Academic literature on the topic 'P 25.5 UL 2013 B752'

Abstract Mobilization failure is seen in 10-15% of patients undergoing G-CSF or Chemo mobilization and the use of plerixafor is limited by its cost in developing countries. This phase II study is being undertaken to study whether the addition of Meloxicam to standard G-CSF will improve rates of mobilization (CTRI/2014/06/004671). After informed consent, patients received Meloxicam 15 mg once daily for 5 days from Day -7 to -3 and G-CSF 5 ug/kg BD from Day -4 to -1. Peripheral blood stem cell harvest was performed on Day 0 and on the following day is the initial harvest CD34 dose was < 4 x 106 CD34/Kg. Patients with myeloma proceeded immediately to an autologous transplant (auto SCT) with Single agent Melphalan conditioning while patients with lymphoma and acute myeloid leukemia had cryopreservation of harvest and then proceeded with transplant using either BEAM or BuCy2 conditioning. Between November 2013 till July 2014, 25 patients (20 males and 5 females) with a median age of 51 years (range: 25-63) received meloxicam with G-CSF. There was no toxicity in any of the patients during the 5 days of administration of meloxicam. A cell dose of > 2 x 106 CD34/kg was achieved in 21 (84%) with a cell dose of > 3 x 106 CD34/kg being achieved in a single harvest in 15 (60%). Four patients needed additional cyclophosphamide mobilization to achieve the target cell doses. Analysis of peripheral blood CD34 counts revealed that 20 (80%) had counts > 20/ul on Day 0 [median count of 65.5/ul (range: 21.1 – 313.02) and of these 15 (60%) had achieved counts of > 20/ul on Day -1 itself [median count of 45.3/ul (range: 21.4 – 130.2)]. None of the patients had toxicity related to meloxicam. Subsequently 21 patients underwent auto SCT and their data was compared with 50 age and disease matched controls who had mobilization and auto SCT at our centre between January 2013 and March 2014. Though mobilization rates and cell doses were not significantly different, the use of meloxicam and G-CSF was associated with faster neutrophil engraftment. Following auto SCT, there was lower Grade III – IV toxicity, lower transfusion requirement of red cells and reduction in the duration of hospital stay post SCT [Table 1]. Conclusion: The addition of meloxicam to G-CSF improves stem cell mobilization and is associated with faster engraftment, no additional toxicity, lower supportive care and lower duration of hospitalization. It is also potentially possible that we may be able to harvest the patients a day earlier depending upon the peripheral blood CD 34 counts achieved. This data warrants a prospective randomized trial comparing Meloxicam + G-CSF with G-CSF alone as a mobilization strategy prior to autologous stem cell transplantation. Table 1 – Comparison of demographic data, mobilization characteristics and post transplant outcome in patients using meloxicam + G-CSF compared with historical controls Abstract 2455. Table 1VariablesMeloxicam + GCSF (n = 25)G-CSF alone (n = 50)P valueMedian age (years)51 (25 – 63)50 (18 -65)0.902Sex M: F20: 536:140.577Diagnosis MM NHL/HD APML/AML15 (60%) 8 (32%) 2 (8%)32 (64%) 14 (28%) 4 (8%)Successful mobilization (> 2 x 106 CD34/kg after 2 harvets)21 (84%)42 (84%)1.000CD 34 > 5 x 106 /kg12 (48%)18 (36%)0.138CD 34 > 3 x 106/Kg20 (80%)32 (64%)0.191Conditioning regimen High dose Melphalan BEAM Bu/Cy215 (60%) 8 (32%) 2 (8%)32 (64%) 14 (28%) 4 (8%)ANC > 500/cumm (days)11.09 + 0.5311.53 + 0.920.044ANC > 1000/cumm (days)11.61 + 0.4511.95 + 0.990.216Platelet count >20000/cumm (days)14.7 + 4.516.4 + 6.30.291Platelet count >50000/cumm (days)17.4 + 7.524.7 + 19.30.143Platelet count >100000/cumm (days)23.1 + 11.951.2 + 58.20.025Number of red cell units transfused1.19 + 1.12.31 + 2.450.031Number of platelet units transfused12 + 9.117 + 160.327No of pts with Grade III-IV toxicity7/21 (31.8%)33/47 (59.5%)0.040Duration of hospital stay from day 0 (days)16 + 3.320 + 7.30.025 Disclosures Srivastava: Octapharma: Consultancy, Other.

e14500 Background: In previous studies separately, it has already been determined how the inflammatory response measured by it neutrophilia and also lymphopenia s with temozolamide have determined that they are important at the time of initiation of treatment and have a prognostic value in patients with high-grade gliomas, the objective This study was the prognostic value of leukocyte disorders, absolute neutrophil count and absolute lymphocyte count in a retrospective cohort of patients with high-grade glioma who receive concomitant temozolomide and radiation plus maintenance. Methods: Clinical records of patients treated at the Guatemalan Social Security Institute were registered in the Oncology service within the period from January 1, 2013 to December 2018, the treatment consisted of temozolomide (75 mg / m2 per day) and concomitant radiation and subsequent maintenance with temozolomide (150 mg / m2 D1-5) every 28 days for 6 cycles. The prognostic value of neutrophilia and lymphopenia, prior to treatment in survival, was defined as a neutrophil count greater than 7x10 3 / uL and lymphopenia less than 2 x10 3 / uL. The analysis was performed using Kapplan Mayer curves, log rank test and Cox analysis. Results: We identified 64 high-grade patients (grades III and IV according to WHO), all treatments with concomitant chemoradiotherapy based on temozolomide and subsequent maintenance with temozolamide. The initial surgery was lost in the majority (75%), with resection > 90% in 25 patients (34%). 79.4% were treated with radiotherapy plus concomitant chemotherapy followed by adjuvant chemotherapy with temozolamide of these, 69% completed the treatment, thirty-two patients (50%) with pre-treatment neutrophilia. The overall survival at 2 years was 55%. In the univariate analysis, neutrophilia is associated with a worse overall survival (p = 0.019), as well as lymphopenia (p = 0.003), in addition to the age ≥65 years (p = 0.0001), surgical resection < 90% (p = 0.045) and prednisolone consumption ≥50mg / day (p = 0.045). In the multivariate analysis, neutrophilia (p = 0.017), age ≥65 (p = 0.001), lymphopenia (p = 0.0056) were associated with a worse prognosis with reduced survival. Conclusions: In high-grade gliomas treated with temozolomide and concomitant radiation followed by maintenance with temozolamide, neutrophilia and lymphopenia can be a significant prognostic factor for overall survival, with the advantage that it is not an expensive test and is accessible at all times of patient follow-up.

Abstract Background: The vast majority of births with sickle cell anemia occur in Africa 1 and early-life mortality, generally before age five years, is as high as 90% 2,3. Hydroxyurea was approved for sickle cell anemia by the US FDA in 1998 but is not commonly used in Africa due to fear of toxicity, lack of awareness and limited availability. Hemoglobin F is a protective factor that decreases severity of sickle cell anemia, and hydroxyurea treatment leads to an increase in hemoglobin F. In the US, hydroxyurea is typically initiated at a dose of 15 mg/kg followed by dose escalations of up to 35 mg/kg if tolerated with a goal of maximal tolerated dose and maximal response in hemoglobin F. Neutropenia and thrombocytopenia are the usual limitations to achieving maximal dose. In the landmark Multicenter Study of Hydroxyurea, the clinical response to hydroxyurea correlated strongly with a reduction in the neutrophil count as well as an increase in the fetal hemoglobin concentration as reflected in percentage of F cells. A striking decrease in pain crises was observed in the first three months of therapy, before dose escalation and before maximal increase in hemoglobin F levels 4. Furthermore, hydroxyurea in the range of 10-15.9 mg/kg/day was reportedly effective in decreasing the frequency of pain episodes in children and adolescents in Oman 5, and hydroxyurea 10 mg/kg/day decreased pain episodes in children and adults with sickle cell anemia in India 6. From these perspectives, we reasoned that a fixed dose of hydroxyurea 10 mg/kg/day is reasonable to investigate in the African setting where the safety in relationship to the resources and infectious exposures is not known. Methods: We assigned 48 sickle cell anemia patients to hydroxyurea 500 mg/day for 24 weeks to determine safety and efficacy; 28 had high-risk disease based on hemoglobin F&lt;8.6% and absence of alpha-thalassemia. We defined a clinically meaningful adverse outcome category as ≥10% of patients developing platelets &lt;50,000/uL, granulocytes &lt;500/uL, clinical malaria and/or active tuberculosis. Picking up refills every four weeks was the adherence metric. We analyzed the results on an intent-to-treat basis. Results: The median (interquartile range) age was 25 (22-27) years and the median hydroxyurea dose 9.8 (9.1-10.4) mg/kg per day. The patients complied with treatment for a median of 20 (16-24) weeks. Four (8.3%) developed a pre-specified adverse outcome: clinical malaria (N=2), thrombocytopenia in combination with malaria (N=1), pulmonary tuberculosis (N=1). During therapy the median hemoglobin increased by 9.0 g/L, mean corpuscular volume by 11.2 fL and body weight by 3.0 kg while median white blood cells declined by 2600 per uL and platelets by 127,000 per uL (P&lt;0.001). The median hemoglobin F increased from 4.1% (2.3-6.3%) at baseline (N=27) to 8.5% (6.3-12.9%) during therapy (N=24) (P&lt;0.001). Conclusion: Our results suggest that low, fixed-dose dose hydroxyurea for sickle cell anemia in Nigeria is associated with a low adverse outcome rate and with improvements in blood counts, hemoglobin F and body weight. The effects on vaso-occlusive episodes and on the risks of recrudescent tuberculosis and malaria-associated thrombocytopenia should be assessed in further studies. Acknowledgment: Supported by a grant from the Doris Duke Foundation. References 1. Williams TN, Obaro SK. Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 2011;27:315-20. 2. Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med 2011;41:S398-405. 3. Makani J, Cox SE, Soka D, et al. Mortality in sickle cell anemia in Africa: a prospective cohort study in Tanzania. PLoS One 2011;6:e14699. 4. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300-26. 5. Sharef SW, Al-Hajri M, Beshlawi I, et al. Optimizing Hydroxyurea use in children with sickle cell disease: low dose regimen is effective. Eur J Haematol 2013. 6. Patel DK, Mashon RS, Patel S, Das BS, Purohit P, Bishwal SC. Low dose hydroxyurea is effective in reducing the incidence of painful crisis and frequency of blood transfusion in sickle cell anemia patients from eastern India. Hemoglobin 2012;36:409-20. Disclosures Ezekekwu: American Society of Hematology: Other: The Visitor training program was sponsored by ASH. Hsu: AstraZeneca steering committee for HESTIA trial: Research Funding. Gordeuk: Emmaus Life Sciences: Consultancy.

Abstract Introduction: Interleukin 2 receptor-α (CD25) expression on myeloid leukemic blasts may be a marker for chemotherapy-resistant leukemia stem cells (Saito et al., 2010) and has been associated with poor overall survival (OS) in AML patients (pts) <60 years treated with cytotoxic chemotherapy (Terwijn et al., 2009; Gonen et al., 2012; Cerny et al., 2013). The prognostic impact of CD25 expression in older pts remains unclear. We therefore retrospectively analyzed CD25 expression in baseline bone marrow (BM) of newly diagnosed AML pts >60 years enrolled in a Phase I clinical trial combining the CXCR4 antagonist, plerixafor and the DNA methyltransferase inhibitor, decitabine (Roboz et al., 2013). Methods: BM aspirates were available for 69 newly diagnosed older AML pts treated with 1-4 cycles of 5 days of plerixafor combined with 10 days of decitabine. Pts with favorable risk cytogenetic or mutational profiles were excluded from the clinical trial. Multi-parameter flow cytometry was used to evaluate the expression of CD25 in blast and progenitor (CD34+) populations. Cells were gated on CD45dim/SSClo characteristics. Pts were considered positive (CD25+) when greater than 10% of the gated population expressed CD25. Results: Of 69 pts, 58 were evaluable for survival and 57 for response; one pt died prior to scheduled response assessment. Of 58 pts evaluated at baseline (pre-treatment BM), 20 (34.5%) were CD25+ vs. 38 (65.5%) CD25-negative (CD25-). CD25+ pts had significantly inferior median OS (152 days vs. 419 days, p=0.003) and were at higher risk of dying within 1 year of diagnosis, relative risk (RR) 1.58 (95% 1.04-2.41). Similarly, pts surviving less than 1 year had significantly higher percentages of CD34+ cells expressing CD25 than those who lived greater than 1 year (7.82% vs. 4.77%, p=0.028). CD25+ pts were less likely to respond to therapy, RR 1.90 (95% CI 1.23-2.93) and, in turn, pts who were resistant to therapy had higher baseline CD25 expression level than those who responded (7.82% vs. 4.87%, p=0.033). Five CD25+ pts (25%) and 12 CD25- pts (32%) received an allogeneic transplant. Transplanted CD25+ pts had improved OS vs. CD25+ pts without transplant, (median OS not reached (NR) vs. 107 days), p=0.005. In contrast, there was no significant difference in survival between CD25- pts with and without allogeneic transplant, p=0.96. Also, there was no difference in median OS between CD25+ pts receiving transplant vs. CD25- pts (median OS NR vs. 419 days), p<0.40. There was no difference in survival between CD25+ pts with intermediate risk cytogenetics vs. CD25+ pts with unfavorable cytogenetics (OS 153 vs. 172, p=0.77). Lastly, CD25+ pts had significantly worse OS compared to CD25- pts with unfavorable cytogenetics, (median OS 152 vs. 333 days) respectively, p=0.05. Compared to CD25- pts, CD25+ pts were older (median age 74.5 vs. 71.5, p=0.096), more likely to be male (75% vs. 47.3%, p=0.055) and had higher baseline WBC (19x1000/uL vs. 5x1000/uL, p=0.089) and pretreatment lactate dehydrogenase (LDH) (median 365 vs. 271, p=0.04). Analysis of diagnosis BM blast percentage yielded no difference between CD25+ and CD25- pts (62% and 46%, p=0.44). Sixteen (80%) and 4 (20%) of CD25+ patients had intermediate and unfavorable cytogenetics vs. 21 (55%) and 17 (44%) CD25- pts respectively, p=0.09. No significant difference between groups was noted when evaluating the mutational status of TET2, TP53, RUNX1, DNMT3A, NPM1, or FLT3. Conclusions: Interleukin 2 Receptor-α expression on leukemic blasts is known to correlate with poor prognosis and OS in young pts with AML who have been treated with cytotoxic chemotherapy. We have demonstrated that >10% CD25 expression on CD34+ blasts is associated with poor OS and resistance to therapy in AML pts > 60years of age treated with the combination of plerixafor and decitabine. Pts with >10% CD25 expression on CD34+ cells were at increased risk of death within one year and increased risk of resistance to induction therapy. Thirty-four percent of the pts in this study were CD25+, consistent with previous reports (Terwijn et al., 2009). This study highlights the importance of CD25 expression on CD34+ leukemic cells in determining prognosis, OS, response to hypomethylating agent therapy and benefit of transplant in older pts with newly diagnosed AML. Further investigations into the aggressive nature of CD25+ AML, mechanisms of resistance and novel therapeutics are ongoing. Disclosures Roboz: Teva Oncology: Consultancy; Novartis: Consultancy; Sunesis: Consultancy; Astra Zeneca: Consultancy; Glaxo SmithKline: Consultancy; Celgene: Consultancy; Agios: Consultancy; Novartis: Consultancy; Astex: Consultancy. Ritchie:Celgene, Incyte: Speakers Bureau.

Abstract Despite the increasing availability of novel agents for RRMM, many patients run out of treatment options due to disease refractoriness and/or progressive toxicities, both hematological (cytopenia) and non-hematological (cachexia, asthenia, renal and cardiopulmonary).Patients who are refractory to both proteasome inhibitors and immunomodulatory agents (IMIDs) carry an ominous prognosis with a median overall survival (OS) of 9 months (Leukemia, Kumar 2013). We previously reported on the efficacy and toxicity profiles of a metronomically scheduled chemotherapy regimen administered over the course of 16 days (Haematologica, Papanikolaou 2014). Encouraged by the results of that treatment, we have since modified metronomic chemotherapy to cover a 28-day period (metro28). The regimen consisted largely of bortezomib 1.0mg/m2 on days 1, 4, 7, 10, 13,16,19, 22,25,28; along with dexamethasone 12mg on days 1-4, 7-10, 13-16, 19-22, 25-28; thalidomide 100mg days 1-28, continuous 28 day infusion of doxorubicin 1.0mg/m2 (0.5mg/m2 for Ejection Fraction <40%) and cis-platinum 1.0mg/m2 (0.5mg/m2 for creatinine >2mg/dL), with the addition of arsenic trioxide (ATO) at 0.1mg/kg on each day after bortezomib; and lately vincristine (VCR) at 0.07mg daily dose by continuous infusion for 28 days. Patient characteristics included age >65yr, 46%; female, 33%; cytogenetic abnormalities at any time prior to therapy (CA), 86%; Gene Expression Profile (GEP) 70-defined high risk, 44%. The median number of prior therapies was 8 (1-64), prior transplants, 83% (1, 2, >=3), 20%, 32%, 31%; prior exposure to novel agents including Carfilzomib/Pomalidomide was 81%. Thrombocytopenia prior to treatment was present in 75% including thrombocytopenia <50,000/uL in 15%. Clinical outcomes are depicted in Figure 1. At a median follow up of 8.1 months, the median number of metro 28 cycles administered was 1 (1-5), with 37% achieving a partial response and median OS not yet reached. Interestingly, the 6 month - partial response duration estimate for the patients achieving PR was 53% (Figure 1A), while the one year OS estimate for all patients receiving metro 28 was 59% (Figure 1B). Prognostic factors that held statistical significance in univariate analysis for overall survival were albumin <3.5 g/dl (HR 2.56, P=0.009), beta-2-microglobulin (B2M) ≥3.5 mg/L (HR 3.03, P=0.003), LDH≥ 190 U/L (HR 2.81, P=0.003), GEP-70 High Risk (HR 2.32, P=0.048), GEP-5 High Risk (HR 5.75, P<0.001) (Figure 1C) and GEP PR subgroup designation (HR 3.71, P=0.003). In multivariate analysis, albumin < 3.5 g/dL (HR 2.81, P=0.035), B2M≥ 3.5 mg/L (HR 3.4, P=0.017), GEP PR subgroup (HR 3.8, P=0.012), and GEP-5 High Risk (HR 8.58, P<0.001) (Figure 1C) achieved statistical significance. The majority of cycles administered in the patient population were done in the outpatient setting (81%), while secondary admissions due to regimen toxicity occurred in 36% of the cycles administered. Grade 3 & 4 neutropenia and thrombocytopenia within 3 months from the start of the metronomic treatment were evident in 64% and 78% respectively of the cases. Treatment related mortality was 2%, due to one instance each of grade 5 infection and cerebrovascular event. In conclusion 28 day metronomic therapy is a feasible treatment with acceptable toxicity and encouraging preliminary results both in terms of ORR and OS for RRMM. Table 1: Patient characteristics at start of Metro28 therapy Factor n/N (%) Age >= 65 yr 56/122 (46%) IgA Isotype 28/110 (25%) Female 40/122 (33%) White 108/122 (89%) Albumin < 3.5 g/dL 47/122 (39%) B2M >= 3.5 mg/L 46/93 (49%) B2M > 5.5 mg/L 26/93 (28%) CRP >= 8 mg/L 54/122 (44%) Creatinine >= 2 mg/dL 15/122 (12%) Hb < 10 g/dL 57/122 (47%) LDH >= 190 U/L 36/121 (30%) Platelet Count < 150 x 10^9/L 92/122 (75%) Cytogenetic abnormalities 105/122 (86%) CA within 1 year of therapy 84/121 (69%) CA within 90 days of therapy 65/119 (55%) New Kit GEP Sample 91/91 (100%) GEP 70 High Risk 40/91 (44%) GEP 5 High Risk 39/91 (43%) GEP CD-1 subgroup 5/91 (5%) GEP CD-2 subgroup 17/91 (19%) GEP HY subgroup 14/91 (15%) GEP LB subgroup 6/91 (7%) GEP MF subgroup 9/91 (10%) GEP MS subgroup 9/91 (10%) GEP PR subgroup 31/91 (34%) GEP proliferation index >= 10 28/91 (31%) GEP centrosome index >= 3 26/91 (29%) n/N (%): n- Number with factor, N- Number with valid data for factor ND: No valid observations for factor Figure 1A Figure 1A. Figure 1B Figure 1B. Figure 1C: OS by GEP5 Figure 1C:. OS by GEP5 Disclosures Zangari: Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.

Abstract Background Nucleoside analogues such as cladribine can increase the efficacy of ara-C by modulating deoxycytidine kinase. The addition of cladribine to standard 7+3 chemotherapy has been shown to improve survival in pts with AML (Holowiecki JCO 2012). High dose ara-C (HiDAC) during induction improves outcomes for younger pts (Burnett JCO 2013, Willemze JCO 2013). We conducted a phase-2 clinical trial to study the efficacy of cladribine combined with HiDAC and idarubicin as induction regimen in younger pts with AML. Methods The 3-drug treatment protocol consisted of the combination of cladribine, idarubicin, and ara-C (CLIA) in pts with AML aged ≤ 65. Three cohorts were enrolled: de novo AML, secondary AML (s-AML), and relapsed/refractory (salvage). S-AML was defined as pts with AML arising from MDS, MPN, or AA and treated for that disorder prior to enrolling. Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5, followed by ara-C 1000 mg/m2 IV on days 1-5, and idarubicin 10 mg/m2 IV days 1-3. Consolidation consisted of up to 5 more cycles of CLIA. Pts with FLT3-ITD could receive sorafenib 400mg PO BID added to CLIA. Pts with FLT3+ disease, presenting WBC count > 100 K/uL, or LDH > 700 IU/dL received prophylactic intrathecal ara-C at count nadir during cycle 1. Mutation profiling was performed using next generation sequencing prior to starting therapy. Results A total of 101 pts were enrolled, with a median age of 55 years (range, 19-65), including 47 pts (47%) in the frontline cohort, 8 (8%) pts in the s-AML cohort, and 46 (46%) in the salvage cohort. Pt characteristics by cohort are outlined in Table 1. In the frontline cohort, 47 pts, who received a median of 3 (1-6) cycles, were evaluable for response. 36 pts achieved CR (77%) after a median of 1 (1-4) cycle and 4 pts CRp, giving an ORR of 81%. The 4- and 8-week mortality rates were 0% and 4%, respectively. In s-AML cohort, 8 pts were evaluable for response, receiving a median of 2 courses (1-3). The rates of CR, CRp, and CRi were 0% (0/8), 25% (2/8), and 0% (0/8) for an ORR of 25%. The 4- and 8-wk mortality rates were 13% and 13%. In the salvage cohort, 46 pts received a median of 1 (1-4) cycle, and were evaluable for response. Ten pts achieved CR (22%), 4 CRp (9%), and 4 CRi (9%), achieving an overall response rate (ORR) of 39%. A median of 1 (1-3) cycle was required for response. The 4- and 8-wk mortality rates were 7% and 15%, respectively. At the time of CR, 21 (55%), 0 (0%), and 8 (44%) of pts achieved MRD negativity by multiparameter flow cytometry in the frontline, s-AML, and salvage cohorts respectively. Pts in the salvage cohort were previously treated with a median of 2 (1-5) prior therapies. ORR by subgroup is summarized in Table 2. After a median follow-up of 12 months (0.9 - 24.1), the 6-month OS estimates were 89%, 26% and 58% and 6 month remission durations were 95%, 100%, and 55% for the frontline, s-AML, and salvage cohorts, respectively (Figure 1A-B). Among MRD negative pts, 1 frontline pt relapsed at 6.7 months and 4 salvage pts relapsed at month 3.4, 3.9, 5.1 and 5.2 (median 4.5). In frontline pts, pretreatment serum ferritin level of < 1000 was associated with improved OS compared to those who had ferritin ≥ 1000 (1-year OS 81% vs. 47%, P=0.04). The regimen was well tolerated. The most common ≥ grade 3 non-hematologic adverse events were fever/infection (17), tumor lysis syndrome (1), cardiac arrhythmia (1), Rash (1), elevated bilirubin (1) and creatinine (1). Conclusion The 3-drug combination, CLIA, is safe and effective in younger pts with AML. Outcomes in pts with s-AML were poor, highlighting a subgroup of AML that should be handled separately. Response rates for pts in the newly-diagnosed AML, FLT3-ITD+, and early salvage settings are promising and should be explored further in larger studies and compared to current standard regimens. Disclosures Jabbour: Bristol-Myers Squibb: Consultancy. Daver:Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Celgene: Research Funding. Jain:Genentech: Research Funding; Servier: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Research Funding; BMS: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract Introduction: Presence of advanced OL was recently reported as a risk for poor mobilization in patients with multiple myeloma who had poor HPC collections (Jung et al. J Clin Apheresis 2014; Apr 25. doi: 10.1002). We sought to confirm this finding and also whether poor collection correlated with low peripheral blood CD34+ cell numbers as evaluated by flow cytometry. Patients and Methods: Patients: We performed a retrospective study of patients who underwent autologous HPC collection at our institution between 2005 and 2012 to identify poor mobilizers and mega-mobilizers in a 2:1 ratio for data analysis. We defined poor mobilizers as those who required maximal plerixafor support (4 days) for collection, and mega-mobilizers as those who collected >30 x 106 CD34+ cells/kg in 2 days. We found 79 poor mobilizers, but removed 9 from data analysis because the collection variables of plerixafor timing and G-CSF dose differed from the others, leaving 64 myeloma (MM) and 6 non-myeloma plasma cell dyscrasias (NMPCD) patients for analysis: 41 male, 29 female, age range 43–86 (median 67.5). There were 37 mega-mobilizers: 36 MM, 1 NMPCD: 21 male, 16 female, age range 40–73 (median 61). Cumulative CD34+ cells/kg during leukapheresis and peak peripheral CD34+ cell counts were recorded. Apheresis: Apheresis was initiated using a central venous catheter when the predicted CD34+ cell collection for 30 L of blood processed was at least 1 x 106/kg using a predictive formula (Rosenbaum et al. Cytotherapy 2012; 14(4): 461-6). The volume of blood processed each day was based on the same predictive formula, and ranged from 5 to 30L. Cells were collected on a COBE ® Spectra apheresis machine, software version 7.0, using 1000 mL anticoagulant citrate dextrose (ACD) and 5000 units heparin for anticoagulation at an inlet:anti-coagulant ratio of 31:1, and an inlet flow rate of 150 mL/min with anti-coagulant infused at 5 mL/min. The collection flow rate was set at 1.5 mL/min and 10 mL ACD was added to the component at processed volumes of 10 L, 20 L and 30 L. An infusion of 2 g calcium chloride in 250 mL normal saline (0.9% sodium chloride) ran at 85 mL/h. Flow cytometry: CD34+ cells in peripheral blood and HPC products were quantified by flow cytometry using the ISHAGE protocol. Statistics: Mean peripheral blood CD34+ cells/µL and mean CD34+ cells/kg collected were calculated separately for the mega-mobilizer + poor mobilizer combined group, mega-mobilizer and poor mobilizer groups. All patients were subcategorized into those with ≤10 and >10 OL, and means for CD34+ cells/kg collected and peripheral blood CD34+ cells/uL were compared separately between the ≤10 and >10 OL groups using two-tailed Student’s t-tests and p-values evaluated for significance. Results: For all patients combined (mega + poor mobilizers) there were no significant differences in either peripheral CD34+ cells/µL or mean total CD34+ cells/kg collected between the ≤10 and >10 OL subgroups. Mean CD34+ cells/µL peripheral blood was 276 and 250 for the ≤10 and >10 OL groups, respectively (p=0.73), with means of 27.7 and 23.6 CD34+ × 106 CD34+ cells/kg collected (p=0.41). For the mega-mobilizers there was no significant difference in mean peripheral blood CD34+ cells/µL between the OL (</=10 and >10) groups (722 vs. 709, respectively; p=0.92) or in total CD34+/kg collected (55.8 and 53.8, respectively; p=0.78). For the poor mobilizers there was no significant difference in mean peripheral CD34 cells/µL between the ≤10 and >10 OL groups (27 and 20, respectively; p=0.10); however, there was a statistically significant difference in total number of CD34+ cells/kg collected, 11.9 and 8.4 ×106 CD34+ cells/kg, respectively (p=0.02). Conclusion: No significant difference was seen in mobilization as judged by peripheral blood CD34+ cells/ µL in mega-mobilizers or poor separately or combined, but a difference in the total number of CD34+ cells collected was seen in poor mobilizers. We suggest this difference results from variables in collection protocols, as we have previously shown that both mobilization and collection variables impact total CD34+ cells collected by apheresis (Abuabdou et al 2013; J Clin Aph Dec 18. doi: 10.1002). Disclosures Barlogie: Celgene: Consultancy, Patents & Royalties, Research Funding; Millenium: Consultancy, Patents & Royalties, Research Funding.

Abstract Background: In Chuvash polycythemia (CP) (Problemi Gematologii I Perelivaniya Krovi 1974, 10:30), impaired degradation of hypoxia inducible factor (HIF)-1α and HIF-2α from a homozygous germline VHLR200W mutation leads to augmented hypoxic responses during normoxia (Nat Genet 2002, 32:614). In addition to elevated hematocrit, CP is marked by leg varices, benign vertebral hemangiomas, decreased systemic blood pressure, increased systolic pulmonary artery pressure, and by the defining phenotypes of thrombosis and early mortality (Blood 2004, 103:3924; Haematologica 2012, 97:193). There is no effective therapy. While phlebotomy has been recommended for idiopathic polycythemia by the British Committee for Standards in Haematology (Br J Haematol 2005, 130:174) and is administered to some CP patients, its benefits are unknown. Phlebotomy-induced iron deficiency inhibits PHD2 enzyme, the principal negative regulator of HIFs, which further augments hypoxic responses. This affects the transcription of many genes (BCMD 2014, 52:35). Hypoxia-regulated IRAK1 is augmented in inflammation and may promote thrombosis (Circ Res. 2013, 112:103). Methods: 165 patients with CP were enrolled in a registry between 2001 and 2009 after providing written informed consent. Survival analysis was used to examine the predictors of new thrombosis and death during the follow-up period. mRNA from peripheral blood mononuclear cells (PBMCs) was profiled by Affymetrix Human Exon 1.0 ST Array in 42 of the subjects. Results: The median age at enrollment was 35 years and 90 participants were females, 25 had a history of one thrombosis, 5 of two thromboses and 3 of three thromboses. In the year prior to study entry, 72 had received phlebotomy therapy (Table 1). In July 2015 the median follow-up was 9.0 years (range 1-14.5). During this follow-up period, 30 (18.2%) participants had one new thrombosis, 6 (3.6%) had two new thromboses and 17 (10.3%) died. The median age of death was 55 years (range 16-76) and deaths were related to thrombotic cerebrovascular accident (n = 4), myocardial infarction (n = 4), mesenteric or portal vein thrombosis (n = 3), other major thromboembolic events (n = 2) and trauma or unknown cause (n = 2). Baseline characteristics of older age, prior thrombosis, pentoxifylline treatment, smoking and splenomegaly were independently associated with greater thrombosis risk during follow-up (P < 0.003). After adjustment for these variables, the estimated probability of new thrombosis at 10 years was 26% in those receiving phlebotomies compared to 12% in those not phlebotomized (log rank P = 0.014) (Figure 1). There was also a trend for increased risk of death with phlebotomy: estimated probability 8.7% versus 3.7% (P = 0.15). Examination of gene transcripts affecting thrombosis by logistic regression identified 12 protective and 16 risk genes at 5% false discovery rate. Upregulation of two mRNAs was of singular significance: 1) IL1RAP, a proximal signaling adaptor of IRAK1 (Immunity 1997, 7: 837) and 2) THBS1, encoding thrombospondin1 (Blood 2015, 125: 399). Both genes have known roles in thrombosis promotion and we previously reported that THBS1 is upregulated in CP (BCMD 2014, 52:35). Further analysis revealed a further upregulation of THBS1 in patients with baseline history of phlebotomy (β=0.41, P=0.046). Conclusion: These findings underscore a high rate of thrombosis and death in patients with CP and reveal a potential role of increased IRAK1/IL1RAP signaling in these complications. They raise the possibility that phlebotomy therapy has a detrimental rather than beneficial effect, possibly contributed to by increased THBS1 expression. Table 1. Baseline characteristics by phlebotomy in the year prior to enrollment. Results in median (interquartile range) or n (%); four without phlebotomy data. No phlebotomy N=89 Received phlebotomy N=72 Age (years) 32 (18-48) 37 (26-49) 0.08 Female gender, n (%) 52 (58%) 34 (47%) 0.16 Smoking, n (%) 18 (20%) 24 (33%) 0.060 History of thrombosis, n (%) 20 (23%) 12 (17%) 0.4 Splenomegaly, n (%) 2 (2.3%) 2 (2.8%) 0.8 ASA treatment, n (%) 27 (30%) 36 (50%) 0.011 Pentoxifylline, n (%) 7 (7.9%) 17 (23.6%) 0.005 BMI (kg/m2) 20.4 (18.3-22.9) 21.6 (19.9-24.6) 0.010 Systolic BP (mm Hg) 109 (100-123) 118 (105-124) 0.6 Diastolic BP (mm Hg) 76 (68-84) 78 (71-83) 0.8 Hemoglobin (g/dL) 18.1 (16.4-21.0) 17.9 (16.0-19.8) 0.5 WBC (per uL) 5.7 (4.6-7.0) 5.5 (4.6-6.7) 0.9 Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background For decades, cytogenetic analysis has played an essential role in AML risk stratification. Among the 50% of AML patients (pts) with normal karyotype (NK), outcome can vary widely. More recently, whole genome sequencing (WGS) and whole exome sequencing (WES) have identified several recurrent mutations that play an important role in AML pathogenesis and impact outcome. Pts with secondary AML (sAML) have a particularly poor prognosis, are not as responsive to standard induction chemotherapy, and often are referred in first complete remission to hematopoietic stem cell transplantation. We hypothesized that different genomic patterns exist between primary AML (pAML) and sAML that can distinguish the two, and can alter treatment recommendations. To negate the impact of chromosomal abnormalities, we focused our analyses on pts with NK. Methods We performed WES and multi-amplicon targeted deep sequencing on samples from bone marrow and peripheral blood of pts diagnosed with sAML at our institution between 1/2003- 1/2013 and who had NK cytogenetics. We compared them to pts with NK primary AML (pAML) whose data were extracted from The Cancer Genome Atlas (TCGA). A panel of 62 gene mutations that has been described as recurrent mutations in myeloid malignancies was included. Mutations were considered individually and grouped based on their functional pathways: RNA splicing (SF3B1, U2AF1/2, SRSF2, ZRSR2), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin modification (ASXL1, EZH2, MLL, SUZ12, KDM6A), transcription (RUNX1, CEBPA, NPM1, BCOR/BCORL1, SETBP1, ETV6), activating signaling (FLT3, JAK2), cohesion (STAG2, SMC3, RAD21), RAS superfamily (K/NRAS, NF1, PTPN11, CBL) and tumor suppressor genes (TP53, APC, WT1, PHF6). Using deep sequencing methodology for resequencing or targeted sequencing, variant allelic frequency (VAF) was measured for each mutation detected. VAF was adjusted by zygosity evaluated by SNP-array karyotyping. For confirmation of clonal architecture, serial sample sequencing and single colony PCR were applied. Differences were compared using Fisher-exact test and Mann-Whitney U test for categorical and continues variables respectively. Results: Of 143 pts included, 101 (71%) had pAML and 42 (29%) had sAML. Compared to pAML, sAML pts were older (59 vs 69 years, p <.001), and had lower white blood cell count (28 vs 3.5 X 109/L, p <.001). Median hemoglobin (10 vs 10) g/dl and platelet counts (57 vs 60) k/uL were similar between the two groups. With a median follow up of 26.4 months (mo, range, .93-95.4), median OS was shorter for sAML than for pAML (12.9 vs 16.2 mo, p= .03). Overall, the most common mutations were: NPM1 (35%), DNMT3A (27%), FLT3 (25%), RUNX1 (14%), IDH1 (12%), IDH2 (12%), STAG2 (12%), TET2 (11%), NRAS (8%), ASXL1 (8%), U2AF1 (8%), PTPN11 (7%), WT1 (6%), BCOR (5%), and PHF6 (5%). Mutations in SF3B1, U2AF1/2, BCOR/BCORL1, ETV6, ASXL1, JAK2, STAG2, and APC were more common in sAML compared to pAML, whereas mutations in DNMT3A, NPM1, CEBPA, and FLT3 were more common in pAML. Mutations in activated pathways in splicing machinery, transcription, chromatin modification, cohesion and RAS pathway were more prominent in sAML, while mutations in DNA methylation and signaling pathways occurred more frequently in pAML. Serial sample analyses at multiple time points demonstrated intra-tumor heterogeneity in most cases of sAML, which was supported by additional cross sectional analyses of VAF in multiple gene mutations in each case. These findings prompted us to evaluate secondary events in the cohort of pts whose sAML originated from an initial MDS stage, defined by ancestral mutations. Among genes frequently affected by mutations, TET2 and ASXL1 were identified as founder events, whereas STAG2, NRAS and PTPN11 were observed in subclonal sAML derived from founder MDS clones. In pAML, however, TET2 and ASXL1 mutations were found to be secondary lesions, while IDH1 and DNMT3A were identified as ancestral events. Conclusion Clear genomic variations exist between sAML and pAML that suggest differences in the pathophysiology of both diseases. Specific therapies should be directed to the activated pathways according to the unique clonal hierarchy in each AML subtype. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction. Allogeneic hematopoietic stem cell transplantation using UCB is an alternative approach for pts (pts) with hematological malignancies lacking an HLA matched donor. However, for pts with severe aplastic anemia (SAA), UCB transplants are associated with delayed engraftment, high graft failure rates and poor survival. Ex-vivo expanded UCB using nicotinamide (NAM) can engraft in NOD/SCID mice, and in pilot studies in pts with hematological malignancies, results in rapid engraftment and durable hematopoiesis. Here we investigated a novel transplantation approach using NAM-expanded UCB in refractory SAA pts who lacked an HLA matched donor, hypothesizing this regimen would accelerate engraftment and immune reconstitution compared to conventional UCB transplants. PTS AND Methods. Eligible pts had SAA with severe neutropenia (ANC<1000) unresponsive to immunosuppressive therapy (IST) underwent a NAM-expanded UCB-transplant at a single center in a phase II trial (NCT03173937). Pts were conditioned with cyclophosphamide (60 mg/kg x 2), horse ATG (40 mg/kg x 4), fludarabine (25 mg/m2 x5) and 200cGy of TBI. GVHD prophylaxis included tacrolimus and MMF. Cohort I is designed to transplant six pts with a single NAM-expanded unit combined with 3 x 106 CD34+ cells/kg from a haploidentical donor as a backup stem cell source. Once adequate cord engraftment is established in Cohort 1, the study will proceed to Cohort 2 to transplant a NAM-expanded unit alone without haplo-CD34+ cells. Engraftment, chimerism, and immune recovery were assessed and compared with SAA pts who received a conventional non-expanded UCB transplant combined with haplo-CD34+ cells using the identical conditioning and GVHD prophylaxis. Results. From 2017 to 2018, two SAA pts (22 years male and 45 years female, pre-transplant ANC ≤300/uL, and had failed ATG/CSA/Eltrombopag) were successfully transplanted with a single ≥ 6/8 HLA-matched NAM-expanded UCB unit combined with haplo CD34+ cells from a relative. The UCB units before expansion contained a median total nucleated cell (TNC) dose of 2.8 x 107/kg and 1.7 x 105 CD34+ cells/kg. At transplant, the cultured NAM-expanded units contained a median 6.0 x 107 TNCs/kg and 96.4 x105 CD34+ cells/kg, representing a median post TNC and CD34+ cell expansion of 2-fold and 52-fold, respectively. At 12 months and 5 months post-transplant, both pts survive with stable engraftment, transfusion independence, and without acute or chronic GVHD. The median time to neutrophil recovery (ANC > 500/ μL) was only 6.5 days (range 6-7), and platelet recovery was 35.5 days (31-40); chimerism studies showed that both pts achieved >95% cord donor myeloid chimerism and T-cell chimerism at a median 6.5 (6-7) and 23.5 days (21-26) respectively . Immune recovery in both pts receiving NAM-expanded UCB was brisk (Figure 1): absolute CD4+ count > 200 cells/μL occurred at 17 and 60 days; at day 100, median CD4+ numbers was 382/μL and median IGA was 92 mg/dL. In comparison to 16 SAA pts transplanted sequentially at our institute from 2013-2016 using a single unexpanded CBU combined with haplo CD34+ cells, median cord graft doses were 3.6 x 107 TNCs/kg and 1.2 x105 CD34+ cells/kg; b) median time to ANC and platelet recovery was 10 and 51 days; c) median time to >95% cord donor myeloid chimerism was 63 days; d) at day 100, only 3/16 (19%) unexpanded UCB recipients had CD4+ count > 200 cells/μL, and the median CD4+ number was only 74 cells/μL and the median IGA was only 31 mg/dL. This first in human transplant trial suggests neutrophil engraftment, platelet recovery, and post-transplant immune recovery are superior inSAA pts transplanted with NAM expanded UCB compared to conventional nonexpanded UCB (all P<0.05, Figure 1). Conclusion. These encouraging preliminary results show for the first time that NAM-expanded UCB results in rapid cord engraftment, sustained hematopoiesis and accelerated immune recovery in treatment refractory, neutropenic SAA pts. The high numbers of transplanted CD34+ progenitor cells in NAM-expanded grafts could potentially overcome graft failure associated with conventional UCB transplantation for SAA, obviating the need for co-transplanting haplo CD34+ cells as a stem cell back-up. Disclosures No relevant conflicts of interest to declare.