Patnaik, Mrinal M.

Abstract Aims/Objective:Congenital antithrombin (AT) deficiency, estrogen-containing oral contraceptive pills (OCPs) and pregnancy are associated with increased risk of venous thromboembolism (VTE). Little is known about reproductive decision-making in women with AT deficiency. We sought to explore the attitudes and choices regarding reproductive health in this population. Study Design/Methods:We conducted a provider-administered survey of women identified from the Mayo Clinic congenital AT deficiency database. Participants were asked to discuss their diagnosis of AT deficiency (age at diagnosis and VTE history including diagnosis and treatment) and questioned about (1) any lifetime methods of contraception, (2) pregnancies and pregnancy outcomes, (3) use of assisted reproductive technology, (4) history of menorrhagia, and (5) how their AT diagnosis had impacted each reproductive health experience and how this impact made them feel (open-ended question). Results:Of 31 women with congenital AT deficiency, 18 (58%) were reached, 8 (26%) were not reachable and 5 (16%) were deceased. Of the 18 women who completed the survey, median age at AT deficiency diagnosis was 40 years (range 7 - 65). Twelve (67%) women had experienced a VTE; 2 and 5 women had VTE in the setting of pregnancy OCP use, respectively. Reported contraceptive methods included OCPs, intrauterine device (IUD), and male condoms. Of the 5 women diagnosed with AT deficiency while taking OCPs, three switched to IUD, one to condoms, and one did not report an alternative method of contraception. Fifteen (83% ) women reported at least one pregnancy (median number of pregnancies = 2; range 1 - 6). Of 42 total pregnancies among the 18 women, 33 (79%) resulted in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in miscarriage/spontaneous abortion at a median of 12 weeks into the pregnancy. Four women (22%) reported the use of anticoagulation during pregnancy (presumed to be low molecular weight heparin, but most women could not specify), and 1 woman reported use of assisted reproductive technology leading to a successful pregnancy. Eleven women (61%) reported menorrhagia, 4 (36%) while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the AT deficiency diagnosis had affected their reproductive health in at least one way. Patient-reported comments are presented in Table 1, and a "word cloud" diagram (an image composed of words from the women's comments regarding contraception), in which the size of each word indicates its frequency) is presented in Figure 1. Conclusion:Women with AT deficiency require careful multidisciplinary management to avoid complications in the settings of hormonal contraception and pregnancy. Many women reported that their reproductive health experiences were impacted by their diagnosis, but also reported successful pregnancy outcomes. Validated questionnaires should be developed to assess women's reproductive health experiences. Strategies for reproductive risk management should be discussed carefully, and patient involvement in reproductive decision-making is key in this population. Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Noonan syndrome, characterized by dysmorphic facies, webbed neck, short stature, chest deformity, developmental delay and congenital heart defects, occurs as a result of mutations affecting the RAS-MAPK signaling pathway. A wide range of coagulation abnormalities are observed in these patients including: thrombocytopenia, platelet dysfunction and coagulation factor deficiencies. Screening for coagulation defects is recommended in childhood and especially prior to surgical procedures. Data available is limited and the extent of the hemostatic evaluation needed is not clearly defined. We carried out this study to outline the spectrum of coagulation abnormalities seen in patients with Noonan syndrome and their impact on surgical outcomes. Methods: In this retrospective cohort study, the electronic medical record system was queried for patients with Noonan syndrome seen at Mayo Clinic between 2000 and 2016. A detailed chart review was undertaken. Results i) Phenotypic correlates: 142 patients (58% male) met our study criteria, median age 21 years (range 14 days to 68 years). The referral specialty for initial evaluation was: cardiology 69 (49%), endocrinology 10 (7%), urology 10 (7%), neurology 8 (6%), pulmonary 6 (4%), orthopedic surgery 3 (2%), gastroenterology 2 (1%), psychiatry 2 (1%) and other specialties 4 (3%). Ten patients (7%) were referred for developmental delay, 13 (9%) for dysmorphism and 4 (3%) after having a family member diagnosed with Noonan syndrome. One patient (1%) presented with hematochezia. Twenty-seven (52%) of the 52 patients screened with genetic testing had a Noonan-associated gene defect. Bleeding was reported by 22 patients (15%) with a median International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) score of 2 (range 1-8). Of those tested, 11/121 (9%) patients had thrombocytopenia (platelets < 150 x 10^9/L). Screening coagulation tests were done in 58 (41%) patients, and included PT/aPTT in 43 (74%) and extended coagulation panels (including platelet function studies) in 15 (26%). Of the 22 patients with history of bleeding, 20 (90%) had screening coagulation testing. Twenty-two (38%) of patients screened had one or more coagulation laboratory abnormality. Ten (66%) patients with clinically suspected platelet dysfunction had normal platelet function analyzer (PFA)-100 testing and normal light transmission aggregometry, while 5 (33%) had decreased platelet aggregation with epinephrine. Four patients (7%) (including 2 siblings) had low vWF levels consistent with type 1 vWD, 9 (16%) had mild clotting factor deficiencies ( FIX- 3, FXII-2 and multiple clotting factors-5) and 4 (7%) had a prolonged baseline PT and/or aPTT without additional coagulation factor assessment (Table 1). Thirteen patients (9%) had both a bleeding phenotype and abnormal coagulation laboratory results. ii) Surgical outcomes: A total of 274 surgical procedures were performed in 89 patients (63%). These included: cardiac 118 (43%), orthopedic 30 (11%), ENT 27 (10%), neurosurgical 26 (10%), abdominal 17 (6%), urologic 17 (6%), gynecologic 12 (4%) thoracic 8 (3%), ophthalmologic 7 (3%), plastic surgery 5 (2%), maxillofacial 4 (1%) and lymph node dissection 3 (1%). Platelets were utilized in 26 procedures (10%), fresh frozen plasma in 19 (7%) and cryoprecipitate in 7 (3%). Two procedures were performed in patients with type 1 vWD using vWF concentrates. Abnormal intra or postoperative bleeding was seen in 5/274 procedures (1.8%) performed in 4 patients. One patient had a known functional platelet disorder, one had normal PT and aPTT and two were not screened for coagulation defects. Bleeding was managed with transfusional supportive care in 3 (60%) surgical cases, while in 2 (40%) cases patients required re-intervention to achieve surgical hemostasis (bleeding from femoral access site and pacemaker pocket hematoma). There was no mortality related to the excess perioperative bleeding. Conclusion: Varying hemostatic abnormalities are seen in patients with Noonan syndrome, ranging from thrombocytopenia to multiple coagulation factor deficiencies. Frank bleeding manifestations however are uncommon and when present are usually mild. Clinical evaluation focused on the bleeding history and basic coagulation screening allows for successful perioperative hemostatic support and good surgical outcomes. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Over 10,000 new cases of myelodysplastic syndrome (MDS) are diagnosed in the US annually (MA X, Cancer 2007). Hypomethylating agents (azacitidine and decitabine), immunomodulating drugs (lenalidomide) and erythropoietin stimulating agents (epoetin α and darbepoetin) have been approved for more than a decade for the treatment of MDS. However, changes in overall outcome after the approval of these treatments are unknown. We used the National Cancer Data Base (NCDB), a nationwide oncology registry covering 70% of the US cancer population to answer these questions. Methods: We identified patients with MDS diagnosed from 2004-2013 using ICD-O-3 codes 9980-9983 and 9985-99912. Overall survival (OS) was estimated using the Kaplan-Meier method. We compared OS using the log-rank test according to demographic subgroups (sex, age [<40, 41-65, and ≥65 years], race [White, Black, Native American, Asian/Pacific Islander, and other], and ethnicity) across years of diagnosis (Period 1: 2004-2006, Period 2: 2007-2009, and Period 3: 2010-2013). Results: i) Characteristics: There were 54,953 MDS patients in our study. The median age at diagnosis was 76 years (78.7% older than 65) and 44% were females. White race (88.9%) was the most common, followed by black (7%). Four percent were Hispanics. A third (30.8%) of all patients were treated in academic centers. Three quarters (75.8%) had either Medicaid or Medicare insurance. ii) MDS Subtypes: 5q Syndrome was seen in 2008 cases (3.7%) while the most common subtype was MDS-Unclassifiable (U) (55.6%). Therapy related MDS (t-MDS) was seen in 1125 cases (2%), however coding for t-MDS was discontinued in 2009. Refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), and refractory anemia with excess blasts were seen in 9%, 7.6%, 6%, and15.6%, respectively. iii) OS: Compared to their counterparts, patients who were male, older, had a diagnosis of RAEB, covered by Medicare insurance, and treated at non-academic centers had the worse OS (all P <0.001). Across Periods 1-3, we did not see improvement in OS among demographic subgroups except for those who were <40 years old (P=0.03). Conclusions: In the past decade, the overall outcome of MDS did not improve despite the advent of new therapies. More than half of the cases were classified as MDS-U reflecting the difficulty of subtyping MDS based on World Health Organization classification. We found disparity in outcomes by demographics and type of treatment facility. This is the largest study of MDS outcome to-date and should help in understanding the gaps and areas that need future research. Figure Figure. Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

Abstract Background : The 2016 revision to the World Health Organization classification of myeloid neoplasms has recommended distinction between "proliferative" (WBC ≥ 13 x 10(9)/L) and "dysplastic" (WBC < 13 X 10(9)/L) subtypes of chronic myelomonocytic leukemia (CMML). In addition, CMML is characterized by a spectrum of cytogenetic and molecular abnormalities (Patnaik Leukemia 2014). In the current study, we looked for correlations between gene expression profiles (GEP) and morphologic or molecular categories of previously untreated patients with CMML. Methods : 35 patients with CMML were included in the study. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for 28 myeloid-relevant genes (Patnaik Blood C. J.). RNA sequencing (Stranded Total RNA- Illumina, San Diego, CA), was performed on 9 normal BM controls, and 35 CMML samples (25 peripheral blood (PB) and 10 BM). The RNA-Seq data was analyzed using MAPRSeq v.2.0. Normalization and differential expression analysis was performed using edgeR 2.6.2. We selected genes that were differentially expressed with a False Discovery Rate (FDR) <0.1 and a fold change bigger than 2. Pathway enrichment analysis was performed using Ingenuity Pathway Analysis (IPA). Results: Among the 35 study patients, 75% were males and median age was 71 years (range, 55-87). 21 (60%), 9 (25%) and 5 (15%) patients were classified as CMML-0, 1 and 2, respectively. 16 (45%) had a dysplastic while 19 (55%) had a proliferative phenotype. At a median follow-up of 16 months, 5 (14%) deaths and 4 (14%) leukemic transformations were documented. Mutational frequencies included; 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%. Abnormal cytogenetics (n=9, 35%) included; -Y 8%, trisomy 8 6%, monosomy 7 3%, del(13q) 3% and monosomal karyotype 3%. i) Differential GEP in PB samples: 25 PB CMML samples were analyzed. Unsupervised GEP demonstrated two unique clusters (figure one); cluster one was enriched with dysplastic CMML (90%) and cluster two with proliferative CMML (64%). Consistent with the difference in the distribution of morphologic categories, in comparison to cluster one, patients in cluster two had a higher white blood count (p=0.003), higher monocyte count (p=0.02) and higher risk prognostication by the Mayo Model (p=0.016); there was no significant difference between the two clusters in terms of age and gender distribution, hemoglobin level, neutrophil and platelet counts, PB or BM blast content, cytogenetic risk stratification, ASXL1, TET2, RAS, CBL and SETBP1 mutational status. Genes significantly upregulated (FDR<1e-5 and fold change ≥ 16x); in cluster two (proliferative CMML) in comparison to cluster one included; PRG2, CTSG, BEX1, CD34, CRISP2, while those significantly down-regulated included (FDR<1e-15 and fold change ≥ 5x); IL2RB, PRF1, GNLY, PDGFRB. IPA analysis identified the following pathways preferentially expressed in cluster two (proliferative CMML) 1) mitotic roles of polo-like kinase (KIF23, WEE-1, PLK1, PLK4), 2) Cell cycle: G2/M checkpoint regulation (CDC25C, WEE-1, AURKA, CDK1), 3) Cell cycle: chromosomal replication (CDC45, RPA3, MCM2, CDC7), and 4) BRCA1 in DNA damage response (BARD1, RBBP8, PLK1, RAD51). Whereas in the cluster one (dysplastic CMML), preferentially expressed pathways included; 1) T-cell receptor signalling (CD247 PRKCQ, CD4, PLCG1, CD28) and 2) STAT3 signalling (SOCS3, MAP3K9). ii) Differential GEP in BM samples: 10 BM CMML samples were analyzed along with 10 normal controls. Samples and controls clustered separately and within the CMML samples two clusters were identified (figure two). These clusters had equal representations of dysplastic (n=5) and proliferative (n=5) CMML sub-types. Additional samples are being processed. Conclusions: Differential gene expression profiling in patients with CMML identifies two unique clusters, clinically demarcated, at least in PB samples, by "proliferative" and "dysplastic" CMML subtypes. The proliferative cluster is enriched in genes involved in cell cycle regulation and DNA damage response; whereas the dysplastic cluster is enriched in T-cell receptor and STAT3 signalling. The prognostic and therapeutic impact of these gene clusters remains to be assessed in a larger group of informative patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding; Celgene: Research Funding.

Abstract Background: Adult relapsed/refractory acute lymphoblastic leukemia/lymphoma (rALL) carries a very poor prognosis with limited options for effective salvage therapy. To date, there has been only a single retrospective report on the use of clofarabine in adult rALL demonstrating CR rate of 31% in this setting (Barba P et al. 2012). Aim: To evaluate the efficacy and toxicity of clofarabine based therapy in a relatively large cohort of adult rALL patients. Method: After IRB approval, a retrospective single institution study of all patients (pts) diagnosed with rALL treated with a clofarabine based regimen at Mayo Clinic between 2000 - 2014 was performed. Categorical variables were analyzed using Pearson's chi-squared test while continuous variables were analyzed using the Wilcoxon / Kruskal-Wallis test with P < 0.05 considered statistically significant. Survival estimates were calculated using Kaplan-Meier method and means were compared using log ranks. Results: Presenting features: We identified a total of 22 pts with a diagnosis of rALL who received clofarabine based therapy. 20 patients were evaluable and 2 were excluded (one received clofarabine as salvage for positive MRD and the other as systemic maintenance with CNS directed therapy for an isolated CNS relapse). Among evaluable pts, median age at time of Clofarabine based chemotherapy was 39 years (range 19-65) and 50% were males. Thirteen had B-ALL while 7 had T-ALL. Median leukocyte count was 6 x109 (0.2-28.7), hemoglobin 9.8 g/dL (7-12.9), platelet 65 x109 (12-493), peripheral blood blast 4% (0-88) and bone marrow blasts 80% (0-95) while five pts had extramedullary disease. Median number of prior regimens was 2 (1-7).. 8 (40%) pts were post allogeneic transplant Treatment and Response: 10 pts (50%) received clofarabine monotherapy, 7(35%) clofarabine and cytarabine, and 3 (15%) had clofarabine, etoposide and cyclophosphamide. Overall response rate (CR/CRi + PR) was 35%. Five (25%) achieved CR/CRi, and 2 achieved PR. Among those who achieved CR, 4 out 5 proceeded to further therapy; 2 to allogeneic stem cell transplant and two additional patients received donor lymphocyte infusion (DLI). One pt with PR also proceeded to allogeneic stem cell transplant. In comparative analysis, there were more males 6 (86%) vs 1(14%) in the responding arm (P = 0.014), otherwise the number of regimens prior to clofarabine, type of clofarabine regimen, transplant status, T vs B cell ALL, did not impact response. Median overall survival was 2.4 months (1.3-2.9) in non-responders vs. 12.8 months (3-27.4) in responders (P =0.0007) (Figure 1). All pts who proceeded to transplant or DLI relapsed with a median time to relapse of 6.4 (4.8-13.7) months. Toxicity: Rash/Hand Foot syndrome was observed in 3 pts (19%), Grade III-IV liver toxicity occurred in 4 (26%) with no permanent sequela. Opportunistic infection occurred in 3 pt (17%). Conclusion: Clofarabine based chemotherapy was a well-tolerated salvage regimen in heavily pretreated patients and was an effective bridge to definitive therapy in a significant proportion of cases. Prospective evaluation of these findings is warranted. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.

Abstract Background: MDS is a clonal bone marrow disorder characterized by ineffective hematopoiesis with peripheral blood cytopenias and an increased risk for transformation to acute leukemia. Patients with MDS who have a history of prior exposure to chemotherapy and/or radiotherapy are called therapy-related MDS (t-MDS). We hereby describe our experience with this entity and compare it to our experience with de novo MDS patients. Aim: To study the differences of clinical outcome between t-MDS and de novo MDS patients. Method: A retrospective single institution study chart review of cases with MDS at Mayo Clinic Rochester between 1993- 2011 was performed. De novo MDS, t-MDS and leukemic transformation (LT) were defined according to the World Health Organization (WHO) classification (Swerdlow et al 2008). Prior exposures to chemotherapy, radiotherapy and/ or both were defined as t-MDS; while lack of any as de novo MDS. Appropriate IRB approval was obtained in accordance with the Helsinki declaration. Comparison between group medians was done using Wilcoxon test, comparison between values was done using contingency and One-way analyses (Means/Anova/Pooled t), while survival estimates were calculated using Kaplan-Meier curves JMP V10 Results: Out of 827 patients with MDS, 153 (19%) patients were t-MDS (group (Gr) 1) versus 674 (81%) (rest of patients, Gr 2). Out of the t-MDS, 79 (52%) pts had CTX, and 42 (27%) had XRT, and 32 (21%) pts had both CTX/XRT). Upon comparison between Gr 1 vs 2, statistical significant difference was seen in median age 69 vs 72 (p=0.01), Platelets 68 vs 114 x109(<p0.0001), and WBC 3.2 vs 3.6 x109(0.02), respectively. No significant statistical difference was found in median Hg 9.6 vs 9.7 gm/dL (p 0.6), peripheral blood (PB) blasts 0% in both groups, and bone marrow (BM) blasts 2% in both groups. IPSS was low, int-1, int-2, high in 16%, 40%, 34%, 9%in Gr 1 and 32%, 46%, 18%, 4% in Gr 2. IPSS-R was very low, low, int, high, very high in 9%, 24%, 18%, 20%, 28% in Gr 1 vs 18%, 36%, 20%, 16%, 10% in Gr 2. AML transformation (LT) was identical in both groups at 12%. Upon comparison between Gr 1 and 2, median time to AML transformation was 7.9 vs 13 months (p=0.08). Median overall survival (mOS) was shorter in Gr 1 vs 2 at 16 vs 34 months (P<0.0001). When analysis was limited to diploid cytogenetics, median OS was 63 vs 50 months, respectively (p=0.9). Both IPSS and IPSS-R were prognostic of mOS in t-MDS (p<0.0001). On multivariate analysis; age (<0.0001), IPSS-R (p<0.0001) and previous CTX and/ or XRT (P=0.02) were the only variables that affected mOS. Conclusion: T-MDS comprises a small portion of all MDS cases (19%). Median overall survival in the de novo MDS group was longer than t-MDS group; however this difference was not maintained in patients with diploid cytogenetics. Similarly, time to AML was longer in de novo MDS compared to t-MDS (although similar rates of incidence). All of age, IPSS-R and t-MDS did affect median OS on multivariate analysis. Disclosures Al-Kali: Celgene: Research Funding.

Abstract Background: Pracinostat, a potent oral Class I, II, IV histone deacetylase (HDAC) inhibitor, exhibited modest single-agent activity in relapsed AML. Inhibition of histone deacetylation and DNA hypermethylation induces re-expression of silenced genes in myeloid malignancies in a synergistic fashion. A pilot study of pracinostat with azacitidine (AZA) in myelodysplastic syndromes showed the combination to be active and well tolerated (Blood2012;120:3821). We conducted a Phase 2 study to evaluate pracinostat + AZA in patients ≥65 years with AML not eligible for induction chemotherapy. Minimum 1-year survival data were reported previously (Blood 2015;126:453). Here we report long-term survival and response analyses. Methods: Main eligibility: Age ≥65, untreated de novo or secondary AML, ≥20% bone marrow (BM) blasts, not candidate for intensive therapy due to co-morbidities and/or AML features, intermediate or high-risk cytogenetics, and no prior treatment with HDAC inhibitors or hypomethylating agents. Treatment consisted of pracinostat 60 mg orally 3 days/week on alternate days for 3 weeks and AZA 75 mg/m2 subcutaneously or intravenously daily for 7 days, with cycles repeated every 28 days until disease progression, lack of response or poor tolerability. The primary endpoint was a composite complete response rate (cCR) of CR + CRi+ MLFS by IWG criteria. Response was assessed at the end of Cycles 2, 4, 6 and then every 3 cycles or when clinically indicated. Secondary endpoints included overall response rate (cCR + PR), duration of response and overall survival (OS). Study registered under NCT01912274. Results: Between December 2013 and December 2014, 50 patients were enrolled at 15 U.S. sites. Baseline characteristics: Median age 75 years (range 66-84 years); 33 de novo and 17 secondary AML; 27 intermediate-risk and 21 high-risk cytogenetics and 2 not known; median BM blasts 40% (range 20%-89%), ECOG performance status 0-1 in 84% and 2 in 16%. The median number of treatment cycles was 6.5 (range 1-24+). A CR was achieved in 21 patients (42%), CRi in 2 (4%), and MLFS in 3 (6%) for a cCR rate of 52%. Median time to BM blasts <5% was 57 days (range 25-243 days) and exceeded 168 days (6 cycles) in 3 patients (12%). Median duration of cCR is 13.2 months (95% CI 10.9-21.5 months), with 6 of 26 patients (23%) continuing on therapy for a periods ranging from 20.5 to 29.5 months. With a median follow-up of 21 months, the median OS is 19.1 months (95% CI, 10.0-not reached). One-year and 2-year OS are 62% and 45%. Non-protocol therapies (NPT) were administered in 23 patients (46%). There was no effect on OS after censoring survival duration at the start of NPT. Response and OS by population subsets are summarized in Table 1. Non hematologic adverse events Grade ≥3 reported in >5% of patients: Fatigue 34%; anorexia 10%, cellulitis, pneumonia, asthenia and sepsis in 8%; urinary tract infection, nausea, back pain, hypoxia, hyponatremia, and syncope in 6%. Grade ≥ 3 hematologic toxicities in> 5% of patients: thrombocytopenia 46%; febrile neutropenia 44%; neutropenia 36%; anemia 30%; pancytopenia 6%. The 30-day and 60-day mortality rates were 2% and 10%. Conclusions: Pracinostat + AZA led to a high rate of responses in elderly patients with AML. Responses were durable and observed irrespective of age, cytogenetics risk, ECOG performance status, and de novo or secondary AML. Marrow remission was typically achieved early, but prolonged exposure was required in some patients to maximize response. The results compare favorably with historical single-agent AZA data in a similar AML population. A phase 3 study of AZA +/- pracinostat in untreated patients with AML unfit for standard induction chemotherapy is starting. Table 1. Response and Survival According to Baseline Characteristics Table 1. Response and Survival According to Baseline Characteristics Disclosures Atallah: Incyte: Consultancy; CTI biopharma: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Other: Grant review; Takeda: Research Funding; Ariad: Honoraria. Arellano:Cephalon: Research Funding. Odenike:Geron: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghalie:MEI Pharma: Employment.

Introduction Novel high-risk groups have been identified in adult ALL, including secondary (sALL) and Philadelphia-like ALL (Ph-like, based on CRLF2, IgH, ABL2, JAK2 and other tyrosine kinase translocations), and those with minimal residual disease >0.1% (MRD+) after induction therapy. Novel targeted therapies are now routinely incorporated into 1st line regimens, including tyrosine kinase inhibitors (BCR-ABL1-pos), rituximab (CD20+) and blinatumomab (Blina) for MRD+. The impact of these novel high risk groups and therapies after alloHCT is unknown; therefore, we evaluated their impact on overall survival (OS), relapse rate (REL), non-relapse mortality (NRM) and acute and chronic GVHD. Methods We evaluated pts receiving 1st Allo-HCT for ALL at Mayo Clinic (Rochester, Phoenix, and Jacksonville) from 2008-2018 for outcomes of interest, specifically the impact of novel therapies and risk groups. Associations of patient factors with outcomes were examined using univariable (UVA) and multivariable (MVA) Cox proportional hazards regression models, where the cause-specific hazard of the given outcome was modeled to account for the competing risk of death. Results We identified 261 consecutive AlloHCT recipients during the study period. Median age at transplant was 48 years (18-72) and 147 (56.3%) were male. The median comorbidity (HCT-CI) score was 2 (0-8). 213 pts (81.6%) had B-lineage ALL, of which 85 (32.6%) were BCR-ABL-pos, 17 (6.5%) Ph-like (identified by FISH), 16 (6.1%) hypoploidy/near triploidy (Hy/Tri), and 67 (25.7%) pre-B ALL NOS. The remaining 48 (18.4%) had T-ALL. 30 pts (11.5%) had sALL (i.e. prior chemo/radiotherapy for another malignancy). HyperCVAD was the most common 1st line regimen (68.2%). 243 (93.1%) pts achieved Complete Remission (CR1) after induction therapy, and 203 (77.8%) were in CR1 at the time of alloHCT. Blina was administered for MRD+ in 14 pts (5.4%), and for relapsed/refractory ALL (R/R) in 13 (27% of R/R pts), 7 of whom received Blina as initial therapy for R/R. Donors were matched unrelated in 149 (57.1%), matched related in 98 (37.5%), and haploidentical in 14 (5.4%). Peripheral blood (PB) grafts were used in 233 (89.3%). 103 (54.5%) were donor:recipient (D:R) sex-matched, and 86 D:R mismatched [47 (24.9%) M:F; and 39 (20.6%) F:M]. Myeloablative conditioning was used for the majority (78.5%) mostly with Cy/TBI (60.5%). Standard GVHD prophylaxis regimens were used. Outcomes Median follow-up after transplant was 22.4 months (0.5-135), and 51 (19.5%) had REL. The 1, 2 and 5-year survival rates were 71.9%, 64.9%, and 54.1%, respectively (Figure 1). Acute GVHD developed in 144 (55.2%) and chronic GVHD in 100 (38.3%). Ph-like ALL, Blina for MRD+, Blina for R/R, sALL and CD20-pos had no independent impact on OS. In contrast, age>60, Hy/Tri, and >CR1 at alloHCT were associated with worse OS in UVA, however, in MVA only pre-B ALL NOS was associated with better OS. Female:male D:R status was associated with inferior OS. Blina for R/R disease was associated with increased risk of REL in UVA [HR 5.26 95% CI (1.33, 20.00), p=0.017], whereas other novel high risk groups had no impact on REL. In contrast, T-ALL, Hy/Tri and >CR1 at AlloHCT were associated with increased REL in UVA, but only T-ALL and Hy/Tri continued to predict for increased REL in MVA. Secondary ALL was associated with increased NRM in UVA [HR 1.96 95% CI (1.07, 3.57), p=0.028], whereas other novel high risk groups had no impact on NRM. In contrast, age>60, >CR1 at AlloHCT and D:R sex mismatch were associated with higher NRM in UVA, but only sex mismatch and >CR1 at AlloHCT were associated with higher NRM in MVA. TBI use was associated with higher risk of acute GvHD (p=0.008) and ATG use with lower risk chronic GVHD (p<0.001). Similarly non-PB grafts were associated with a lower risk of chronic GVHD (p=0.005). Results for OS, REL, NRM, acute and chronic GVHD analysis are shown in Table 1. Conclusion Novel high risk groups (CD20+, Ph-like and sALL) do not appear to adversely impact OS after alloHCT, although sALL was associated with increased risk of NRM. Interestingly, pre-B-ALL NOS appear to be associated with favorable OS. Novel targeted therapies also do not independently predict outcome, with the exception of Blina for R/R ALL which may be associated with REL after subsequent alloHCT (a subgroup for whom novel maintenance strategies should be explored). Our analysis highlights the importance of allo-HCT for novel high risk ALL subgroups. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Foran:Agios: Honoraria, Research Funding.

Introduction: Allogeneic stem cell transplant (HCT) is the only potential curative option for patients with inherited marrow failure (iBMF) and myeloid germline predisposition syndromes (GPD). HCT outcomes are influenced by inherent disease specific-nuances such as alkylating agent and radio-sensitivity, immune deregulation, and higher risks for graft failure and GVHD; factors contributing to transplant related mortality (TRM) and morbidity. We carried out this retrospective study to assess survival outcomes and long term complications (LTC) in patients with IBMF and GPD that underwent HCT. Patients and methods: We queried our institutional database and identified patients with iBMF and GPD as defined by the 2016 WHO classification. These included Fanconi anemia (FA), short telomere syndromes (STS), Diamond-Blackfan anemia (DBA), GATA2 and RUNX1 haploinsufficiency, congenital amegakaryocytic thrombocytopenia (CAMT), deficiency of adenosine deaminase 2 (DADA2), among others. Patients with acquired causes of BMF were excluded. Statistical analyses were performed using SAS (JMP v14.1). Results: Twenty eight patients, median age 10 years (1 month-63 years), 46% males, were included in the study (table 1). Fanconi anemia Seven (25%) patients with FA underwent HCT, 5 (71%) without myeloid transformation and 2 after transformation to MDS/AML. Five (71%) patients received a RIC, 4 (57%) prior to transformation. At a median follow up (FU) of 126 m, the median OS was 194 m (95% CI 34m; NR) and 10 year survival was 64%. Grade 1 aGVHD was seen in four (57%) and 3 (42%) developed mild cGVHD, while 1 developed a donor derived AML (sibling not tested for FA). LTC included second primary malignancy (SPM) - squamous cell cancer (SCC) of skin and muscle invasive bladder cancer (MIBC) in 1(14%) and SCC of head/neck and anogenital region in 3 patients (43%), psychosocial complications (PS) in 6(85%), premature ovarian failure (POF) in 3(43%), and avascular necrosis (AVN) in 4(57%) patients. Short Telomere Syndromes (STS) Seven patients with STS underwent HCT, 2 (28%) after transformation to MDS. Five (71%) received RIC, including both the transformed patients. At a median FU of 67m, median OS was NR (95% CI 2m; NR) and 5 year survival was 47%. One (14%) patient developed grade 2 aGVHD and mild cGVHD of skin. Three (43%) developed SPM - skin cancers in 2 and MIBC in 1. PS was noted in 1(15%), and AVN in 3(43%). Three (43%) patients had concomitant mild IPF/restrictive lung disease. GATA2 haploinsufficiency : Seven patients with GATA2 haploinsufficiency underwent HCT; 2(28.5%) after transformation to MDS and 3(43%) to AML, of which 2(40%) received MAC. At a median FU of 57m, median OS was NR (95% CI 7m; NR) and 5 year survival was 71%. Three (50%) developed grade 2 aGVHD of skin and GI tract and 2(33%) developed mild cGVHD. LTC include PTLD, AVN and POF in 1 patient each. Ribosomopathies : One patient (13y) with DBA underwent RIC HCT and developed grade 2 aGVHD, secondary iron overload, and died at 10 months due to severe fungal infection. Others : Identical twins with CAMT underwent HCT (at 4y and 5y) from the same unrelated donor and at last FU (74m and 87m, respectively) remain 100% donor without GVHD. Two children with primary immunodeficiency and marrow failure underwent HCT (at 2y and 7y), one after transformation to MDS. The non-transformed patient is currently alive (120m), while the patient with transformation died 1month after HCT from disseminated cytomegalovirus infection. One patient with germline RUNX1 deletion developed CMML and underwent a RIC HCT and is alive at a FU of 4 months, with no GVHD. One patient with DADA2 (n=1) underwent RIC HCT without LTC. Due to the smaller cohort size, we compared OS in transformed and non-transformed patients for the IBMF and GATA2 patients only (n=24, 9 with transformation) (figure1). At a median FU of 74m, the median OS of transformed vs non-transformed patients was 108m(95% CI 1;108m) and 163m(95% CI 67m; NR), respectively (p=0.033). Conclusions: Our study demonstrates that HCT remains an important intervention for IBMF and GPD, with the maximum impact being gained prior to transformation. While only mild chronic GVHD was noted (37%), inherent syndromic issues resulted in a high rate of SPM (FA/STS) and organ failure (STS- IPF). Notably, one FA patient who received an MRD HCT developed donor derived AML, underlining the importance of genetic screening in asymptomatic related individuals. Disclosures Kenderian: Lentigen: Research Funding; Kite/Gilead: Research Funding; Morphosys: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.