Remission Of Myeloid Leukemia Research Articles

Comparing Older Matched Related to Younger Matched Unrelated Donors in Acute Myeloid Leukemia in Remission Using Post-Transplant Cyclophosphamide

Backgroud. Over the past 25 years, the landscape of allogeneic stem cell transplantation (allo-SCT) changed from being rarely performed in patients 50 years or older to accounting for a little less than half of the transplantations reported in USA and Europe. Older patients will on average have older matched related siblings (MRD) being considered as donors with issues such as comorbidities, risk of clonal haematopoiesis of indeterminate potential, and impaired immune and regenerative potential of stem cells. Although younger HLA-matched unrelated donors (MUD) are an important alternative in this context, it remains unclear whether the use of MUD is associated with better outcomes. This is especially true in the context of post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis. Methods. The aim of this study was to compare the graft-relapse-free survival (GRFS) for patients diagnosed with acute myeloid leukemia (AML) in first complete remission (CR1), aged 50y or more, and having received a first allo-SCT from a 10/10 MUD younger than 40y or a MRD older than 50y using PTCy for in-vivo T-cell depletion. All transplants were performed between 2015-2021 at the EBMT centres. Results. A total of 410 consecutive patients were included, 172pts receiving a MRD, 238pts transplanted from a MUD. All patients with detailed conditioning regimen dosages were classified according to the transplant conditioning intensity (TCI) score in low (1-2), intermediate (2.5-3.5), high (4-6). TCI-score was available for 345 patients and was as follows: low in 53pts (36.8%), intermediate in 79pts (54.9%) and high in 12pts (8.3%) for MRD, low in 91pts (45.3%), intermediate in 93pts (46.3%) and high in 17pts (8.5%) for MUD (p=0.26). Only patients with available TCI-score were analysed. In univariate analysis the 2-year GRFS was 58% (49.8-65.3%) for TCI intermediate-high and 43.1% [34.3-51.5] for TCI low (p=0.005). In TCI-score intermediate-high non-relapse mortality (NRM) wasn't higher compared to TCI-score low (12.7% [12.2-24] vs 13.7% [8.4-20.3], p=0.53) but relapse incidence (RI) was lower (17.7% [12.2-24] vs 33.2% [25.1-41.5], p=0.003). As a strong interaction between TCI-score and type of donor was found, we compared transplant outcomes between MRD and MUD separately for TCI-score low and TCI-score intermediate-high. In TCI-score low, 2-year GRFS was 44.4% [33.5-54.8] for MUD and 40.9% [26.4-54.9] for MRD (p=0.83) (Figure 1A). In multivariable analysis (MVA) type of donor was not a risk factors for neither GRFS (HR 0.98, CI: 0.57-1.69; p=0.95) nor for any other transplant outcome. In TCI-score intermediate-high, 2-year GRFS was 67.2% [55.8-76.2] for MUD and 46.1% [34.4-57.1] for MRD (p=0.001) (Figure 1B). In MVA MUD were associated to better GRFS (HR 0.41, CI: 0.24-0.7; p=0.001), lower NRM (HR 0.19, CI: 0.07-0.55; p=0.002) and lower RI (HR 0.32, CI: 0.14-0.73; p=0.007) without advantages in terms of neither aGvHD nor cGvHD. Conclusions. In patients with AML in CR1, aged 50y or more and receiving a conditioning regimen with TCI-score ≥ 2.5 in the PTCy setting, a MUD younger than 40y is associated to longer GRFS, lower NRM and lower RI compared to a MRD older than 50y. For patients receiving regimens with TCI-score low transplant outcomes are independent on the type of HLA-matched donor.

Thiotepa-busulfan-fludarabine Compared to Treosulfan-based Conditioning for Haploidentical Transplant With Posttransplant Cyclophosphamide in Patients With Acute Myeloid Leukemia in Remission: A Study From the Acute Leukemia Working Party of the EBMT.

We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m2 and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II-IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III-IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo (P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.

Oral azacitidine modulates the bone marrow microenvironment in patients with acute myeloid leukaemia in remission: A subanalysis from the QUAZAR AML-001 trial.

Oral azacitidine (Oral-AZA) maintenance therapy improved relapse-free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML-001 study. Immune profiling was performed on the bone marrow (BM) at remission and on-treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on-treatment immune effects by Oral-AZA with clinical outcomes. Post-IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T-cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD-L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD-L2+. High co-expression of T-cell exhaustion markers PD-1 and TIM-3 was associated with inferior outcomes. Oral-AZA augmented T-cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T-cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T-cell content and expression of T-cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral-AZA modulates T-cell activity in the maintenance setting of AML, and these immune-mediated responses are associated with clinical outcomes.

Economic Burden of Hospitalizations for Patients with Newly Diagnosed Acute Myeloid Leukemia in Remission in the United States: Retrospective Analysis of an Administrative Claims Database

INTRODUCTION: Managing patients with acute myeloid leukemia (AML) requires extensive healthcare resource utilization and costs; hospitalization is the largest component of medical costs for AML. In the phase 3 QUAZAR AML-001 trial, oral azacitidine (Oral-AZA [CC-486]) was associated with significant improvements in overall survival and relapse-free survival (RFS) vs. placebo (Wei, 2020). Prolonged RFS with Oral-AZA may translate into substantial economic benefits, with lower hospitalization-related costs due to reduced rates of hospitalization and days in hospital (Oliva, ASH 2020). Real-world economic benefits of prolonged remission remain insufficiently studied.OBJECTIVE: This study aimed to examine the economic burden of hospitalizations among patients with newly diagnosed AML in remission from a retrospective analysis of real-world data from a US claims database.METHODS: Using a retrospective cohort design, adult patients were selected from the IBM MarketScan TM Commercial and Medicare Supplemental Databases, with ≥2 outpatient claims or 1 inpatient claim with a primary International Classification of Disease 9th/10th Revision (ICD-9/ICD-10) code for AML between July 1, 2012, and September 30, 2019. Patients were required to have 1) at least 6 months of continuous enrollment, with pharmacy benefits, prior to diagnosis, 2) received systemic induction therapy as first-line (1L) therapy for AML on or after the index diagnosis date, and 3) attained remission from 1L systemic therapy.Patients were followed from remission after systemic induction therapy, with or without consolidation, until the end of the follow-up period. Eligible patients were organized into cohorts based on their duration of remission (DOR): Cohort A included patients with < median DOR and Cohort B had patients with ≥ median DOR. Hospitalization incidence and duration during the follow-up period were calculated using a per-patient per-year (PPPY) metric. Hospitalization-related costs were compared using a generalized linear model (GLM) with gamma distribution and log-link function. Generalized estimating equations (GEE) clustered on the patient were used to compare incidence and duration of hospitalizations. All costs were adjusted for inflation and reported in 2019 US dollars (USD).RESULTS: In all, 693 patients met all selection criteria and were assessed for DOR. The median DOR for all patients was 167 days; cohorts A and B included 346 and 347 patients, respectively, with median times from remission to end of follow-up of 106.5 and 460 days. Baseline characteristics were comparable between cohorts; mean [SD] age was 55.1 [14.4] years, 49.4% of patients were male, and mean [SD] Charlson comorbidity index [CCI] was 0.8 [1.2]. The PPPY number of hospitalizations was higher in Cohort A than in Cohort B (4.56 vs 2.09, respectively), as was the PPPY total length of hospital stay (51.1 vs 19.7 days). The PPPY hospitalization-related costs were $345,728 in Cohort A and $125,018 in Cohort B; the cumulative hospitalization cost per patient was $148,430 higher in Cohort A at 12 months and $177,500 higher at 18 months (Figure). Multivariate GEE and GLM models with adjustment for patient characteristic covariates (eg, age, sex, CCI) identified prolonged remission was significantly associated with reduced number, duration, and cost of hospitalization (P < 0.001, all comparisons).CONCLUSIONS: In a real-world setting, prolonged AML remission was associated with significantly lower rates and durations of hospitalization, which were estimated to result in substantial cumulative cost savings. These data underscore the importance of active maintenance therapies that delay relapse for patients with AML. While the costs of long-term therapy face increasing scrutiny, these costs should be weighed relative to the potential economic benefit of prolonged remission and reduced burden of healthcare resource utilization. [Display omitted] DisclosuresChen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Papademetriou: SmartAnalyst Inc.: Current Employment. Potluri: Bristol Myers Squibb: Consultancy.

Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial.

Not available.

Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial

BackgroundMost older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors’ clinical experience treating patients in the trial.MethodsQUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug.ResultsA total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1–80) oral azacitidine treatment cycles or 6 (1–73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3–4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications.ConclusionOral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy.Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.

Therapy-Related Acute Lymphoblastic Leukemia/Lymphoma in the Elderly

IntroductionTherapy-related ALL (t-ALL) is a rare entity. It was recently estimated to occur in about 4.7%-6.9% of adult ALL cases and has been associated with a worse prognosis(Aldoss et al ., 2017; Abdulwahab et al ., 2012). However, these studies included very few patients over the age of 60. Since t-ALL specifically in the elderly has never been described, we sought to characterize its clinical features and treatment outcomes.MethodsAfter IRB approval, we performed a retrospective study of patients (pts) ≥60 years old diagnosed with ALL from 2000-2017 at Mayo Clinic Rochester, Arizona, and Florida. We included pts who received known leukemogenic chemotherapy prior to being diagnosed with ALL. We excluded pts with malignancies who were not exposed to leukemogenic chemotherapy. We also excluded pts diagnosed with chronic myeloid leukemia (CML) with blast crisis. Moreover, we excluded pts treated with radiation therapy other than to the whole pelvic region. Statistical analysis was performed using JMP 10.0 software.ResultsBaseline characteristicsOut of 124 consecutive pts with elderly ALL, we identified 20 (16%) pts who fit our inclusion criteria. 16 (80%) were female. The median latent time to developing ALL was 9.25 years (range 0.26-28.67). The median time of follow-up was 12.6 months (range 0.9-63.2). 11 (55%) were deceased at the time of follow-up: 3 deaths related to disease, 6 from infection or other causes, and 2 unknown.Of the 20 pts with t-ALL, 13 (65%) had been treated for hematological malignancies prior to ALL, which included multiple myeloma (3), acute myeloid leukemia in remission (2), diffuse large B-cell lymphoma (2), myelofibrosis (2), myelodysplastic syndrome (1), MALT lymphoma (1), hairy cell leukemia (1), chronic lymphocytic leukemia (1), and light-chain (AL) amyloidosis (1). Additionally, 6 pts had prior treatment for breast cancer; 1 of these was the pt who also had AL amyloidosis. Finally, 1 pt had a history of receiving cyclophosphamide for bronchiolitis obliterans with organizing pneumonia and myositis.Median age at time of ALL diagnosis was 67 (60-82). 19 (95%) had B-cell ALL, of which 5 (26%) were positive for the Philadelphia chromosome. Only 1 (5%) pt had T-cell ALL.Cytogenetics and FISH studies18 pts had available cytogenetic data at time of diagnosis. 8 (44%) had complex cytogenetics (≥5 abnormalities), 7 (39%) had a monosomal karyotype, 4 (22%) were hyperdiploid, 2 (11%) were hypodiploid, 1 (6%) was a mixture of hyper- and hypo-diploid. Furthermore, FISH analysis was available in 10 pts: 3 had CDKN2A deletion, 2 had a duplication of 1q, 2 had a TCF3-PBX1 translocation, 1 had a MLL rearrangement, and 1 had a deletion of IKZF1 .Treatment and Outcomes15/20 (75%) underwent induction chemotherapy. 6 of them received Hyper-CVAD. The other 9 received various regimens, including asparaginase-based chemotherapy in 6 (67%). 13 (87%) had a complete remission (CR/CRi), within a median time of 32 days (range 19-128). 1 (7%) had primary refractory disease. The other 5 (25%) pts chose palliative treatment up-front; this included chemotherapy (e.g. vincristine and steroids), tyrosine kinase inhibitors, or hospice. 3 (60%) of these pts got into CR.Of the 16 total pts who achieved CR, 5 (31%) relapsed within a median time of 20.67 months (range 9-22.3). All of them were treated with salvage chemotherapy. Median survival after relapse was 4.8 months (range 0.1-42.2). Overall, 7/20 (35%) underwent allogeneic HSCT; all were in CR1. Median survival after HSCT was not reached (IQR 7.6-NR). Only 2 (29%) relapsed after HSCT within a median time of 6.4 months (range 3.1-9.6).The median overall survival (mOS) in patients with t-ALL was 13.83 months (interquartile range [IQR] 11.73-not reached), which was not significantly different (P=0.9935) from elderly patients without t-ALL, who had a mOS of 20.93 months (IQR 8.73-56.63) (Figure 1).ConclusionsTherapy-related ALL (t-ALL) seems to be relatively more common in the elderly compared to younger adults, with an incidence of 16% in our elderly ALL cohort. Almost all cases were B-cell ALL. In addition, MLL rearrangements appeared to be less frequent in our elderly cohort (7%), in contrast to what has been reported in younger adults (25-35%). Moreover, the overall survival in elderly t-ALL was not significantly different compared to elderly ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Improved Survival Outcomes By Iron Chelating Therapy with Deferasirox after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia

▪BackgroundThe negative prognostic impact of hyperferritinemia before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established in hematologic malignancies, and recent two small prospective studies of post-transplantation iron-chelating therapy (ICT) with deferasirox reported the safety and efficacy in lowering serum ferritin (SF), but the impact of ICT on survival is not yet known.Material and methodsWe retrospectively evaluated 326 consecutive patients with acute myeloid leukemia in remission who underwent allo-HSCT at a single institution between 2007 and 2012. The SF levels and immune subsets in peripheral blood (PB) were regularly monitored before and after transplantation. With an exclusion of 50 patients with SF levels less than 1000 ng/ml at a month after transplantation, 276 patients with hyperferritinemia (≥1000 ng/ml) after transplantation were recommended to receive deferosirox, and finally 128 patients (46%) agreed (ICT group), whereas 148 patients (52%) did not (non-ICT group). Deferosirox (10 or 20 mg/kg) was started mostly at a month after transplantation with a median of 30 days (range, 18~50), and continued to the ferritin level lower than 500 ng/ml unless serious adverse effects and/or relapse.ResultsThe ICT group consisted of higher aged and more haploidentical-related donors than non-ICT group, which were associated with more reduced-intensity conditioning and HLA-mismatched donors in the ICT group, and otherwise similar in both groups. The median duration of ICT was 5.4 months (range, 1.0~13.1). The starting dose of deferosirox was mainly 20 mg/kg (91%) with an exception of 11 patients (10 mg/kg, 9%) due to remained mild gastrointestinal symptoms after transplantation. The ICT group showed a significantly faster decline in SF than non-ICT group. Adverse events were frequent (65%), but mild to moderate and transient. Dose reduction and temporary interruption of deferosirox were required in 64% and 4% of patients, respectively, mainly because of creatinine elevation and gastrointestintal symptoms.With a median follow-up of 41 months (range, 1~100 months) for survivors, the 4-year overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were 55%, 53%, 24%, and 23%, respectively. The ICT group had significantly better OS (68% vs. 43%, P<0.001) and DFS (66% vs. 40%, P<0.001) with lower CIR (13% vs. 33%, P<0.001) than non-ICT group, but no significant difference of NRM (20% vs. 26%, P=0.285). Multivariate analysis with significant factors in univariate analysis and an adjustment with different factors between the two groups revealed that the ICT with deferosirox independently improved OS, DFS, and CIR. Of note, chronic graft-versus-host disease (GVHD) developed more in the ICT group (66% vs. 39%, P<0.001), which was significant on multivariate analysis, but no difference in acute GVHD. Immune subsets analysis with PB within a year after transplantation showed no significant difference between the two groups in immune recovery of CD3, CD4, CD8, CD19, and CD56 positive cells. However, we found that regulatory T cells were significantly suppressed at 3 months after transplantation in the ICT group compared to non ICT group (0.01% vs. 3.6%, P<0.001).ConclusionsThe present study demonstrates that the ICT by deferosirox was well tolerated and beneficial when initiated after allo-HSCT. The increased occurrence of chronic GVHD in the ICT group might be related with less frequency of regulatory T cells induced by iron chelation with deferosirox, which could promote graft-versus-leukemia effects resulting in the reduced incidence of relapse and better survival outcomes, even though the ICT group had more high risk features. Further controlled studies would be worth to confirm the benefit of ICT after allo-HSCT. DisclosuresNo relevant conflicts of interest to declare.

Dasatinib as a Probable Cause of Bilateral Chylothorax in a Patient with Chronic Myeloid Leukemia: Case Report

Dasatinib-induced chylothorax has been sporadically reported, and its pathophysiology has yet to be fully elucidated. We report a 53-year-old man with underlying chronic myeloid leukemia in remission on regular dasatinib who was referred to pulmonology team with an incidental finding of a right upper lobe lung nodule with bilateral pleural effusion on chest radiograph. Computed tomography confirmed a solid spiculated solitary pulmonary nodule (SPN) with bilateral pleural effusions with no mediastinal or intra-abdominal lymphadenopathy. Initial diagnostic thoracentesis of the left pleural effusion revealed serous fluid, which was exudative with negative cytology and medical thoracoscopic pleural biopsy yielded only chronic inflammatory changes. Post-procedurally, as appetite further improved, intercostal tube drainage turn chylous, centrifugation and triglyceride levels confirmed chylothorax. Diagnostic thoracentesis was then done over the right pleural effusion, which revealed serous appearance, biochemically exudative with triglyceride of 1.7 mmol/l. Bilateral chylothorax probably due to dasatinib was suspected, and the drug was withheld. Chest tube was removed after 10 days. PET/CT scan showed only hypermetabolism in the SPN and hilar lymph node with no mediastinal involvement. Tuberculosis workup was negative. The SPN was biopsied under fluoroscopy-guided bronchoscopy, which confirmed limited stage neuroendocrine carcinoma of the lung. Patient remained well at 1 month follow-up with no recurrence of bilateral chylothorax. We discuss the implications of concurrent bilateral exudative chylothorax in SPN and the diagnostic challenges of chylothorax.

Comparative Analysis of Total Body Irradiation (TBI)-Based and Non-TBI-Based Myeloablative Conditioning for Acute Myeloid Leukemia in Remission with and without Measurable Residual Disease

Background:Myeloablative allogeneic hematopoietic cell transplantation (HCT) is a common post-remission treatment strategy for medically fit adults with acute myeloid leukemia (AML) in morphologic remission. Several conditioning regimens have been utilized for this purpose, with ongoing controversy regarding the benefit of high-dose total body irradiation (TBI) in this setting. It is also unknown whether the relative value of TBI- versus non-TBI-based myeloablative conditioning differs for patients presenting with measurable residual disease (MRD) at the time of HCT from those in MRDnegremission. These open questions prompted us to compare outcomes among a large cohort of adult AML patients in MRDposand MRDnegremission who had myeloablative allogeneic HCT at our institution. Patients and Methods:We retrospectively studied 387 consecutive adults ≥18 years with AML in first or second morphologic remission (i.e. &amp;lt;5% bone marrow blasts by morphologic assessment) who had myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 4/2006 and 1/2019. Patients receiving radiolabeled antibodies as part of their conditioning were excluded. Pre-HCT disease staging included 10-color multiparametric flow cytometry (MFC) on bone marrow aspirates in all patients. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Results: Fifty-eight of the 387 patients (15%) received high-dose (HD; ≥12 Gy) TBI-based conditioning (HD-TBI/Cy [n=32], HD-TBI/thiotepa/Flu [n=22], HD-TBI±Flu [n=4]). Regimens for the other 329 patients included Bu/Cy [n=160], Bu/Flu [n=72], and treosulfan/Flu±low-dose TBI [n=97]. Patients receiving HD-TBI conditioning were younger (median: 33 [range: 18-58] vs. 51 [18-70] years, p&amp;lt;0.001), had a higher white blood cell count at AML diagnosis (34.5 [0.6-280] vs. 8.4 [0.2-297] x103/µL, p=0.004), less often had secondary AML (5% vs. 25%, p&amp;lt;0.001), and less often had an unrelated donor as stem cell source (43% vs. 67%, p&amp;lt;0.001) than those receiving non-HD-TBI conditioning. The cytogenetic risk profile (revised MRC criteria) was similar (p=0.76), as was the proportion of patients in second rather than first remission (HD-TBI vs. non-HD-TBI: 28% vs. 22%, p=0.31), the proportion of patients with MRD by MFC at the time of HCT (19% vs. 21%, p=0.86), and the proportion of patients with recovered peripheral blood counts at the time of HCT (66% vs. 77%, p=0.10). Overall, 3-year estimates of overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse, and non-relapse mortality (NRM) were similar for patient with HD-TBI and those without HD-TBI conditioning (OS: 63% [95% confidence interval: 51-78%] vs. 64% [59-70%]; RFS: 55% [43-70%] vs. 60% [55-65%]; relapse: 39% [26-52%] vs. 25% [20-30%]; NRM: 6% [1-13%] vs. 15% [11-19%]). Likewise, when stratified by the pre-HCT MRD status, OS, RFS, relapse, and NRM estimates were similar for patient with HD-TBI and those without HD-TBI conditioning (Figure). In multivariable models accounting for type of conditioning (HD-TBI vs. not), pre-HCT MRD status, age, cytogenetic risk, type of AML (de novo vs. secondary AML), CR1 vs. CR2, pre-HCT karyotype (normalized vs. not), and pre-HCT peripheral blood counts (recovered vs. not), MRDposremission remained statistically associated with increased mortality (hazard ratio [HR]=2.99 [95% confidence interval: 2.08-4.30], p&amp;lt;0.001), failure of RFS (HR=4.49 [3.18-6.33], p&amp;lt;0.001), and increased risk of relapse (HR=7.21 [4.77-10.88], p&amp;lt;0.001) but not NRM (HR=0.63 [0.29-1.37], p=0.24). On the other hand, compared to non-HD-TBI conditioning, HD-TBI conditioning was not associated with different outcomes: OS (HR=0.91 [0.56-1.48], p=0.70), RFS (HR=0.83 [0.53-1.32], p=0.44), relapse risk (HR=1.06 [0.59-1.88], p=0.85), or NRM (HR=0.44 [0.15-1.28], p=0.54). Conclusion:For adults with AML undergoing myeloablative allogeneic HCT in morphologic remission, our analyses found no differences in survival and relapse risks between patients who received HD-TBI and those who received non-HD-TBI containing conditioning. Considering the known late effects of HD-TBI, non HD-TBI regimens should be used preferentially. Figure Disclosures Othus: Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Jazz Pharmaceuticals: Consultancy.

Azacitidine and Venetoclax in Treating Patients With High Risk Acute Myeloid Leukemia in Remission

Azacitidine and Venetoclax in Treating Patients With High Risk Acute Myeloid Leukemia in Remission

Phase 2 Study of Lenalidomide Maintenance for Patients with High-Risk Acute Myeloid Leukemia in Remission

Phase 2 Study of Lenalidomide Maintenance for Patients with High-Risk Acute Myeloid Leukemia in Remission

Pre-Transplant Monocytic Myeloid-Derived Suppressor Cell Frequency Has No Prognostic Role for Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Remission

INTRODUCTION: Emerging data indicate myeloid-derived suppressor cells (MDSCs) adversely impact outcomes of patients with a variety of malignancies. However, it is less clear how MDSCs affect acute myeloid leukemia (AML) disease biology or the response of AML patients to treatment. Here, we studied a cohort of people with AML undergoing hematopoietic cell transplantation (HCT) in first complete remission (CR1) to examine the relationship between the monocytic subtype of MDSCs (M-MDSCs), pre-transplant measurable residual disease (MRD) status, and outcome after HCT.PATIENTS AND METHODS: Adults ≥18 years of age were included if they underwent first allogeneic HCT with myeloablative or nonmyeloablative conditioning for AML in CR1 from April 2006 until October 2014. Prospective MRD testing in bone marrow aspirates was performed routinely via 10-color multiparameter flow cytometry (MFC) as part of the pre-transplant work-up. Pre-transplant MFC data were used retrospectively to quantify M-MDSCs as the proportion of monocytes (identified by side scatter properties and CD14 positivity) with low or negative expression of HLA-DR. M-MDSC frequency was then expressed as a percentage of the total number of viable cells in the sample. Available combinations of antigens measured by MFC did not allow for the identification of other MDSC subsets (e.g. granulocytic MDSCs).RESULTS: We identified 349 adults undergoing allogeneic HCT for AML in CR1 for whom pre-transplant MRD testing was performed and for whom follow-up data were available. Of these, 8 had to be excluded because of insufficient MFC events available for identification of M-MDSCs. In the remaining 341 patients, M-MDSC frequency ranged from <0.001% to 6.53%, with a median of 0.18% (25th percentile: 0.06%; 75th percentile: 0.40%). Patients with lower (i.e. <median) frequency of M-MDSCs were less likely male (p=0.01) and more likely had recovered neutrophil and platelet counts (p=0.001) than patients with higher (i.e. ≥median) frequency of M-MDSCs. There was no difference with regard to all other examined characteristics (age, WBC and cytogenetic risk at diagnosis, type of AML, median CR duration before HCT, donor type, and conditioning intensity). The proportion of MRD positive (“MRDpos”) patients was similar between those with lower vs. higher M-MDSC frequency (18.8 vs. 24.6%, p=0.20). Moreover, while MRD negative (“MRDneg”) patients (n=267) differed statistically significantly from MRDpos patients (n=74) with regard to several characteristics such as more favorable disease risk and lower proportion of secondary AML, there was only a statistically non-significant trend toward lower M-MDSC frequency in MRDneg patients (0.16% [range <0.001-5.61%] vs. 0.22% [range <0.001-6.53%], p=0.09).The median follow-up time after HCT among all survivors was 5.8 (range, 2.0-11.4) years. The time was slightly longer for survivors with lower compared to those with higher M-MDSC frequency (6.1 [range 2.6-11.4] vs. 5.1 [range 2.0-11.3] years; p=0.0076). Stratified by the median M-MDSC frequency, the 3-year estimates of overall survival were similar for patients with lower and higher pre-HCT M-MDSCs (58.2% [95% confidence interval 50.4-65.2%] vs. 57.6% [49.8-64.7%]), as were 3-year estimates for relapse free survival (53.5% [45.7-60.7%] vs. 48.3% [40.6-55.6%]), 3-year estimates of the cumulative incidence of relapse (31.8% [24.9-38.8%] vs. 34.6% [27.6-41.8%]), and 3-year estimates of non-relapse mortality (14.7% [9.9-20.5%] vs. 17.0% [11.8-23.0%]). Analyses restricted to the subset of patients undergoing myeloablative (MA) conditioning or those undergoing MA conditioning in MRDneg remission showed qualitatively similar results.CONCLUSIONS: In the largest study to date examining the role of M-MDSCs in AML, we found no convincing evidence for a prognostic role of these cells for adults undergoing allografting in CR1. DisclosuresWalter:Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding; Amgen Inc.: Other: Clinical trial support, Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy.

Persistent IDH1/2 mutations in remission can predict relapse in patients with acute myeloid leukemia.

Persistence of IDH1 or IDH2 mutations in remission bone marrow specimens of patients with acute myeloid leukemia has been observed, but the clinical impact of these mutations is not well known. In this study, we evaluated 80 acute myeloid leukemia patients with known IDH1 R132 or IDH2 R140/R172 mutations and assessed their bone marrow at the time of remission to determine the potential impact of persistent IDH1/2 mutations. Approximately 40% of acute myeloid leukemia patients given standard treatment in this cohort had persistent mutations in IDH1/2. Patients with an IDH1/2 mutation had an increased risk of relapse after 1 year of follow-up compared to patients without a detectable IDH1/2 mutation (59% versus 24%; P<0.01). However, a persistent mutation was not associated with a shorter time to relapse. High IDH1/2 mutation burden (mutant allelic frequency ≥10%) did not correlate with relapse rate (77% versus 86% for patients with a low burden, i.e., mutant allelic frequency <10%; P=0.66). Persistent mutations were also observed in NPM1, DNMT3A and FLT3 during remission, but IDH1/2 mutations remained significant in predicting relapse by multivariate analysis. Flow cytometry was comparable and complementary to next-generation sequencing-based assay for predicting relapse. Monitoring for persistent IDH1/2 mutations in patients with acute myeloid leukemia in remission can provide information that could be used to justify early interventions, with the hope of facilitating longer remissions and better outcomes in these patients.

Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial

As part of the UK NCRI AML17 trial, adult patients with acute myeloid leukemia in remission could be randomized to receive the mammalian target of rapamycin inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse-free survival. At 5 years there was no difference in relapse-free survival [29% versus 40%; odds ratio 1.19 (0.9-1.59) P=0.2], cumulative incidence of relapse [60% versus 54%: odds ratio 1.12 (0.82-1.52): P=0.5] or overall survival [45% versus 58%: odds ratio 1.3 (0.94-1.81): P=0.11]. The independent Data Monitoring Committee advised study termination after randomization of 339 of the intended 600 patients because of excess mortality in the everolimus arm without any evidence of beneficial disease control. The delivery of the everolimus dose was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mammalian target of rapamycin inhibition to chemotherapy provides no benefit.

Reduced-Intensity Conditioning with Busulfan, Fludarabine, and Antithymocyte Globulin for Hematopoietic Cell Transplantation from Unrelated or Haploidentical Family Donors in Patients with Acute Myeloid Leukemia in Remission

To investigate the role of antithymocyte globulin (ATG)-containing reduced-intensity conditioning (RIC) in hematopoietic cell transplantation (HCT) from unrelated (UD) or haploidentical family donors (HFD), we conducted a phase 2 trial of 237 patients (age range, 16 to 69 years) with acute myeloid leukemia (AML) in remission. Patients undergoing UD-HCT (n = 93) or HFD-HCT (n = 59) received RIC comprising busulfan, fludarabine, and ATG, 9 mg/kg, whereas those undergoing HCT from matched sibling donors (MSD, n = 85) received myeloablative busulfan and cyclophosphamide conditioning or aforementioned RIC with ATG, 4.5 mg/kg. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and methotrexate were administered. The median follow-up period was 44.7 months after HCT for 161 survivors. For UD-HCT versus HFD-HCT, there were no significant differences in leukemia recurrence, nonrelapse mortality, relapse-free survival, grades 2 to 4 acute GVHD, and moderate-to-severe chronic GVHD. Furthermore, when the outcomes of UD-HCT and HFD-HCT were combined and compared with those of MSD-HCT, there were no significant differences in leukemia recurrence (3-year cumulative incidence, 30% versus 29%), nonrelapse mortality (3-year cumulative incidence, 7% versus 8%), relapse-free survival (3-year estimate, 63% versus 63%), and grades 2 to 4 acute GVHD (120-day cumulative incidence, 16% versus 13%). Moderate-to-severe chronic GVHD, however, occurred less frequently in UD/HFD-HCT (2-year cumulative incidence, 22% versus 40%; P = .006). The addition of ATG to conditioning regimen was a significant predictor for less chronic GVHD (subdistribution hazard ratio, .59). In AML in remission, UD/HFD-HCT after ATG-containing RIC achieved leukemia control equivalent to that of MSD-HCT. Despite HLA disparity in UD/HFD-HCT, chronic GVHD occurred less frequently after ATG-containing RIC, suggesting a strong GVHD-modulating effect of ATG.

The prognostic value of serum C-reactive protein, ferritin, and albumin prior to allogeneic transplantation for acute myeloid leukemia and myelodysplastic syndromes.

We sought to confirm the prognostic importance of simple clinically available biomarkers of C-reactive protein, serum albumin, and ferritin prior to allogeneic hematopoietic cell transplantation. The study population consisted of 784 adults with acute myeloid leukemia in remission or myelodysplastic syndromes undergoing unrelated donor transplant reported to the Center for International Blood and Marrow Transplant Research. C-reactive protein and ferritin were centrally quantified by ELISA from cryopreserved plasma whereas each center provided pre-transplant albumin. In multivariate analysis, transplant-related mortality was associated with the pre-specified thresholds of C-reactive protein more than 10 mg/L (P=0.008) and albumin less than 3.5 g/dL (P=0.01) but not ferritin more than 2500 ng/mL. Only low albumin independently influenced overall mortality. Optimal thresholds affecting transplant-related mortality were defined as: C-reactive protein more than 3.67 mg/L, log(ferritin), and albumin less than 3.4 g/dL. A 3-level biomarker risk group based on these values separated risks of transplant-related mortality: low risk (reference), intermediate (HR=1.66, P=0.015), and high risk (HR=2.7, P<0.001). One-year survival was 74%, 67% and 56% for low-, intermediate- and high-risk groups. Routinely available pre-transplant biomarkers independently risk-stratify for transplant-related mortality and survival.

Abstract IA17: T cell receptor-like antibody 8F4 targets leukemia and non-hematopoietic cancer

Abstract Adaptive anti-tumor immune surveillance of leukemia, called the graft-versus-leukemia (GVL) effect in the setting of allogeneic stem cell transplantation (alloSCT), is responsible for inducing and maintaining long term remission. However, although donor T cells mediate GVL, they also mediate graft-versus-host disease (GVHD), which results in significant morbidity and can be fatal, and is thus a substantial barrier to the more widespread application of alloSCT for many patients with hematological malignancies. CD8 T cells are activated by cognate peptide/MHC-I target cell antigens through binding of clonally unique αβ-heterodimer T cell receptors (TCRs) on the cell surface. Thus, because GVL and GVHD target antigens can be unique, immunotherapy strategies that target GVL antigens such as adoptively transferred T cells could be developed to mediate GVL without GVHD. Likewise, TCR-like monoclonal antibodies (mAbs) that similarly bind to peptide/MHC-I also could be useful as novel immunotherapeutic agents to mediate GVL in the absence of cellular therapies. Moreover, if potent anti-tumor activity was mediated by such TCR-like mAbs, they could have advantages over adoptively transferred donor T cells, including easier standardized manufacturing, ease of dose and scheduled administration, and they could be given to patients in the absence of an alloSCT. We identified PR1, an HLA-A2-restricted 9-mer peptide a peptide derived from aberrantly expressed proteinase 3 (P3) and neutrophil elastase (NE) in myeloid leukemia, as a leukemia-associated target antigen for CD8 T cells that mediate GVL. PR1-specific CD8 T cells target HLA-A2+ AML, CML and MDS but not normal hematopoietic cells and they contribute to cytogenetic and molecular remission of myeloid leukemia. We developed a murine TCR-like mAb that binds to PR1/HLA-A2 (8F4) and showed that 8F4 mediated complement-dependent cytotoxicity (CDC) of AML, CML and MDS progenitor cells and blasts, but not normal bone marrow cells. Because 8F4 did not eliminate normal human hematopoietic cells in a xenograft model, we humanized 8F4 to an IgG1 isotype (h8F4). In AML PDX models, 8F4 and h8F4 eliminated HLA-A2+ AML and leukemia stem cells (LSCs). In preclinical safety models, only mild reversible blood cytopenia was observed after multiple-dose IV administration of high-dose 8F4. Based on these findings, h8F4 is being developed for a first-in-human phase I safety study in HLA-A2+ patients with high-risk AML. In addition, 8F4 also mediated lysis of many non-hematopoietic cancers due to PR1 cross-presentation on surface HLA-A2, which increased cancer cells susceptibility to 8F4-mediated lysis. Therefore, 8F4 also could be tested for the treatment of non-hematopoietic HLA-A2+ cancers such as breast cancer, non-small cell lung cancer, and colon cancer. Citation Format: Jeffrey J. Molldrem, Anna Sergeeva, Hong He, Amanda C. Herrmann, Tian-Hui Yang, Celine Kerros, Haley Peters, Jin Seon Im, Sapna Parshottam, Sijie Lu, Qing Ma, Karen C. Dwyer, Elizabeth Mittendorf, Gheath Alatrash. T cell receptor-like antibody 8F4 targets leukemia and non-hematopoietic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA17.

Comparison of Allogeneic Hematopoietic Stem Cell Transplant from HLA-Matched Related Donors and from Unrelated Donors for Intermediate- to High-Risk Adult Acute Myeloid Leukemia in Remission

Introduction: Allogeneic hematopoietic stem cell transplant (allo-HSCT) is currently the most powerful method to treat intermediate- to high-risk acute myeloid leukemia (AML). Human leukocyte antigen (HLA) matched related donors (MRD) are considered the best donors in allo-HSCT, but they are only available for a small proportion of patients. With the progress of transplant skills over decades, outcome of unrelated donor (URD) HSCT has improved significantly, and the difference between MRD and URD HSCT has been steadily declining. But the role of URD HSCT has still not been well defined in AML, especially for different risk groups. We therefore compared the results of URD HSCT with MRD HSCT in adult AML patients with intermediate- to high-risk in our center.Methods: During January 2005 to December 2012, 108 adult patients with intermediate- or high-risk AML receiving allo-HSCT in complete remission (CR) in our center were admitted in this study. All patients received a standard-dose cytarabine with anthracycline or homoharringtonine as induction therapy. Consolidation courses include high-dose cytarabine or standard-dose cytarabine with anthracycline, homoharringtonine, or mitoxantrone. After consolidation, all patients received allo-HSCT in CR. High resolution DNA typing for HLA-A, -B, -C, -DRB1, and -DQB1 was performed during CR. Patients with HRD would receive HRD HSCT; while for those without HRD, URD with at least 8/10 locus match were selected as donor source. Among the 108 patients, 51 received grafts from HRD and 62 from URD. The conditioning regimen mainly involved BuCy without total body irradiation. All patients received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine A, methotrexate and low-dose mycophenolate mofetil. Rabbit antithymocyte globulin (Thymoglobulin, IMTIX-SangStat, Lyon, France) was also administered to some patients receiving URD HSCT (4.5–6 mg/kg total dose).Results: Most of the baseline characteristics were well balanced between two groups. However, The interval from diagnosis to transplantation differed significantly between two groups, with a median interval of 7 months for HRD group versus 10 months for URD group (P=0.008). Bone marrow was used as graft source in 100% and 80.7% of patients in HRD and URD groups, respectively. Another 19.3% of patients in URD group received peripheral blood stem cell as graft source. The median follow-up was 37.5 months in the whole cohort.The cumulative incidence of acute grade 2 to 4 GVHD was significantly higher in URD group compared with HRD group (40.3% vs. 13.8%, P=0.002). Chronic GVHD and extensive chronic GVHD were also significantly more frequent in URD group (chronic GVHD: 49.2% vs. 29.6%, P=0.037; extensive chronic GVHD: 22.0% vs. 3.7%, P=0.005). The treatment-related mortality (TRM) was significantly higher in the URD group (17.9% vs. 4.3%, P=0.015). While the overall survival (OS), relapse-free survival (RFS), and relapse rate were comparable between two groups (OS at 3 years: HRD 79.9% vs. URD 70.3%, P=0.146; RFS at 3 years: HRD 73.1% vs. URD 66.7%, P=0.239; relapse rate at 3 years: HRD 23.5% vs. URD 18.0%, P=0.643). Clinical characteristics were subjected into univariate and multivariate Cox analysis for OS to find prognostic factors. Cytogenetics, status at transplant (CR1 vs. CR2 to CR3), and MRD levels at transplant were identified as factors that were significantly associated with OS, whereas donor type had no significant impact.When the analysis was done in patients divided by risk stratification, we found that for intermediate-risk patients, the HRD group had a 3-year improved survival rate than URD group (RFS: 85.2% vs. 70.5%, P=0.043; OS: 85.2% vs. 72.7%, P=0.062) with a significantly reduced TRM rate (3.8% vs. 18%, P=0.025). The relapse rate were comparable between two groups (HRD 11.3% vs. URD 12.7%, P=0.649). While for high-risk patients, no differences were observed between two groups in terms of OS, RFS, TRM and relapse rate.Conclusions: For intermediate-risk AML patients, compared with URD HSCT, the results from HRD HSCT were better with improved survival rate and reduced TRM; while for high-risk AML patients, donor types had no effect on transplant outcome. Cytogenetics, status at transplant, and MRD levels at transplant were found to be independent prognostic factors for OS. DisclosuresNo relevant conflicts of interest to declare.

Results of a Phase 1 Study of Quizartinib (AC220) As Maintenance Therapy in Subjects with Acute Myeloid Leukemia in Remission Following Allogeneic Hematopoietic Cell Transplantation

FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Hematopoietic cell transplantation (HCT) is a recommended treatment for patients with FLT3-ITD(+) AML. However, a high rate of relapse after a HCT is observed when compared to FLT3-ITD(-) patients with the 2 year relapse rate of 30% vs. 16% in FLT3-ITD(+) and FLT3-ITD(-) patients, respectively (Brunet, J. Clin. Oncol. 2012). Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown a high level of single agent activity in nearly 500 patients with FLT3(+) relapsed or refractory AML and is currently in a Phase 3 study.This Phase 1 study examined maintenance therapy with quizartinib in AML patients (aged 18 years or older) in remission after receipt of an allogeneic HCT. Dose escalation was conducted using a modified 3+3 design, where 6 subjects were enrolled at each dose level. Two dose levels were tested; dose level 1 (DL1) at 40 mg and dose level 2 (DL2) at 60 mg given daily in continuous 28 day cycles. Dose limiting toxicities (DLTs) were assessed for the first 2 cycles and subjects were allowed to continue up to a maximum of 24 cycles.Thirteen subjects were recruited and enrollment was completed in June 2013. The median age was 43 (range 23 to 61) years. All subjects had received an HLA-matched allogeneic HCT (3 related and 10 unrelated) a median of 56 (range 41 – 70) days before study enrollment. All subjects were positive for the FLT3-ITD mutation by local testing at the time of diagnosis.Seven subjects were enrolled at DL1, including one who relapsed after 22 days on study and was replaced per protocol as deemed not evaluable for DLTs. There was 1 DLT of Grade 3 gastric hemorrhage which resolved and the subject was able to continue on a reduced dose (30 mg) of quizartinib. Six subjects were enrolled at DL2, including one subject who experienced 1 DLT of Grade 3 anemia but was able to continue on a reduced dose (30 mg).Of the 13 total subjects, 10 (77%) received quizartinib for more than a year. Six (45%) subjects are continuing to receive quizartinib currently (15, 16, 18, 18, 23, and 23 cycles) and 2 (15%) subjects have completed 24 cycles. Three subjects (23%) discontinued due to AE: Grade 4 neutropenia (Cycle 4), Grade 2 corneal epithelium defect (Cycle 9), and Grade 3 autoimmune hemolysis (Cycle 15); 1(8%) discontinued for disease relapse (Cycle 1) and 1 (8%) for protocol non-compliance (Cycle 13).The most common (≥20%) treatment-related adverse events (AEs) were diarrhea (38%; 5 subjects), neutropenia (31%; 4 subjects), nausea (23%; 3 subjects) and leukopenia (23%; 3 subjects).This is the first study conducted to determine whether or not quizartinib can be safely administered as post-transplant maintenance therapy in patients with AML. The data from this study support the use of post-transplant maintenance therapy with quizartinib and show early evidence indicating a reduced relapse rate with only 1 relapse reported out of 13 subjects, which compares favorably to historical reference data. No MTD was identified but 60 mg daily was selected as the highest dose for continuous daily administration based on Phase 2 study data in relapsed or refractory subjects (J Cortes, Blood (ASH Annual Meeting Abstracts) 2013 [Abstract]). Quizartinib maintenance has been included in the current Phase 3 QUANTUM-R study comparing quizartinib vs. salvage chemotherapy in relapsed or refractory FLT3-ITD(+) AML. DisclosuresSandmaier:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Khaled:Ambit Bioscience Corporation: Research Funding; Astellas Pharma, Inc: Research Funding. Oran:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Gammon:Ambit Bioscience Corporation: Employment, Equity Ownership. Trone:Ambit Bioscience Corporation: Employment, Equity Ownership. Frankfurt:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding.