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7021 Background: CMML is a lethal myelodysplastic/myeloproliferative neoplasm (MDS/MPN) characterized by peripheral monocytosis and bone marrow (BM) dysplasia with limited therapeutic options. Prec...

Severe aplastic anemia (SAA) is a rare and life-threatening disorder characterized by peripheral blood cytopenias and a hypocellular BM.1 Allogeneic hematopoietic cell transplantation is the mainstay of therapy for patients < 40 years of age. Because < 30% of patients have an appropriate HLA-compatible donor, research efforts are focused on immunosuppressive treatments as first-line therapy to improve outcomes. Antithymocyte globulin (ATG) and cyclosporine (CsA) have been the standard initial regimen for nearly 2 decades, with response rates from 50%-70%, and this remains the current recommendation for initial therapy for SAA.2 To examine the current best evidence of the various alternative regimens to ATG/CsA as a first-line therapy for severe aplastic anemia, we performed a comprehensive computerized literature search of the PubMed database combining the MESH terms “treatment of severe aplastic anemia” (6542 hits) AND “immunosuppressive therapy” (1767 hits) AND “not transplant” (199 hits) from 2005 through 1 June 2011. References chosen for discussion here include one systematic review on ATG/CsA,3 2 randomized controlled trials,4,5 3 observational studies,6-8 and one meta-analysis.9 Review of the references listed in a recent review article10 added one additional pilot study.11 The study of the addition of sirolimus to ATG/CsA was found to have a lower overall response rate at 6 months than ATG/CsA alone (51% vs 62%).4 Another study of the addition of mycophenolate mofetil to ATG/CsA with a 62% overall response rate also did not show improvement over standard ATG/CsA.12 A systematic review of the addition of growth factors to standard therapy showed no difference in overall response at 12 months or in overall mortality.9 Alternative therapies to ATG/CsA have also been explored and demonstrated no benefit. Tacrolimus in place of the CsA with ATG was tested in a small study of children and found to be equivalent, with a complete response of 88% for tacrolimus and 85% for CsA. Alemtuzumab was also used as first-line therapy and found to have a total response rate of 58%.11 Androgens were a mainstay of SAA therapy before ATG/CsA and are still used if ATG/CsA not available. However, the overall response rate in children was reported to be only 46%.7 Finally, high-dose cyclophosphamide has been evaluated with ATG and alone. The randomized controlled trial5 showed no difference in response, but demonstrated higher mortality with cyclophosphamide. The observational study showed an overall response rate of 77%,8 but there was no control for comparison (Table 1). Table 1 Regimens reviewed The addition of drugs to the standard ATG/CsA regimen or alternative regimens is routinely reported in the literature as novel therapy for SAA. In clinical practice, there is the admirable desire to improve a patient’s response rate, and these agents are often administered despite little evidence to suggest that they are improvements over the standard of care and some evidence of detriment. Based on this review, we conclude that multiple regimens for SAA have been explored as alternatives to ATG/ CsA, without evidence of benefit in response rates or overall survival. This conclusion is based on both randomized controlled trials and small observational series. Therefore, based on the highest grade of evidence3 (grade 1A), ATG/CsA alone is the only appropriate first-line therapy that can be recommended to the patient described above.

Background: Although HMA (azacitidine [aza] or decitabine [dac]) are standard of care therapies for HR-MDS pts, responses may not be seen for 4-6 months and occur in Methods: The combined MDS database obtained from six institutions in the MDS Clinical Research Consortium (Moffitt Cancer Center, Cleveland Clinic, MD Anderson Cancer Center, Dana Farber Cancer Institute, Weill Medical College of Cornell University, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins) was used to identify patients with HR-MDS (IPSS intermediate-2 [INT-2] and high) who received HMA therapy (aza or dac). Responses were defined per International Working Group 2006 criteria. Overall response rate (ORR) was defined as the sum of rates of complete response (CR), partial response (PR), hematologic improvement (HI), and marrow CR. Pts with stable disease (SD) and progressive disease (PD) were considered non-responders. Logistic regression models were fitted and tested for association of response with prognostic risk categories using chi-square deviance tests. Overall survival (OS) was calculated from the time of diagnosis to time of death or last follow-up. Kaplan-Meier (KM) curves were generated for OS and the log-rank test was used to compare median OS. Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models. Results: We identified 595 pts with HR-MDS (70.3% with INT-2 and 29.7% with high IPSS) who received HMA as upfront therapy (83% aza, 17% dac). Median follow-up from diagnosis was 13.1 months (M), 95% confidence interval (CI): 11.5-15.1 M. 66% of pts were male, 88% white, 85% were >60 years, and 18% had therapy-related MDS. Median number of HMA cycles was 5.7 (range, 0.7-51) with 75% of pts receiving ≥3 cycles of therapy. Median time from diagnosis to start of HMA therapy was 1.5 M. ORR was 42.1% (CR 25.8%, PR 6.7%, HI-E 3.3%, HI-P 2.3%, HI-N 4.0%) while 57.2% were non-responders (SD 28.6% and PD 28.6%) and 0.7 were un-evaluable. None of the prognostic systems predicted overall response to HMA. Median OS for the entire cohort was 16.3 M (CI, 15.0-17.8 M). Figure 1 shows the KM survival curves and Table 1 shows the median OS, the corresponding CI and associated p-value for the risk categories in each prognostic model. Scores generated using the AIC (n=294) to assess the relative goodness of fit (lower is better) were 2139 (MDAPSS), 2148 (FPSS), 2155 (IPSS-R), and 2174 (IPSS). Conclusions: We report the largest direct comparison of the major MDS prognostic models among HMA-treated patients. None of the models predicted overall response to HMA therapy. Nonetheless, the IPSS-R, MDAPSS, and the FPSS all functioned well to separate HMA-treated pts with HR-MDS into different prognostic groups in terms of survival. The MDAPSS and FPSS appear superior to the IPSS-R and IPSS for survival prediction. HR-MDS pts with poor projected survival with HMA therapy should be considered for up-front HCT or for experimental approaches. Figure 1 Figure 1. Abstract 1935. Table 1 IPSS (n=595) IPSS-R (n=555) FPSS (n=296) MDAPSS (n=508) Risk Group (n) Median OS in months (CI) Risk Group (n) Median OS in months (CI) Risk Group (n) Median OS in months (CI) Risk Group (n) Median OS in months (CI) Low (0) NA Very low (1) NA Low (19) 38.4 (23.1-NR) Low (4) Not reached (NA) INT-1 (0) NA Low (3) 28.1 (27.0-NR) INT (241) 17.8 (15.9-19.6) INT-1 (55) 26.2 (18.8-40.4) INT-2 (418) 16.8 (15.3-18.3) INT (59) 39.1 (23.9-49.6) High (36) 10.6 (7.2-13.4) INT-2 (143) 18.6 (17.4-24.1) High (177) 15.2 (13.4-17.8) High (197) 18.8 (16.8-22.2) High (306) 13.4 (11.8-15.0) Very High (295) 12.2 (11.0-14.1) P-value P=0.014 P Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Novartis Pharma: Research Funding. Steensma:Amgen: Consultancy; Ariad: Equity Ownership; Celgene: Consultancy; Novartis: Consultancy. List:Celgene Corporation: Consultancy.

Introduction:Myelodysplastic Syndromes (MDS) represent a heterogeneous group of hematopoietic stem cell (HSC) disorders with varying clinical outcomes, but prognosis uniformly worsens with transformation to secondary acute myeloid leukemia (AML). Despite recent progress in genomics, the mechanisms responsible for disease progression are not fully understood as most of the somatic mutations defined thus far can be found at early stages of the disease. Previous studies have identified aberrant activation of the Hedgehog (Hh) signaling pathway in a subset of AML patients and the expression of the Hh-regulated transcription factor GLI2 correlated with inferior overall and progression free survival. In solid tumors, Hh pathway activation has been associated with metastatic disease progression, and we examined its role in MDS progression and transformation to AML. Methods/Results: We initially quantified changes in Hh pathway activity in CD34+ cells isolated from serial bone marrow samples collected from MDS patients at the time of diagnosis and following progression to AML. We found that the expression of the Hh target genes GLI1 and PTCH1 was increased in 67% of patients (4/6) suggesting that pathway activation was involved in the development of secondary AML. We also analyzed gene expression in 135 MDS patients and found significantly higher GLI2 expression in high-risk MDS (N=80) compared to low-risk MDS (N=55) (p=0.036). In addition, bone marrow blast percentage was significantly higher in the MDS cohort with higher GLI2 expression (mean±SEM=7.1±0.7%) than with lower expression (5.4±0.5%, p=0.039). In order to mechanistically study the effects of Hh pathway activation on MDS progression, we studied mice expressing the Nup98-HoxD13 (NHD13) fusion gene under the control of the vav promoter that generates progressive cytopenia and, in some animals, progression to AML. We crossed NHD13 mice with mice conditionally expressing the constitutively active mutant of the Hh signal transduction regulator Smoothened (SmoM2) in hematopoietic cells expressing Mx1-Cre. The survival of double transgenic animals (NHD13/SmoM2) was significantly shorter compared to mice expressing NHD13 (median survival of 3 months vs. 12 months, p Within the bone marrow, hematopoietic stem/progenitor cells (Lin-Sca1+cKit+) were depleted within both NHD13 and NHD13/SmoM2 mice. To examine the impact of Hh activation on clonogenic growth and self-renewal potential, we plated bone marrow cells in methylcellulose and found that NHD13/SmoM2 cells contained a significantly higher number of CFU compared to NHD13 cells (37 vs. 2, p=0.002) that was sustained with subsequent passages (400 vs. 30, p Conclusions:We found that the Hh signaling pathway may be aberrantly activated in a subset of secondary AML patients progressing from MDS. We also demonstrated that activation of Hh signaling induces fatal AML in a mouse model of MDS characterized by inferior survival and widespread expansion of immature myeloid cells. This disease progression is driven by the acquisition of self-renewal and tumor initiating potential in differentiated Lin+ hematopoietic cells. Our findings suggest that Hh pathway inhibition may be a promising approach for AML arising from MDS. Figure 1 Figure 1. Disclosures Maciejewski: Alexion: Speakers Bureau; Celgene: Speakers Bureau.

Background: Several validated prognostic models exist for patients (pts) with MDS, including the International Prognostic Scoring System (IPSS), the Revised IPSS (IPSS-R), and the MD Anderson Prognostic Scoring System (MDAPSS). All were developed in pts with newly diagnosed MDS, and their prognostic value in subsequent stages of disease, such as at the time of failure of hypomethylating agents (HMAs, azacitidine (AZA) and decitabine (DAC), has not been established. Despite this, the IPSS is often used to determine clinical trial eligibility for pts who fail HMAs and is being considered for drug labeling for this indication. Methods Clinical data were combined from the MDS Clinical Research Consortium institutions (Moffitt Cancer Center n=259, Cleveland Clinic n=221, MD Anderson Cancer Center n=192, Cornell University n=100, Dana-Farber Cancer Institute n=45, and Johns Hopkins n=29). The IPSS, IPSS-R, and MDAPSS were calculated at the time of diagnosis and HMA failure. HMA failure was defined as no response to AZA or DAC following ≥ 4 cycles, loss of response, or progression to acute myeloid leukemia (AML). Responses were defined per International Working Group criteria (IWG 2006). Overall survival was calculated from the time of HMA failure to time of death or last follow up (OSHF). Survival curves were compared using stratified log-rank tests. Akaike information criterion (AIC) was used to compare fits from Cox proportional hazards models. Results A total of 488 pts who failed HMAs and had clinical data available at the time of failure were included in the final analyses. Overall, 406 (83%) were treated with AZA and 82 (17%) with DAC. At diagnosis: median age was 70 years (26-91), median absolute neutrophil count 1.06 k/mL (0.06-36.41), hemoglobin 9.3 g/dL (3.4-38.6), platelets 75 X 103/mL (2-969), and bone marrow blasts 7% (0-28). Prognostic scoring systems at diagnosis included, IPSS: 6 (2%) low, 46 (14%) intermediate-1, 206 (60%) intermediate-2, 83 (24%) high; IPSS-R: 3 (1%) very low, 12 (4%) low, 49 (16%) intermediate, 114 (37%) high, 129 (42%) very high; and MDAPSS: 11 (4%) low, 36 (13%) intermediate-1, 89 (31%) intermediate-2, 149 (52%) high. With median follow up from diagnosis of 18.2 months (mo) (0.7-224.6), median time from diagnosis to HMA start was 1.3 mo (0-162.4). Median number of HMA cycles received was (6, range 4-51): AZA (6, range 4-51), and DAC (4, range 4-21). Median OS from time of diagnosis was 19.5 mo (95% CI, 18.3-22.0). At the time of HMA failure, the median OSHF was 7.1 mo (95% CI, 6.2-7.9). Median OSHF by IPSS (n=311, low 10.9, intermediate-1 11.0, intermediate-2 7.1, high 5.1, p=.005), IPSS-R (n=285, very low 22.4, low 10.3, intermediate 5.6, high 9.4, very high 5.7, p Conclusion When applying three of the most widely used prognostic scoring systems in MDS to pts at the time of HMA failure, the IPSS-R performed the best, followed by the MDAPSS and the IPSS. No system was ideal, though, and should be used with caution for clinical trial eligibility or drug labeling in MDS pts failing HMAs. Figure 1A. Overall survival by scoring systems: (A) IPSS, (B) IPSS-R, (C) MDAPSS Figure 1A. Overall survival by scoring systems: (A) IPSS, (B) IPSS-R, (C) MDAPSS Figure 1B Figure 1B. Figure 1C Figure 1C. Disclosures Roboz: Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy.

Background: Therapy with HMA is now the standard of care for pts with MDS and chronic myelomonocytic leukemia (CMML) with complete response (CR) rates of 7% to 35%, median response durations of 9 to 10 months, and median survival of 20 to 24 months. While allogeneic stem cell transplantation (ASCT) is curative in pts with MDS, the long-term outcome of pts treated with HMA remains unknown. Aims: The aims of the study are to assess the long-term outcome of pts with MDS treated with HMA and to identify prognostic factors of long-term outcome. This may help selecting patients for this long-term treatment in whom ASCT may not be indicated. Methods: We reviewed the records of 511 pts with diagnosed MDS (n=409) and CMML (n=102) treated from 4/2000 to 4/2014 and who were treated with HMA. Pts who received ASCT (n=65) were excluded. Thus, a total of 446 pts were evaluable for the study. The probabilities of leukemia-free survival (LFS) and overall survival (OS) were estimated using the method of Kaplan and Meier. Univariate and multivariate analyses were performed to identify potential factors associated with the achievement of response with logistic regression models and survival with Cox proportional hazard regression models. Results: The median follow-up for the entire cohort was 13.6 months. Pt characteristics are outcomes described in Table 1. Best responses to HMA were CR in 124 (28%) pts, CRp in 27 (6%), PR in 9 (2%), HI in 31 (7%). Median duration of response was 7 months (1-68). 130 (29%) transformed into AML after a median of 11 months (11-60). At the last follow-up 133 (30%) remained alive. The median LFS and OS were 16.1 and 16.2 months respectively. The 2- and 5-year LFS and OS rates were 29% and 11% and 34% and 12%, respectively. By multivariate analysis, baseline characteristics associated with OS included WBC (>4 vs. ≤4), ferritin (>500 vs. ≤500), hemoglobin (>10 vs. ≤10), platelets (>500 vs. ≤500) and cytogenetics (high vs. intermediate vs. low risk) (p4 vs. ≤4), ferritin (>500 vs. ≤500), platelets (>500 vs. ≤500) and cytogenetics (0=low risk; 1=intermediate risk; and 2=high risk) as independently associated with survival improvement Patients with 0-2 (n=244) or 3-5 (n=162) adverse factors had a median survival of 19 and 13 months, respectively (p Conclusion: Our current analyses identified a small subset of pts with MDS in whom outcome of therapy with HMA is excellent and can be differentially predicted. Table 1. Patient Characteristics and Outcomes Parameter (N=446) Number (%); Median [range] Age (years) 70 (13-92) White Blood Cell Count (x 109/L) 3.5 (0.5-212) Ferritin 465.0 (0-10971) Hemoglobin (g/dL) 9.7 (6-16) Platelets (x 109/L) 68.0 (4-987) Bone marrow blasts (%) 6.0 (0-19) Prior malignancy 198 (44) Prior chemotherapy 133 (30) Prior radiotherapy 85 (19) Prior Transfusion 134 (30) Cytogenetics (by IPSS) Low 213 (48) Intermediate 78 (17.5) High 144 (8) Missing 11 (2.5) WHO RA 47 (10.5) RARS 16 (4) RCMD 75 (17) RAEB 204 (46) MDS-U 8 (2) CMML 95 (21) Missing 1 (0.2) IPSS Low 46 (10) Intermediate-1 193 (43) Intermediate-2 156 (35) High 36 (8) Missing 15 (3) MDA Score Low 59 (13) Intermediate-1 113 (25) Intermediate-2 124 (28) High 113 (25) Missing 37 (8) Type of HMA Azacitidine/ AZA+ 189 (42) Decitabine/DAC 257 (58) Response to HMA CR 124 ( 28) CRp 27 (6) PR 9 (2) HI 31 (7) NR 121 (27) Died on therapy 23 (5) NE 6 (1.4) Missing 105 (23.5) Median duration of response (mos) 7.2 (1-68) Transformed into AML 130 (29) Dead 313 (70) Disclosures No relevant conflicts of interest to declare.

Background The primary treatment goal in higher-risk MDS patients (pts) is to prolong survival by altering the natural history of the disease and delaying progression to acute myeloid leukemia (AML). Treatment with HMA such as azacitidine (AZA) improves overall survival (OS) in pts who achieve a response of stable disease (SD) or better (complete remission [CR], partial remission [PR], or hematologic improvement [HI]) (Gore et al, Haematologica, 2013). However, it is not well established if pts who achieve SD by 6 months (mo) of therapy should be offered different therapies to optimize their response or continue with the same HMA regimen. Methods Clinical data were obtained from the MDS Clinical Research Consortium database. Pts treated with either AZA or decitabine (DAC) were included and categorized per the Revised International Prognostic Scoring System. Responses were evaluated per International Working Group (IWG 2006) criteria. SD was defined as no evidence of progression and without achievement of HI. Early response was defined as achievement of CR, PR, HI, or SD between 3-6 months (mo) of therapy. Best response was assessed after 6 mo of treatment. OS was calculated from the start of therapy to date of death or last follow up. Differences were evaluated using the Fisher-exact test and Mann-Whitney U tests for categorical and continuous variables, respectively. Results Of 291 pts with higher-risk MDS and available response data, 248 (85%) received treatment with AZA and 43 (15%) with DAC. Median age was 70 years (range, 35-99), median absolute neutrophil count (ANC) was 1.05 X109/L (range, .58-68), hemoglobin 9.3 g/dL (range, 3.7-14.3), platelets 73 X109/L (range, 4-659), and bone marrow blasts 10% (range, 0-19). Per IPSS-R, 20% of pts were intermediate risk, 37% high, and 43% very high. A total of 142 pts (49%) progressed to AML. Median time from diagnosis to start of HMA was 28 days. Early responses (3-6 mo) were: CR 10%, PR 5%, HI 10%, and SD 49%. Among the 144 pts who achieved SD at 3-6 mo, 29 (20%) achieved a better response (CR, PR, or HI) later during their treatment, with a median time to better response of 3.7 mo (range,1.2-14.5); 113 (89%) remained with stable disease, and 2 (1%) progressed to AML. With a median follow up of 16.5 mo (range, 2.5-120.2), the median OS by best response at any time point during therapy: CR 19.7 mo, PR 12.6 mo, HI 15.4 mo, and SD 13.8 mo. Pts who achieved CR had superior OS compared to SD (p=.03) but similar survival compared to pts who achieved PR (p=.45) or HI (p=.24). Of 29 pts with SD who achieved a better response > 6 mo, 16 (55%) achieved a CR and 13 (45%) achieved a PR or HI. Pts with SD who subsequently achieved CR had superior OS compared to pts who remained in SD (28.1 vs 14.4 mo, respectively, p=.04), while pts who subsequently achieved PR or HI had a similar survival compared to pts who remained in SD (12.1 vs 14.4 mo, respectively, p=.81). Conclusion Among MDS pts treated with HMAs, 20% who have SD at initial assessment go on to have a better response later in their treatment course, However, only 11% of SD pts achieved a CR thereafter, which predicted better OS. Thus, pts who achieve SD by 6 mo should be offered a clinical trial with novel agents to improve their chances of achieving CR. If a clinical trial is not available, pts should remain on HMA therapy until disease progression. Disclosures No relevant conflicts of interest to declare.

Abstract 3475 Cytopenias in the context of cellular marrows cause significant morbidity for patients and are challenging for clinicians to diagnose and treat. Often the differential diagnosis includes pure red cell aplasia (PRCA), large granular lymphocyte leukemia (LGL), marrow suppression associated with systemic inflammation, and clonal bone marrow failure disorders such as myelodysplastic syndrome (MDS) or paroxysmal nocturnal hemoglobinuria (PNH). Unfortunately, it can be difficult to differentiate between these possibilities, and correct treatment depends on accurate diagnosis. The diagnostic algorithm for these patients includes multiple studies: cytogenetics, fluorescence in situ hybridization, T cell gene rearrangements, and flow cytometry. These multiple tests rarely provide a definitive diagnosis and do not consistently predict response to therapy. Functional tests of effective hematopoiesis are lacking. Colony growth assays quantifying BFU-E in bursts per 105 marrow mononuclear nuclear cells (MMNC) have been shown to predict response to immunosuppressive therapy (IST) for the bone marrow failure disorder of PRCA. (Charles et al. Blood 1996) However, these data were from an era before it was recognized that PRCA had several etiologies, one of which was LGL. We hypothesize that colony growth assays might provide diagnostic and therapeutic information in the evaluation of patients with bone marrow failure disorders. As part of an IRB-approved study, we performed a retrospective analysis on patients presenting for evaluation of cytopenias in the context of cellular marrows from January 2007-June 2012. Inclusion criteria were a recorded BFU-E assay performed prior to therapy, established diagnosis for the cytopenias and at least 6 months of follow up after treatment initiated. Response was defined as transfusion independence and ANC >1000/μL. For comparison, BFU-E in healthy controls was used. Thirty-six patients meeting the above criteria had BFU-E assessed over the study. All patients' marrows were cellular or hypercellular for age, with a median cellularity of 60% (range 20–100). The diagnoses included 13 patients with LGL (8 of which had red cell aplasia only); 9 patients with PRCA (non-LGL in etiology); 8 patients with MDS; and 6 patients with cytopenias from systemic inflammation. The median follow up was 10.5 months (range 1–42). There were 8 deaths. There were 25 normal controls for comparison of BFU-E growth. The median growth in the normal controls was 40.3 BFU-E/105 MMNC (range 23.7–87). The eight patients with MDS had the lowest median growth of all categories at 5 BFU-E/105 MMNC (range 0–38). Four of these patients with MDS died from progression to acute leukemia in less than 9 months after initiation of therapy. The 4 patients still alive remain red cell transfusion dependent despite therapy with demethylating agents. Two have increased blasts on restaging marrows. The 13 patients with LGL grew a median of 61.3 BFU-E/105 MMNC (range 24.7–101). Nine patients (69%) responded to first or second line IST with durable remissions of 9 months or greater. One of the nonresponders died at 31 months from infection after multiple relapses and treatments. The 9 non-LGL PRCA patients grew a median of 23 BFU-E/105 MMNC (range 4.5–49). Only three patients (33%) of these patients responded to IST. The etiologies of the PRCA included 2 associated with thymoma, 2 with anti-erythropoietin antibodies (2 deaths at 1 and 11 months), 2 with ABO-incompatible transplants, and 3 idiopathic PRCA patients (1 death at 15 months). The 6 patients with cytopenias from systemic inflammation had documented autoimmunity (4 with Evan's syndrome and 2 with systemic lupus erythematosus) and grew a median of 105.5 BFU-E/105 MMNC (range 33–137). All 6 (100%) patients responded to IST. In conclusion, patients with cellular marrows and cytopenias can be distinguished by BFU-E growth as seen in Figure 1. MDS patients have very low to undetectable growth. LGL and PRCA associated with LGL have high BFU-E growth, similar to other autoimmune processes, whereas non-LGL PRCA has low BFU-E growth. BFU-E predicts for response to IST in PRCA, as it seems to predict for LGL. In this cohort, nonmalignant diseases are well distinguished from MDS by BFU-E growth. Prospective studies of colony growth assays as part of the diagnostic algorithm for bone marrow failure disorders appear warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract 2357 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, hematopoietic stem cell disorder that manifests with a hemolytic anemia, bone marrow failure and thrombophilia. Eculizumab is an FDA-approved humanized monoclonal antibody for treatment of PNH that has been shown to improve anemia, decrease intravascular hemolysis, reduce risk of thrombosis, and improve quality of life. The quality of response to eculizumab is quite variable, especially with respect to normalization of hemoglobin levels. Thus, it is important to identify the factors that predict response to eculizumab therapy. As part of an IRB-approved study, we performed a retrospective analysis on all patients diagnosed with a PNH clone between January 2005 and March 2012. The diagnosis of PNH was defined as a population of GPI-AP deficient granulocytes ≥ 0.1% by peripheral blood flow cytometry. The patients were categorized by PNH phenotype per the International PNH Interest Group (IPIG) guidelines as 1)classical PNH (PNH); 2)PNH in the setting of another specified bone marrow disorder (PNH/AA and 3) Subclinical PNH (PNHsc). Complete response (CR) was defined as transfusion independence with normal hemoglobin for age and sex for ≥ six months with an absence of PNH symptoms and a lactate dehydrogenase (LDH) < 1.5 times the upper limit of normal. A good partial response (GPR) was defined as a decrease in transfusions from pretreatment and LDH level Thirty patients with PNH were treated with eculizumab. Of these patients, 21 (70%) were classical PNH and 9 (30%) had PNH/AA. Of the 30 treated patients, 27 (90%) had LDH levels >1.5 upper limit of normal prior to therapy. Only 8 patients (26.7%) had not been transfused prior to the start of therapy. Seventeen patients would have fulfilled SHEPHERD eligibility criteria for enrollment. These eligibility criteria include age > 18 years, a diagnosis of PNH greater than 6 months, PNH red cell clone > 10%, at least one transfusion in the last two years, a LDH > 1.5 times the upper limit of normal, platelets > 30,000/mm3 and an absolute neutrophil counts above 500/uL. Thirteen patients (43.3%) would have been ineligible due to platelet counts less than 30,000/ul (7 patients) or red cell transfusion independence (6 patients). These patients were prescribed eculizumab to treat thrombosis, intravascular hemolysis or both. A total of 863 patient- months of treatment with eculizumab are reviewed for this study. With a median follow-up of 24 (range, 6 to 80) months, the overall survival was 96.66%. A CR was achieved in four (13.3%) patients; all of whom had a decrease in the size of their red cell clone after treatment with eculizumab. GPR was achieved in 16 (53.3%) and 10 patients (33.3%) had a SR response. The percentage of PNH red cells decreased in all four patients achieving CR and increased in all patients achieving a GPR. The kinetics of the red cell clone size decreases for CR patients are shown in Figure 1. Transient breakthrough intravascular hemolysis was observed was observed in 9 patients following viral or bacterial infections. Two patients with classical PNH and suboptimal responses required dose adjustments. This was in the context of recurrent or breakthrough hemolysis that was not addressed easily with standard eculizumab dosing in the setting of autoimmune diseases (Crohn's and rheumatoid arthritis). Three patients in this cohort underwent bone marrow transplant for their marrow failure. Eculizumab had been prescribed for thromboses and allowed for successful bridging to transplant. This data demonstrates that even patients that would not have met eligibility criteria for previous eculizumab trials, especially patients with thrombosis, may benefit from terminal complement inhibition. Coexistent autoimmune disease with ongoing inflammation can lead to suboptimal responses. While the mechanism for this potential association is unclear, it is conceivable that chronic inflammatory states lead to increased complement activation that requires high dosages of eculizumab because standard doses resulted in incomplete C5 blockade. Decrease in the size of the red cell clone allows for normalization of hemoglobin and predicts for a complete response. Disclosures: Brodsky: Alexion Pharmaceuticals: Serves on international advisory board. Other.

Abstract 2172 AML patients with FLT3/ITD mutations have an inferior survival compared to AML patients with wild-type (WT) FLT3, primarily due to an increased relapse rate. Allogeneic transplant represents a post-remission therapy that is effective at reducing the risk of relapse for many cases of poor-risk AML. Whether or not allogeneic transplant in first complete remission (CR) can improve outcomes for patients with FLT3/ITD AML remains controversial. Our institution has adopted a policy of pursuing allogeneic transplant, including the use of alternate donors, for FLT3/ITD AML patients in remission. As part of an IRB-approved study, we performed a review of the clinical data from November 1, 2004 to October 31, 2008 on all adult patients under the age of 60 presenting in consecutive fashion to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins with newly diagnosed non-M3 AML. We followed their outcomes through August 1, 2010. During the study period, 133 previously untreated AML patients between the ages of 20 and 59 were diagnosed and received induction and consolidation therapy at our institution. Of these 133 patients, 31 (23%) harbored a FLT3/ITD mutation at diagnosis. Fourteen of the total 133 patients were deemed unfit for intensive therapy, all WT patients. Of these, 6 (5%) received investigational agents on protocol while the other 8 (6%) were treated with combinations of supportive care and cytotoxic agents off protocol. Of the remaining patients, 119/133 (89%) received timed- sequential intensive induction therapy (TST) with infusional cytarabine, an anthracycline or anthracenedione, and a third drug. The majority, 95/133 (71%), received the three drug TST regimen of cytarabine, daunorubicin, and etoposide delivered in a timed sequential fashion, while 24/133 (18%) were treated with TST containing cytarabine, mitoxantrone, and the investigational agent flavopiridol on an institutional protocol. 72/119 (61%) achieved a CR with induction therapy (55 patients in AcDVP16 group and 17 patients in FLAM group). The OS (overall survival) from the time of diagnosis for the FLT3/ITD AML patients was compared to the OS of the entire cohort (n=133) (Figure 1). The median OS for the FLT3/ITD group was 19.3 (range 0.0–69.9) months and the median OS for the WT patients was 15.5 (range 0.7 to 64.6) months (p=0.56). Of the FLT3/ITD patients, 20/31 (65%) achieved a complete remission with intensive induction therapy. Of these 20 patients in CR1, 11 (55%) underwent an allogeneic transplant in first remission (4 HLA-matched myeloablative sibling, 5 HLA-matched myeloablative unrelated donor, and 2 nonmyeloablative haplo-identical related donor) compared to only 18/102 (17%) WT patients were transplanted in first CR, a statistically different proportion compared to the FLT3/ITD patients (p Historically, OS for FLT3/ITD AML patients is significantly worse than for AML patients lacking this mutation. However, the OS for the 31 FLT3/ITD patients reported here was comparable to the 102 patients with WT FLT3 over the same 4 year time period. One difference that might have contributed to the surprising outcomes for the FLT3/ITD group is our aggressive pursuit of allogeneic BMT in CR1 within this group (60% of FLT3/ITD vs 17% with WT). Our single institution study of consecutively treated AML patients supports the hypothesis that allogeneic transplant in early CR1 improves the long term outcomes for FLT3/ITD AML. Disclosures: Levis: Ambit Biosciences, Inc: Consultancy.

Abstract 3412 Poster Board III-300 Introduction High-dose cyclophosphamide (HD CY) is a potent immunosuppressive agent that is used as conditioning for HSCT in most patients with both hematologic malignancies and autoimmune diseases. HD CY is highly toxic to lymphocytes, but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase (the primary mechanism of CY inactivation). We and others have shown that HD CY without stem cell support can induce durable remissions in a variety of severe autoimmune diseases. Here, we report the long term follow-up of 124 patients with a variety of severe autoimmune diseases treated with HD CY. Methods From August 1996 through August 2008, 124 consecutive patients with severe, refractory autoimmune diseases (excluding acquired severe aplastic anemia) were treated with HD CY (50mg/kg/d) for 4 consecutive days without HSCT. Six days after the last dose of CY, all patients received granulocyte colony stimulating factor (5 μg/kg/day) until the neutrophil count exceeded 0.5 × 109/liter. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune modulating drugs. Relapse was defined as worsening disease activity and/or a requirement of an increase in dose or administration of a new immunosuppressive medication. Results The most common diseases treated with HD CY included lupus (n=42), multiple sclerosis (MS, n=32), myasthenia gravis (n=14) scleroderma (SSC, n=10), autoimmune hemolytic anemia (n=9) and pemphigus (n=9). The median follow up is 47 (range 1-127) months. All patients experienced rapid hematopoietic recovery: an absolute neutrophil count (ANC) > 500/μL was achieved at a median of 13 (range 8-22) days after the last dose CY and the median duration of an ANC < 500/μL was 9 (range 4-23) days. The median time to last platelet transfusion after completion of CY was 13 (range 0-33) days and the median time to last packed red blood cell transfusion was 12 (range 0-24) days. The median number of PRBC transfusions was 2 (range 0-27) and the median number of platelet transfusions was 2 (range 0-18.) The overall treatment related mortality was 0.8% with the lone death occurring in a non-neutropenic SSC patient on day 51 after HD CY. Median number of hospitalized days was 4 (range 0-55) days. The overall response rate was 94% with 42% of responders maintaining a durable response at the time of analysis. Durability of response seemed to vary according to the underlying disease and/or disease severity. The actuarial event-free survival (EFS) at 60 months is 10.6% for SLE, 31% for MS, 42.1% for MG, 50% for AIHA, 33% for pemphigus, and 25% for the other diseases. Interestingly, disease activity improved from pre-HD CY in virtually all patients even at the time of relapse, as many patients became responsive to immunosuppressive agents that were previously ineffective in controlling their disease. Discussion HD CY with or without HSCT has a potent disease modifying effect in wide variety of autoimmune disorders. These data suggest that eliminating HSCT after HD CY maintains both its efficacy and safety. The duration of cytopenias compares favorably with HSCT, especially when factoring in the mobilization phase of HSCT. Furthermore, eliminating mobilization and HSCT may have at least theoretical advantages in that the overall duration of the procedure is shortened, any toxicity associated with mobilization is avoided, and the potential of reinfusing autoreactive lymphocytes with the autograft is averted. Disclosures Jones: Accentia: Patents & Royalties. Brodsky:Accentia: Patents & Royalties.

7010 Background: Isocitrate dehydrogenase 2 ( IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We report the results of the open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS (NCT03383575). Methods: Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes. Results: 48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm. Conclusions: ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03383575. [Table: see text]