Patnaik, Mrinal M.

7064 Background: Obesity is a growing medical challenge that has strong association with many comorbid diseases. Body mass index (BMI) is used as one indicator for obesity. A few papers have linked hematological cancers with a worse prognosis if obesity was present. Aim: to study the influence of obesity clinical outcome in patients (pts) with CMML. Methods: A retrospective chart review of pts with CMML at Mayo Clinic Rochester between 1994–2011 was done. BMI was calculated at diagnosis or first time visit. Overweight was defined as BMI ≥25, while obesity as BMI >30. IRB approval was obtained. Comparison between medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier estimates via JMP software v.9. Results: We found227 pts with a median follow-up of 311 days, 68% of which weremales. Median age was 71 years, hemoglobin 11 gm/dL, white blood cells (WBC) 12x 109/L, and platelets 90x 109/L. Obese pts had a median age of 68 (p=0.0058), hemoglobin 11 gm/dL (p=0.0018), WBC 13.5 x 109/L, platelets 115x109/L (p=0.012), PB blasts 0, bone marrow (BM) blasts 3.5% compared to non-obese pts (73, 10, 11, 78, 0, 3%, respectively). Diploid cytogenetics were similar in both groups (68% vs 64%, respectively, p=0.54). Leukemic transformation into acute myeloid leukemia (LT) was found in 13% vs 10% (p=0.83). Overall response (OR) was 24% and 23%, respectively (p=0.2), when limited to hypomethylating agents OR was 33% vs 27%, respectively (p=0.62). Median OS was found to be similar (571 day vs 569 days, respectively, p=0.56). When compared, overweight pts had similar outcome to non-overweight. Median LT was 11% vs 15% respectively, OR was 21% vs 28% respectively (p=0.5), and OS was 571 days vs 549 days respectively (p=0.21). On a multivariate analysis age, hemoglobin, platelets, BM blasts%, gender, and obesity (p=0.048) were of a significant value for OS. Conclusions: When compared, both obesity and overweight did not affect demographic characteristics, overall response, or transformation into AML. When comparing median overall survival, obesity was not a significant factor, possibly due to short follow-up. However, on multivariate analysis obesity did have a negative impact on overall survival.

6614 Background: CDKN2A locus on chromosome 9p21 is implicated in altered molecular pathways leading to leukemogenesis as a tumor suppressor by inhibiting the proliferative kinases CDK4/CDK6 and blocking the cell-cycle division during G1/S phase. Deletion of CDKN2A locus is frequently seen in ALL, although prognostic significance remains unclear. Methods: Retrospective chart review at Mayo Clinic between 8/2005-11/2011 was performed on adult B-ALL patients (pts) who underwent fluorescent in situ hybridization (FISH) studies at diagnosis. Survival estimate was calculated using Kaplan-Meier statistics. Event-free survival (EFS) was defined as time between diagnosis and induction failure, relapse, or death, while overall survival (OS) as time between diagnosis and death Results: Out of 27 pts who had FISH studies for CDKN2A, 15 (56%) pts had CDKN2A deletions (8 homozygous/7 hemizygous), while 12 (44%) pts had diploid cytogenetics (none had abnormalities of MLL, bcr/abl fusion or CDKN2A deletion on FISH). There was no significant difference in median age, gender, WBC, hemoglobin, platelet count, LDH or complete remission (CR) rate (p=0.924) between the two groups. CDKN2A-deleted pts had higher circulating blasts (34% vs 16%, p=0.017). Of 13 CDKN2A-deleted pts, chromosome 9p was intact in 9 (69%) pts using routine cytogenetics. In the CDKN2A-deleted group, allogeneic stem cell transplant (ASCT) was performed in 7 (47%) pts at first CR and 1 at second CR. Four of 15 (27%) CDKN2A-deleted pts also had bcr/abl fusion. Five-year EFS was poorer in CDKN2A-deleted pts compared to normal FISH group (22% vs 60%, p=0.042), while 5-year OS was 72% vs 60% (p=0.308), respectively. Excluding the 4 bcr/abl fusion pts, 5-year EFS was still statistically significant (p=0.008). In the CDKN2A deleted group, both 5-yr EFS (80% vs 0%, p=0.006) and OS (100% vs 42%, p=0.016) were significantly superior in pts who received ASCT. Conclusions: CDKN2A deletions predict earlier relapse in pts with B-ALL. Majority of 9p abnormalities were only found by FISH testing and missed by conventional cytogenetics. In CDKN2A deleted pts, ASCT gave overall survival advantage. Further investigation through larger cohorts of pts is needed to validate these findings.

Background Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. High-expressing CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor-promoting role. Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor in patients with MF, associated with shortened overall survival. We hypothesized that tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, and in particular in patients with monocytosis. Aims To assess safety and evaluate efficacy of tagraxofusp in patients with MF who were relapsed, refractory, or unable to tolerate JAKi. Methods This multicenter, open-label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days 1-3 every 21 days (cycle 1-4), 28 days (cycles 5-7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the recommended Phase 2 dose (12 mcg/kg). Results 27 patients with MF have been treated, including 14 patients who had previously received ≥ 3 lines of therapy. Median age was 69 years (range 54-81), 52% were female, and 26% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate-1, 16 patients (59%) with intermediate-2, and 9 patients (33%) with high-risk. At study entry, median platelet count was 59 K/uL; 67% of patients had baseline platelets <100 K/uL, of which 10 patients had platelets <50 K/uL. 74% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin). In terms of molecular mutations: JAK2 (n=18); CALR (n=3); and MPL (n=1), and additional molecular analysis showed ASXL1 (n=5). In terms of cytogenetics, 30% (8/27) of patients had an abnormal karyotype, mainly 20q- (n=3), -5/5q-, -7/7q-, and 12p- (each n=2). Most common treatment-related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, increased levels of alanine aminotransferase, thrombocytopenia, and anemia. Most common ≥ grade 3 TRAE's were thrombocytopenia (8%) and anemia (15%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 17 evaluable patients with baseline splenomegaly, 53% had spleen size reductions, of which 4 patients had reductions of > 45%. In 5 patients with baseline splenomegaly and monocytosis (>1x109/L monocytes), 80% (4/5) had spleen size reductions, of which 2 had reductions of >45%. Five patients had treatment duration of 12 months or more, with two of those patients ongoing (13+,and 24+ months, respectively). Six patients with platelets <100 K/uL had treatment duration of 6 months or more, including 3 patients with baseline monocytosis who had treatment duration of 12 months or more. 7 patients had objective responses (IWG-MRT 2013 responses), including Clinical improvement (CI) (n=5) and CI (Symptom) (n=2). 20 patients were evaluable for symptomatic assessment (MPN-SAF TSS). Symptom response rate was 45% (defined as ³50% reduction in TSS score). Reductions in both symptom score and spleen size was noted in 6/6 patients who had splenomegaly at baseline. Conclusions Tagraxofusp demonstrated single agent clinical activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor and unmet medical need. Tagraxofusp may offer MF patients, and MF patients with monocytosis in particular, a novel treatment option. Enrollment continues, and updated trial data will be presented. This clinical trial is registered at clinicaltrials.gov: NCT02268253. Disclosures Pemmaraju: affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding. Gupta:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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, Research Funding; Incyte: Honoraria, Research Funding. Yacoub:Dynavax: Equity Ownership; Cara: Equity Ownership; Ardelyx: Equity Ownership; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Agios: Speakers Bureau; Hylapharm: Equity Ownership. Wang:Agios: Other: Advisory role; Amgen: Other: Advisory role; Daiichi: Other: Advisory role; Stemline: Other: Advisory role, Speakers Bureau; Pfizer: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau. Lee:AstraZeneca Pharmaceuticals: Consultancy; Ai Therapeutics: Research Funding; Karyopharm Therapeutics: Consultancy; Roche Molecular Systems: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Helsinn: Consultancy. Schiller:Agios: Research Funding, Speakers Bureau; Karyopharm: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Poradosu:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Talpaz:Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Taparia:Novartis: Consultancy. Verstovsek:Protaganist Therapeutics: Research Funding; Ital Pharma: Research Funding; Astrazeneca: Research Funding; Pharma Essentia: Research Funding; Sierra Oncology: Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Khoury:Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

AbstractDisease overviewChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3‐5 years).DiagnosisDiagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109/L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~ 30% of patients, while >90% have gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%) and the oncogenic RAS pathway (~30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over‐all survival.Risk stratificationMolecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM) and the CMML specific prognostic model (CPSS‐Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count>10 × 109/L, hemoglobin <10 g/dL, platelet count <100 × 109/L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups; high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59 and 97 months, respectively.Risk‐adapted therapyHypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ~40%‐50% and complete remission rates of ~7%‐17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.

Abstract Background: Patients with hematological malignancies are at an increased risk for developing both primary and recurrent Clostridium difficile Infection (RCDI) along with complications such as toxic mega colon and treatment failure likely due to underlying immunosuppression and frequent use of broad spectrum antibiotics that lead to altered gut microbiome. Fecal Microbiota Transplantation (FMT) is an effective treatment for RCDI (Brandt et. al; 2012). However, experience in patients with hematologic malignancies is sparse and most clinical trials exclude these patients due to potential complications. We report the largest case series to date from a single institution evaluating the safety and efficacy of FMT for RCDI in patients with hematologic malignancies. Methods: After IRB approval, a database of 452 RCDI patients treated with FMT between August 2012 and June 2016 was reviewed to identify those with an underlying hematologic malignancy. Data regarding demographics, hematologic disease, C. difficile history, treatments, and outcomes were retrospectively abstracted from the electronic medical record. Results: Sixteen patients (median age 74 years; male 50%) with known hematologic malignancies underwent FMT during the study period. The underlying diagnoses are outlined in Table 1. Five patients had received hematopoietic cell transplantation (3 allogeneic and 2 autologous) prior to FMT. Patients had a median of 4.5 (range 2-9) CDI episodes before FMT, and 4 of them had severe/severe-complicated CDI at some stage. Prior treatments included a median of 3 (range 1-5) standard vancomycin/metronidazole courses, median of 2 (range 0-4) vancomycin taper courses, fidaxomicin in 3 patients, and chronic vancomycin suppression in one patient. Diarrheal symptoms were in remission in all but 3 patients in the week before FMT. FMT was performed via colonoscopy in all patients. At the time of FMT, hematologic malignancies were in complete remission in 9 patients, stable on active treatment in 4, stable off treatment in 2, and relapsed awaiting treatment in 1 patient. Median time from last anti-neoplastic treatment (n = 14) and from last neutropenia (n = 8) to FMT were 10 (range 0-301) and 9.5 (0-68) months, respectively. One patient with hairy cell leukemia was still neutropenic and on prophylactic oral trimethoprim/sulfamethoxazole at the time of FMT. Five patients were on active immunosuppressive medications, including prednisone (n = 2), methotrexate (n = 2), sirolimus (n =1), and cyclosporine (n =1) for related comorbidities at the time of FMT (Table 2). At last follow up (median 12, range 0-32 months), 6 patients had active/relapsed hematological disease, 6 had received additional antineoplastic treatments, and 7 had received additional antibiotics. RCDI developed in two (12%) patients at 8 and 22 months post FMT secondary to exposure to broad spectrum antimicrobials. These patients were successfully treated with a second FMT and with metronidazole, respectively. Severe adverse events included death in one patient that occurred 3 days post FMT due to unexpected cardiac arrest and was deemed unrelated to the procedure. Another patient developed community-acquired pneumonia 15 days post FMT and was treated successfully with oral azithromycin. Minor adverse events within the first two weeks post FMT were noted in 6 (38%) patients (self-limited diarrhea in 3, fecal urgency in 2, abdominal cramps in 2, and constipation in one patient) (Table 3). Only one patient had persistent diarrhea shortly after FMT, with the cause attributed to underlying Crohn's disease. No complications related to the colonoscopy procedure were noted. Conclusion: FMT appears to be a safe and effective therapeutic option for RCDI in patients with hematological malignancies. Considering very few adverse events and particularly no infectious complications in our series, we conclude that immunosuppression should not preclude the use of FMT for treatment of RCDI in this high risk population. These results need prospective validation. Disclosures No relevant conflicts of interest to declare.