral malignancies were seen in 6 (1%) patients. These included; colonic adenocarcinoma (n=2, 29%), bladder adenocarcinoma (n=1, 14%), endometrial adenocarcinoma (n=1, 14%), prostate adenocarcinoma (n=1, 14%), clear cell renal carcinoma (n=1, 14%) and papillary thyroid carcinoma (n=1, 14%). All the cases were localized and surgically resected, with two patients (colonic and endometrial adenocarcinoma) needing adjuvant chemo-radiotherapy. All patients achieved complete remission with no mortality related to second malignancies. Conclusions: Approximately 8% of CMML patients have second cutaneous (3.5%), hematological (3.5%) and visceral (1%) malignancies, with most of these occurring in and beyond the seventh decade (~70%) of life. Mortality related to second cancers was low (2%), with most patients receiving appropriate surgical and adjuvant chemo-radiation therapy. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract Background: Acute T-cell lymphoblastic leukemia (T-ALL)/ lymphoma (T-LBL) are immature T-cell malignancies with very poor outcomes. In patients with relapsed disease, survival is often < 12 months (Marks et al, Blood, 2009). Prognostic correlates and treatment outcomes after relapse remain largely unknown. Aims: To evaluate prognostic correlates and treatment outcomes in patients with relapsed T-ALL/LBL. Methods: After IRB approval, 92 consecutive patients with T-cell ALL/LBL were identified. 41 patients with relapsed disease after achieving a first complete remission (CR1) were included in the study group. Features at the time of relapse were retrospectively abstracted and analyzed. Survival time after relapse was calculated from the time of relapse until death or last follow-up. Conventional methods were used for statistical analysis. Results: A. Baseline characteristics of all patients 92 patients were identified [41 LBL, 51 ALL]. Median age was 33 years (range; 18-88) and 66 (72%) were males. Median follow-up was 25 months (range 0.9-260). 13(14%) received palliative care or were lost to follow-up before treatment initiation. At last follow-up, there were 41 (52%, n = 79) relapses and 42 (46%, n = 92) deaths. Of 79 patients, 71 (90%) achieved a CR1 and 8 (10%) had primary refractory disease. Comparisons between ALL and LBL revealed expected differences in presenting features such as frequency of primary mediastinal mass at presentation in LBL and high leukocyte count in ALL. Significant differences in treatment were seen. Asparaginase-based and ALL-directed therapy were more common in the ALL group (71% vs. 45%, p = 0.009; 88% vs. 71%, p = 0.04). 13 (81%) LBL and 14 (27%) ALL underwent allogeneic SCT. The remaining three in each group underwent autologous SCT in CR1. B. Characteristics of relapsed patients 41 relapsed after achieving CR1 [23 LBL, 18 ALL]. Median time to relapse was 8.0 months (range 2.3-130), with no difference between ALL and LBL groups. Median age was 34 years (range 19-71) and 29 (71%) were males. Median follow-up after relapse was 7.2 months (range 0.3-207). At time of last follow-up, there were 30 (73%) deaths, 25 (61%) achieved a second complete remission (CR2) and 14 (34%) had persistent disease. 12 (48%) had relapse following CR2. 34 (83%) relapsed following CR1 after induction chemotherapy alone. 6 (15%) and 1 (2%) relapsed following allogeneic and autologous SCT respectively. 27 (66%) had BM involvement, 5 (12%) had CNS involvement, 13 (32%) had mediastinal involvement, and 3 (7%) had isolated extramedullary relapse. Ten (43%) patients with LBL relapsed with ALL. Of 27 patients with available data, 9 (33%) had high-risk cytogenetics at relapse, defined as ≥ 5 chromosomal abnormalities and/or markers known to confer an unfavorable prognosis. 16 of these 27 patients had follow-up cytogenetic studies performed, of which 8 (50%) had evidence of clonal evolution. Patients were treated with up to five regimens. 12 (31%) received asparaginase-based therapy and 13 (33%) received nelarabine with CR2 rates of 75% and 25% respectively. Median number of regimens needed to achieve CR2 was one. 18 (46%) went onto SCT following CR2: 14 (allogeneic), 3 (autologous), and 1 (donor lymphocyte infusion). The majority received myeloablative conditioning (92%). C. Outcomes and prognostic correlates for survival after relapse Median survival following relapse was 8.2 months (IQR 4.1-21.3) and did not differ between LBL and ALL. Nine (36%) who achieved CR2 are alive at time of last follow-up. 25 (61%) achieved CR2, but 12 (48%) relapsed following CR2, with median time to second relapse of 7.6 months (IQR 4.7-14). Nine of 18 who underwent SCT following CR2 had disease relapse (8 allogeneic, 1 autologous). Only BM involvement at relapse significantly correlated with post-relapse survival (HR 2.4 [1.1, 5.1], p = 0.03). Clonal evolution, high-risk cytogenetics, nelarabine therapy, achieving CR2, and SCT were not independent predictors of survival in our small subset of patients. Conclusion: Patients with relapsed T-ALL/LBL have dismal outcomes, in spite of advances in therapy with newer agents such as nelarabine and the use of allogeneic SCT. Regardless of T-ALL/LBL subtype, BM involvement at relapse appears to be a significant factor negatively impacting post-relapse survival. Further studies are needed to validate these findings. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background JAK inhibitors (JAKi) currently represent a frontline treatment modality in patients with symptomatic intermediate- or high-risk myelofibrosis (MF). While the efficacy of JAKi in decreasing spleen size and improving disease-related symptoms is well documented, the effect of this drug class on overall survival and risk of leukemic transformation in MF patients is less well understood, primarily due to short follow up in individual patient cohorts. Furthermore, there is scant information on baseline predictors of overall and leukemia-free survival, and also spleen and/or anemia responses, at the onset of JAKi therapy. We conducted a sponsor-independent single-center retrospective review of patients treated with JAKi with long follow up to address the aforementioned issues. Here, we report our findings regarding baseline predictors of clinical outcome and treatment response in MF patients treated with JAKi. Methods Clinical, cytogenetic and molecular data were retrospectively collected on patients treated with one or more JAKi on a clinical trial at the Mayo Clinic, Rochester, MN. Baseline clinical data pertained to the onset of treatment with the first JAKi. Karyotype information was available for all patients. Screening for JAK2V617F, MPLW515, ASXL1, and SRSF2 mutations was performed as previously described (Leukemia. 2013 Apr 26. doi: 10.1038/leu.2013.119). Spleen size was measured by palpation by clinical investigators. Anemia and spleen responses were adjudicated as per IWG criteria (Tefferi, Blood, 2006). Information on survival and leukemic transformation was updated in July 2013. Results A total of 157 MF patients were studied (60% male; median age 65 years, range 34-89 years). Ninety seven patients (62%) had primary MF, 42 (27%) post-polycythemia vera MF, and 18 (11%) post-essential thrombocythemia MF. The DIPSS-plus distribution was: Low/Int-1 20 (13%), Int-2 66 (42%), and High 71 (45%). Other characteristics were: JAK2V617F positive 78%, unfavorable karyotype 17%, hemoglobin <10 g/dL 58%, leukocyte count >25 x 109/L 31%, platelet count <100 x 109/L 15%, peripheral blasts ≥1% 69%, red blood cell transfusion-dependent 37%, and constitutional symptoms 56%. Forty one patients (38%) were ASXL1 mutated (n=108) and 20 (18%) SRSF2 mutated (n=110). One hundred and thirty nine patients (89%) were evaluable for spleen response (median spleen size by palpation 19 cm, range 6-32 cm) and 91 (58%) for anemia response by IWG criteria. The first JAKi was momelotinib (CYT387) in 79 patients (50%), ruxolitinib in 51 (33%) and fedratinib (SAR302503) in 27 (17%). Median follow up from first JAKi treatment was 30 months (range 1-67 months); during this period, 72 deaths (46%) and 14 (9%) leukemic transformations have been documented. The median overall survival of the entire cohort was 41 months. Multivariable analysis identified the following DIPSS-plus independent predictors for survival: palpable spleen size >20 cm (HR 2.5), ASXL1 mutated status (HR 3.1) and SRSF2 mutated status (HR 3.8) (all p<0.01) (Figure). In contrast, there was no difference in survival with regards to the first JAKi used for MF treatment (p=0.3). Multivariable analysis identified the following predictors for leukemia-free survival: SRSF2 mutated (HR 9.7), unfavorable karyotype (HR 8.7), and palpable spleen size >20 cm (HR 9.1) (all p<0.01). Predictors of spleen response included baseline spleen size (≤20 cm 56%, >20 cm 34%; p=0.01), with borderline significance for ASXL1 mutation status (unmutated 51%, mutated 31%; p=0.06). Predictors of anemia response included RBC transfusion status at baseline (transfusion dependent 38%, transfusion independent 12%; p<0.01) and JAK2V617F status (unmutated 46%, mutated 22%; p=0.02). Conclusions Larger baseline spleen size and ASXL1 and SRSF2 mutated status predicted for inferior overall survival, independent of DIPSS-plus, at the onset of first JAKi treatment in MF patients. Similarly, multivariable analysis identified larger baseline spleen size and presence of unfavorable karyotype and SRSF2 mutations as being predictive for inferior leukemia-free survival. Spleen response rates were significantly superior in patients with smaller baseline spleen size and possibly ASXL1 unmutated status. Anemia response rates were significantly higher in patients who were transfusion-dependent at baseline and had JAK2V617F unmutated status. Disclosures: Pardanani: Bristol Myers Squibb: Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; PharmaMar: Clinical trial support, Clinical trial support Other; JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other. Off Label Use: Use of Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting.

Abstract Background In myelodysplastic syndromes (MDS), we have previously shown the adverse prognostic effect of ALC <1.2 x 10(9)/L (Nisha et al. Am J Hematol 2010;85:160). In the current larger study of 889 patients with MDS, we sought to validate and expand on our previous observations and also examine the effect of lymphocyte-to-monocyte ratio (LMR). Methods We retrospectively recruited 889 consecutive patients with primary MDS who were untreated at the time of referral to our institution, and in whom ALC and absolute monocyte count (AMC) at time of referral was documented. The diagnosis of MDS and leukemic transformation (LT) was according to WHO criteria (Blood. 2009;114:937). Complete follow-up information was updated in January 2015. Comparison of laboratory and clinical features was made between patients with subnormal and normal ALC; patients with above normal ALC were considered separately. Overall and leukemia-free survivals of patients with normal ALC was compared to those with either subnormal ALC or, in order to validate our previous observation, with ALC <1.2 x 10(9)/L. Results Patient characteristics: Median (range) values for the 889 study patients (69% males) included: age 72 (18-98), hemoglobin 9.6 g/dL (5.4-15.7), leukocyte count 3.4 x 10(9)/L (0.4-35), AMC 0.2 x 10(9)/L (0-1.7), platelet count 106 x 10(9)/L (2-1804), circulating blasts 0% (0-18) and bone marrow blasts 3% (0-19). Transfusion need was documented in 33% of patients and abnormal karyotype in 49%. Risk stratification by the revised international prognostic scoring system (IPSS-R) was very high in 10%, high in 16%, intermediate in 20%, low in 36% and very low in 16%. The median (range) ALC for the entire study population of 889 patients was 1.16 x 10(9)/L (0.02-8.9). The normal range of ALC at our institution was 0.9-2.9 x 10(9)/L; the number of patients with subnormal, normal and above normal ALC was 261 (29%), 598 (67%) and 30 (4%), respectively. In addition, 442 (50%) and 417 (47%) patients had ALC below 1.2 x 10(9)/L and ALC between 1.2 and the upper limit of normal, respectively. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformations were documented. Comparison of patients stratified by absolute lymphocyte count Compared to patients with normal ALC, patients with subnormal ALC displayed lower hemoglobin (p=0.002), higher red blood cell transfusion need (p=0.0003), lower leukocyte count (p<0.0001), lower monocyte count (p=0.002) and lower platelet count (p<0.0001), whereas borderline association was also apparent for older age (p=0.06). In univariate analysis, survival was adversely affected by lower ALC, treated as a continuous variable (p=0.01). Similarly, when compared to patients with normal ALC, patients with subnormal ALC (p=0.001; HR 1.3, 95% CI 1.1-1.5) and those with ALC <1.2 x 10(9)/L (p=0.0002; HR 1.3, 95% CI 1.2-1.6) experienced significantly shortened survival. There was no difference in survival between patients with above normal ALC and those with either subnormal (p=0.58) or normal (p=0.41) ALC; accordingly, patients with above normal ALC were excluded from subsequent analysis. In multivariable analysis, the adverse effect of subnormal ALC was shown to be independent of age, gender, anemia, thrombocytopenia, neutropenia , circulating blast percentage, bone marrow blast percentage or cytogenetic risk stratification by and IPSS; the same held true for ALC <1.2 x 10(9)/L. The association with IPSS-R was of borderline significance for both ALC <1.2 x 10(9)/L (p=0.06) and subnormal ALC (p=0.1). The adverse effect of ALC was most apparent in patients with very low or low risk disease per IPSS-R (p=0.0007 for subnormal ALC and 0.0003 for ALC <1.2 x 10(9)/L), compared to those with higher risk status (p=0.67 and 0.7, respectively). Neither subnormal ALC (p=0.4) nor ALC <1.2 x 10(9)/L (p=0.1) affected leukemia free survival. Analysis using LMR in place of ALC showed similar but not necessarily superior results. Conclusions Compared to those with normal ALC, MDS patients with either subnormal ALC or with ALC below 1.2 x 10(9)/L experienced shorter overall, but not leukemia-free, survival; this adverse effect was most apparent in lower risk patients and was independent of most of the currently established risk factors for survival in MDS. The observations from the current study suggest the possible therapeutic value of augmenting host immunity in lower risk MDS. Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

Abstract Introduction Steroid refractory chronic graft-versus-host-disease (SR-cGVHD) is the leading cause of late morbidity and mortality in allogeneic transplant patients. Safety of extracorporeal photophoresis (ECP) has led to multiple studies evaluating its role in SR-cGVHD. Overall and organ specific response rates (RR) of SR-cGVHD have varied significantly between studies. We conducted a systemic review and meta-analysis to assess the efficacy of ECP in SR-cGVHD. Methods A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central register of Controlled Trials,, Scopus) for articles published in any language between 1984-2012 was conducted. Unpublished studies using electronic databases from the annual meetings abstracts of hematology/transplant societies were searched. Experts in the field were also contacted for selection of studies and missing data from selected trials. End points included complete response rate (CR), overall RR (ORR), and organ-specific RR's. Results Initial search generated 312 studies, out of which 18 studies (4 prospective) met selection criteria (N=595). Random effects model was used for pooled rates. Pooled CR rate (11 studies) was 29% (CI 19%-42%). Pooled ORR (16 studies) was 64% (CI 65-82%). 1 year overall survival was 49% (CI 29-70%). There was significant heterogeneity between studies (I²=72) likely due to differences in ECP schedules utilized, and a variety of scales used to measure outcomes. Pooled RR's for SR-cGVHD of skin was 74% (CI 60-85%), liver was 68% (CI 57-77%), ocular was 60% (CI 40-78%), oral was 72% (CI 51-86%), lung was 48% (CI 33-63%), gastrointestinal (GI) was 53% (CI 21-83%), and musculoskeletal (MSK) was 64% (CI 18-94%). No significant differences in responses to ECP for pediatric and adult populations were found. Sensitivity analysis could not be done due to limited number of prospective studies. Conclusions ECP is an effective therapy for oral, skin & liver SR-cGVHD, with modest activity in lung and GI SR-cGVHD. Further studies must report standardized outcomes with a uniform schedule of ECP. Disclosures: No relevant conflicts of interest to declare.