Adverse Cytogenetics Research Articles

A Phase 2 Study of Actinium-225 (225Ac)-Lintuzumab in Older Patients with Previously Untreated Acute Myeloid Leukemia (AML) Unfit for Intensive Chemotherapy

A Phase 2 Study of Actinium-225 (225Ac)-Lintuzumab in Older Patients with Previously Untreated Acute Myeloid Leukemia (AML) Unfit for Intensive Chemotherapy

Response-Adapted Lenalidomide Maintenance in Newly Diagnosed, Transplant-Eligible Multiple Myeloma: Results from the Multicenter Phase III GMMG-MM5 Trial

Response-Adapted Lenalidomide Maintenance in Newly Diagnosed, Transplant-Eligible Multiple Myeloma: Results from the Multicenter Phase III GMMG-MM5 Trial

Treatment Practices in Older Adults with Acute Myeloid Leukemia (AML)

Introduction:Controversy exists regarding whether high-intensity (such as 7+3) versus low-intensity (such as hypomethylating agent or low-dose cytarabine) therapy represents an optimal therapy for older patients with AML. While some retrospective studies have demonstrated an overall survival advantage with high-intensity therapy, others including a prospective study (Blood. 2015;126:291-299) failed to confirm these results. Although somewhat arbitrary, several factors influence patients' and physicians' choices of therapy selection. In this context, we performed a single-center retrospective study at the University of Nebraska Medical Center to determine treatment practices in older patients with AML.Methods:We utilized the institutional cancer registry and electronic medical records to extract patient-level data of 248 older patients (aged 60 years or older) diagnosed with AML between the years 2000-2016. Only analytic cases (patients initially diagnosed and/or treated at our institution) were included. Data abstracted include age, gender, race, hematopoietic transplant comorbidity index (HCT CI), body mass index (BMI), year of diagnosis, Karnofsky performance status (KPS), white blood cell (WBC) count, cytogenetic risk categories and type of therapy (none, high- and low-intensity therapy). Fisher's exact test, and logistic regression (for multivariate analysis) were used to determine an association between the type of therapy and other characteristics.Results:Patient characteristics and univariate analysis are provided in table 1. Patients had a median age of 70 years, adverse cytogenetics in 38%, and a median BMI of 28. Median total bilirubin and creatinine were 0.6 mg/dL (range 0.1-2.8) and 1.0 mg/dL (range 0.5-5.5) respectively. 30% had HCT CI score of 0, 27% score of 1-2, 32% score of 3-4, and 10% score of 5+. Patients had KPS of ≤60 (8%), 70-80 (35%), 90-100 (49%). Median number of medications at diagnosis included 6 (range 0-27). Receipt of therapy included none (15%), low-intensity (32%) and high-intensity (53%). 15% of all patients underwent allogeneic HCT. Patients aged 60-69 years were more likely to receive high-intensity therapy. The use of low-intensity therapy such as hypomethylating agents was higher, and fewer patients received no therapy in the years 2008-2016. The use of high-intensity therapy was higher with higher KPS. In a multivariate analysis, only age and time period were significantly associated with the use of low versus high-intensity of therapy. The odds of getting low-intensity therapy for patients aged 70+ years was 7.3 (95% CI: 3.6-15.1) times higher than that for patients aged 60-69 years.Conclusion:Our unselected cohort study provides data regarding comorbidities, BMI and medication use at baseline in older patients. The study demonstrates variations in the treatment practices in older patients, particularly based on age. The use of low-intensity therapy has increased in more recent years. Patients' preferences and physicians' judgment of anticipated therapy tolerance were not captured in this retrospective study and likely accounts for much variation in therapy use. Such unmeasured selection bias may also preclude accurate comparison of the results across trials or across two arms in non-randomized trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Factors and Survival Outcomes in Blast Transformed Chronic Myelomonocytic Leukemia: A Mayo Clinic-MD Anderson Cancer Center Study of 171 Cases

Background:Blast transformed (BT) chronic myelomonocytic leukemia (CMML); defined by ≥20% blood or bone marrow (BM) blasts, occurs in 15-30% of patients and is a major cause of mortality. Reported risk factors include high risk karyotype, circulating blast count, circulating immature myeloid cells (IMC), CMML morphological subtype, and the presence of ASXL1 mutations. In the current study, we reviewed consecutive cases of BT CMML from the Mayo Clinic, MN, and the MD Anderson Cancer Center, Texas, USA, with the intent to examine i) prognostic factors, ii) survival trends, and iii) treatment outcomes.Methods:Diagnoses of CMML and BT-CMML were according to the 2016 WHO criteria. Treatment response in BT-CMML patients was assessed according to standard AML response criteria. Statistical analyses considered clinical and laboratory data collected at the time of BT. Survival was calculated from the date of BT to the date of death or last contact.Results:171 cases of BT CMML were identified from the Mayo Clinic (n=84) and MDACC (n=87). The median age at BT was 69 years and 64% were male. Eight one (49%) had received prior hypomethylating agent (HMA) therapy (Decitabine 50, 5-azacitidine 31), with 30% having achieved a complete remission (CR) prior to BT. CMML patients that received prior HMA therapy were more likely to have thrombocytopenia (p=0.03), higher LDH levels (p=0.007), lower frequency of TET2 mutations (p=0.04) and higher risk stratification by the Mayo prognostic model (p=0.009). The two institutional cohorts were comparable with regards to variables, both at CMML diagnosis and BT.Patient characteristics at time of BT: The median time from CMML diagnosis to BT was 12 months (range, 1-36). At BT, 16 (10%) presented with extramedullary disease, 81 (63%) with an abnormal karyotype, 41 (34%) with cytogenetic clonal evolution, with the following mutational distribution; TET2 50%, ASXL1 39%, NRAS 39%, FLT3 ITD 20%, NPM1 6%, RUNX1 6%, and 5% each for IDH1/2, EZH2 and JAK2 . Molecular clonal evolution was seen in 4 (22%) of 18 evaluable cases.Survival trends: After a median follow-up of 4.4 months (range 0-122), 141 (82%) deaths were recorded. Median overall survival (OS) was 6 months with 1- and 3-year survival rates of 25% and 9%, respectively; survival trends were similar (p=0.4) for patients diagnosed prior to and after the year 2006 (figure 1A).Treatment and response rates: Specific treatment for BT-CMML was documented in 157 cases and included induction chemotherapy (n=61), induction chemotherapy followed by stem cell transplant (HCT, n=18), HCT alone (n=3), HMA (n=18), novel therapeutic agents (n=18), and best supportive care (BSC, n=39). Treatment response was assessable in 113, including 76 treated with induction chemotherapy, 18 with HMA and 16 with novel therapeutics; with respective CR rates of 24%, 0% and 41%; with an additional 24%, 16% and 16% of patients achieving CR with incomplete blood count recovery (CRi), with a survival similar to those with CR (figure 1B). HCT was reported in 25 patients, 17 myeloablative and 8 reduced intensity, with a median OS of 7 months.Predictors of survival in BT-CMML: In univariate analysis of variables recorded at time of BT, risk factors adversely impacting survival included older age, lower hemoglobin, PB blast %, adverse cytogenetics at BT, prior exposure to HMA, not receiving induction chemotherapy, not achieving CR or CRi and not receiving HCT; all of these risk factors remained significant when analysis was adjusted for age. In multivariable analysis, lack of prior HMA exposure (p=0.001, HR 5.1; 95% CI 1.9-14.1) and the achievement of CR/CRi (p=0.02, HR 1.4; 95% CI 1.2-3.4) remained significant while HCT lost its significance (p=0.09). Gene mutations, including FLT3 ITD, cytogenetic and molecular clonal evolution at the time of BT did not impact survival. The 3-year survival rates for BT patients receiving induction chemotherapy, induction chemotherapy followed by HCT, HMA, novel agents and BSC were 8%, 20%, 12%, 3% and 0% respectively (figure 1C).Conclusions: Survival in patients with BT- CMML is dismal (≈6 months) and is adversely impacted by prior exposure to HMA and by the failure to achieve CR/CRi. After BT, the use of HMA therapy is largely ineffective (0% CR), with intensive therapies such as induction chemotherapy with or without HCT, failing to achieve durable remissions. [Display omitted] DisclosuresJabbour:Amgen: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda Oncology: Research Funding. Kantarjian:Amgen: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding.

A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib (MLN9708) for Relapsed/ Refractory Acute Myeloid Leukemia (AML): Final Results

A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib (MLN9708) for Relapsed/ Refractory Acute Myeloid Leukemia (AML): Final Results

Improved Outcome with a Pediatric-Inspired Regimen for Philadelphia-Negative Acute Lymphoblastic Leukemia in the Elderly

Background: Approximately 30% of adult acute lymphoblastic leukemia (ALL) occurs after the age of 60. The improvements observed in the past decade in adults with pediatric-inspired regimen do not translate in this population with increase treatment related toxicity and early deaths. The European Working Group for Adult ALL (EWALL) backbone, adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Our center report the outcome of a regimen designed to improve the outcome of the EWALL backbone taking advantage of the favorable results of pediatric-inspired protocols in younger adults and retrospectively compared it to an historical cohort.Methods: Since 2012, patients > 60 y-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase followed by a third consolidation course. Monthly maintenance course was then started for CR patients. CNS prophylaxis included intrathecal injections and cranial irradiation. Consolidations included 9 cycles alternating cytarabine (8000mg/m2) intermediate-dose methotrexate (1500mg/m2) and cyclophosphamide (1000mg/m2) plus VP-16 (150mg/m2). Patients aged more than 70 years received reduced doses of chemotherapy during consolidation. Treatments are detailed in the table. We retrospectively compared the outcomes with those observed in patients > 60 y-old treated according to the EWALL induction and consolidation backbone (Goekbuget et al. 2008) in our center between 2007 and 2011.Results: Twenty-four patients were included in the study. Median age was 67 [IQR: 64-71]. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Twenty-one patients were included in the historical cohort treated according to the EWALL backbone from 2007 to 2011. Main baseline characteristics were well balanced between the two study cohorts. Complete remission (CR) rate was 81% in the experimental cohort versus 79% in the historical cohort. The induction deaths were 4% in the experimental cohort versus 14% in the historical cohort. All patients in CR (19) in the experimental group were eligible to intensive consolidations and late intensification. Two of these patients were unable to reach maintenance phase (1 deterioration of general status and 1 relapse) and 1 patients omitted late intensification because of renal failure. During late intensification, the median duration with neutrophils < 0.5 X 109/L was 8 days [IQR: 4-14]. Six patients (32%) developed an infection during consolidation courses and 3 patients during late intensification course. Major toxicities during pediatric-inspired consolidation courses included infections (9 patients, including three with bacteremia, two with pyelonephritis and one with pneumonia), grade 3-4 liver toxicity (6), acute kidney failure (3) and hyperglycemia requiring insulin (1). Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. No death was observed during consolidations or late intensification. The median follow up times were 2,6 years and 8,2 years for the experimental cohort and the historical cohort, respectively. The experimental regimen translated into a significantly longer two years disease-free survival (57% [IC95% 31-76] vs 29% [IC95% 11-51] p=0.007 by log-rank test) and a longer two years overall survival than the historical cohort (54% [CI95% 30-73] vs 24% [CI95% 12-47] p=0.01 by log-rank test). The OS and DFS of the experimental and historical cohorts are show in the figure.Conclusion: Results presented here strongly suggest that an intensified pediatric-inspired protocol after an age-adapted induction course might yield significantly better results than former protocols in older adults with Ph-negative ALL. The intensity of this consolidation treatment was tolerable, and the low rate of relapse is promising in this population with an unmet medical need. [Display omitted] DisclosuresForcade:Neovii: Other: Travel grant.

Validation of a Predictive Model for Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome Receiving Hematopoietic Stem Cell Transplantation

▪IntroductionAllogeneic hematopoietic stem-cell transplantation (AHSCT) is an effective treatment for patients with high-risk or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Several factors are known to influence survival post-transplant. Our group developed a model to predict survival in a small number of patients with AML/MDS using 3 disease (cytogenetics and disease status at transplant) and patient-related [Hematopoietic stem cell transplant comorbidity index (HCT-CI)] variables (Bachegowda et al.Blood.2017) . This model effectively stratified AML/MDS patients into 3 risk groups with very different survival. Here we aim to validate this model in a large cohort of AML/MDS patients receiving AHSCT with various donor types.MethodsA total of 934 patients with AML/MDS consecutively treated at the University of Texas MD Anderson Cancer Center were included in this analysis. Donors were HLA matched related (n=377, 40%), matched unrelated (n=416, 45%) mismatched unrelated (n=68, 7%) and T-cell replete haploidentical transplants (n=73, 8%). The median age was 53 years (range 18-65 years). Cytogenetics data at diagnosis was available in 920 patients and was favorable, intermediate and adverse-risk in 340 (37%), 517 (56%) and 63 (7%), respectively. Five hundred and forty patients (58%) were in first or second complete remission (CR1/2). The hematopoietic stem cell transplant comorbidity index (HCT-CI) was available in 914 patients and the median score was 2 (range 0-17). The sources of hematopoietic stem cells were peripheral blood for 586 patients (63%) and bone marrow for 348 patients (37%). Seven hundred and eighty patients (84%) received myeloablative-conditioning chemotherapy.ResultsPatients were stratified into 3 risk groups according to the previously published model: 1) low-risk group (patients in CR1/2 with intermediate/favorable risk cytogenetics, irrespective of HCT-CI (HCT-CI did not impact survival in this group) (n=351), 2) intermediate-risk group (patients beyond CR1/2 and/or with adverse-risk cytogenetics and HCT-CI score ≤4) (n=412), and 3) high-risk group (patients with at least one negative prognostic factor - beyond CR1/2 and/or with adverse-risk cytogenetics and a HCTCI score >4) (n=155).Median follow up duration for 436 survivors was 48 months. For the whole group, the 5-year progression-free survival (PFS), treatment-related mortality (TRM) and relapse rate were 39%, 21% and 39%, respectively. TRM at 5 years for low-risk group was 17%, for the intermediate-risk group was 18% (HR [95% CI] 1.12 [0.79-1.59]; P=0.52), and for the high-risk group was 40% (3.24 [2.26-4.64]; P<0.0001), respectively, whereas cumulative incidence of relapse at 5 years was 24% for low-risk, 52% for intermediate-risk (2.86 [2.20-3.71]; P<0.0001) and 38% for the high-risk group (1.88 [1.34-2.63]; P<0.0001), respectively. In multivariable model, transplantation in >CR1/2 (2.84 [2.38-3.40]; P<0.0001), adverse cytogenetic risk (1.54 [1.29-1.83]; P<0.0001), males (1.23 [1.03-1.46]; P=0.022) were significantly associated with worse PFS while higher age-adjusted HCT-CI scores (1.20 [0.99-1.47]; P=0.06) approached significance. Other factors including conditioning intensity (1.02 [0.82- 1.29]; P=0.84, age (1.01 [1.00-1.01]; P=0.17) and donor type (haploidentical (1.2 [0.83-1.72]; P=0.33), matched unrelated (1.06 [0.88-1.28]; P=0.55) and mismatched unrelated donor (1.07 [0.76-1.50]; P=0.70) as compared with matched related donor) did not significantly influence PFS. Using our previously described predictive model, the patients separated in 3 risk groups with significantly different median PFS, which was not reached for the low-risk group, 9.2 months for the intermediate-risk group (2.4 [1.97-2.99]; P<0.0001), and 6.0 months for the high-risk group (3.3 [2.57-4.21]; P<0.0001), respectively. (Figures 1A and 1B)In conclusion, we were able to stratify allogeneic stem cell transplant patients in 3 risk groups based on a combination of disease (cytogenetics and disease status at transplant) and patient-related factors (HCT-CI) with significantly different survival. HCT-CI appears to have a much higher discriminatory impact in patients with higher risk disease (not in CR1/CR2 and/or adverse risk cytogenetics) compared with those in the lower risk group (CR1/CR2 and intermediate/favorable risk cytogenetics). [Display omitted] DisclosuresOran:AROG: Research Funding; Celgene: Research Funding; Astex: Research Funding. Khouri:Novartis: Research Funding.

Results of Off-Label Venetoclax Use in Combination with Low-Intensity Chemotherapy in Patients with Relapsed and Refractory Myeloid Malignancies

Results of Off-Label Venetoclax Use in Combination with Low-Intensity Chemotherapy in Patients with Relapsed and Refractory Myeloid Malignancies

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

Comparison of Outcomes Following Allogeneic HCT for Adverse Cytogenetic/Molecular Risk AML Using T-Replete Haploidentical Donors to Optimally Matched Related and Unrelated Donors

Outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) for AML patients characterized as adverse risk by cytogenetic or molecular criteria have historically been unsatisfactory. Relapse of AML is the primary cause of treatment failure in these patients and can affect the majority of patients with long term survival seen in only a minority of transplanted patients. We evaluated all consecutive patients who underwent first allo-HCT for AML classified as adverse risk on cytogenetic and molecular criteria by the European LeukemiaNet (Dohner et al Blood 2017) at our center between Feb 2003 and Feb 2017 in order to compare outcomes between patients transplanted using a T-replete HLA-haploidentical donor (HID) to those transplanted from a conventional matched sibling (MRD) or optimally matched unrelated donor (MUD). Patient characteristics and outcome data were prospectively entered into our institutional database from which they were retrospectively extracted for this analysis. Our institutional algorithm for donor selection prioritized MRD followed by 8/8 HLA matched MUD. HID were used for patients lacking timely access to a fully matched donor. All patients were treated using standardized supportive care algorithms in the outpatient setting. All HID transplants received GVHD prophylaxis using post-transplant cyclophosphamide (100mg/kg), tacrolimus (d+5 to +180) and MMF (d +5 to +35), MRD and MUD patients received GVHD prophylaxis with tacrolimus and methotrexate. A total of 78 patients were analyzed (HID =31, MUD=27 MRD=20) Patient characteristics were: median age=53 (23-73); male 47%; HCT-CI 0-2=45%, >3=55%; DRI Into=20%, High=65%, v High =15%; ELN adverse risk criterion - complex/monosomal karyotype = 81% , Other adverse cytogenetics = 13% , High-risk mutation =6% ; Disease Status at BMT CR1=60%, other=40%; Graft Source PBSC=85%, BM=15%; Regimen Intensity MAC=63%, RIC/NST =37%. Median follow-up of survivors was 42 months. Patient characteristics were not significantly different between HID, MRD and MUD transplants except that BM was more often the graft source in HID (23%) than MRD (0%) and MUD (15%) (p=0.06). For the entire population and patients with HID, MRD and MUD respectively, 3 year cumulative incidences of non-relapse mortality (NRM) were 21%, 19%, 20% 24% and of relapse were 45%, 42%, 50%, 44%. Three year Kaplan-Meier estimates of overall survival(OS) were 41%, 47%, 43%, 33% and disease-free survival (DFS) were 34%, 39%, 30%, 32% respectively (p=NS for all endpoints on pointwise and global comparisons for donor type). Disease-risk index (DRI) was a significant predictor of three year OS (77% for DRI-intermediate vs 34% for High/v.High, p=0.013 and 0.03 on pointwise and global comparison respectively), DFS (68% vs 26%, p=0.004 and 0.009), relapse (9% vs. 54%, p<0.001 and p=0.002 respectively). Regimen intensity (MAC vs RIC/NST), patient age (<55 vs >55), year of transplant (2003-2011vs 2012-2017) were not significant predictors of any outcome parameter. Female gender was associated with a lower 3 yr NRM (14% vs 29%), and higher OS (52%vs 41%) (p=0.059 and 0.058 on global comparison). These data demonstrate that in patients defined as Adverse Risk by the current ELN classification, three year DFS can be achieved in approximately a third of patients with a NRM of approximately 20%. DRI remains predictive even within this adverse risk cohort. HID donors produce equivalent outcomes to those using optimally matched conventional donors and specifically, relapse rate is not higher following HID even within this high-risk population. Thus, HID may be used to facilitate early transplantation. [Display omitted] DisclosuresSolh:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau.

Phase IB/II Study of Lirilumab with Azacytidine (AZA) in Relapsed AML

Phase IB/II Study of Lirilumab with Azacytidine (AZA) in Relapsed AML

Feasibility and Outcome of Late Intensification with Native L-Asparaginase for Acute Lymphoblastic Leukemia in the Elderly: A Single Center Experience

Background: The prognosis of Philadelphia-negative Acute Lymphoblastic Leukemia (Ph-neg ALL) in patients over 55 years of age is dismal. The European Working Group for Adult ALL (EWALL) backbone, adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Many attempts to improve this outcome have failed due to increased toxicity. In a report, the French Group for Research on Adult ALL (GRAALL) considered that adjunction of L-Asparaginase (L-Asp) seemed too toxic to be recommended during induction chemotherapy in older patients. The GRAALL-SA2 study recently showed no advantage to the adjunction of erythrocytes encapsulated L-Asp to the EWALL backbone. The question of whether L-Asp could be included in a more intensive consolidation regimen has not been addressed so far.Methods: Since 2012, patients > 60-years-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase (with 6 intravenous infusions of native L-Asparaginase 6000 UI/m2 at Days 8, 10, 12, 20, 22 and 24) according to the GRAALL-2005 (previously published, Huguet et al. 2009). Antithrombin (AT) and fibrinogen levels were monitored prospectively on alternate days. No other coagulation factor was systematically evaluated. Fresh frozen plasma was recommended if fibrinogen levels were below 0.5 g/L, platelet transfusion support was recommended for platelets levels below 20 x 109/L and AT concentrate substitution therapy (Aclotine 25 U/kg) was recommended to maintain AT levels above 60%. AT levels were re-evaluated the days following AT infusion. L-ASP was administrated after correcting the acquired deficiency in AT. Unfractionated heparin at 100 UI/kg/day in continuous infusion or low molecular weight heparin at prophylactic doses in subcutaneous injection was also used. Broad-spectrum antibiotics were administered in case of fever and prophylactic antifungal prophylaxis using micafungin was provided with a daily dose of 50 mg, from the start to the end of neutropenic period (ANC ≤ 0.5×109/L). Toxicity and outcomes were retrospectively analyzed.Results: Twenty-four patients were included in this study between 2012 and 2016 in our single center. Median age was 67 [IQR: 64-71]. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Nineteen (79%) patients were in CR and all received a pediatric-inspired consolidation. One patient (4%) died during induction and 4 (17%) were alive with primary refractory disease. After two consolidation courses, 16/19 of CR patients were eligible for late intensification (two relapses and one renal failure). During late intensification, the median duration with neutrophils < 0.5 X 109/L was 8 days [IQR: 4-14]. A platelet unit transfusion was necessary on 3/16 patients. Infection was diagnosed in 3/16 patients. Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. A patient was switched to Erwinia chrysanthemi L-Asp (Erwiniase 12,000 UI/m2/IV) due to suspected allergic reaction and 2 patients stopped because of grade 4 elevated bilirubin. The rates of grade 3-4 cytolysis, cholestasis and elevated bilirubin were respectively 38%, 25% and 13%. No elevation of amylase or lipase was noticed. No thrombo-embolic event and no grade 3-4 renal, cardiac or neurological event was reported. The median AT nadir was 46% [IQR 42-53]. The median dose of AT substitution for the patients who underwent late intensification was 166 UI/kg [IQR: 135-243]. No patient needed insulin therapy. No death was observed during late intensification. With a median follow up of 2.6 years, the 2y-EFS and 2y-OS were 54% and 55% respectively, highlighting a marked improvement compared to historical controls.Summary/conclusion: Late intensification with high dose of L-ASP according to GRAALL-2005 pediatric-inspired protocol for ALL in the elderly is feasible and well tolerated in this population with an unmet medical need. DisclosuresForcade:Neovii: Other: Travel grant.

HMGA2 Gene Expression Profile Improves Risk Stratification in Acute Myeloid Leukemia

Abstract Introduction: In adult acute myeloid leukemia (AML), clinical outcome is mainly predicted by age, cytogenetics and specific gene mutations (Papaemmanuil et al ., N. Engl. J. Med., 2016; Dohner et al., Blood, 2017). The 2017 European LeukemiaNet (ELN) expert panel for AML diagnosis recommends screening for mutations in NPM1, CEBPA, RUNX1, FLT3, TP53, and ASXL1 genes inaddition to chromosomal anomalies (Dohner et al., Blood, 2017). The genetic and cytogenetic risk stratification guides AML therapy, but it remains insufficient to select the optimal therapy especially in the intermediate genetic risk category. Several gene expression signatures have been proposed to further refine AML risk stratification (Li et al ., J. Clin. Oncol., 2013; Ng et al ., Nature, 2016). However, they have not been widely adopted because of technical challenges in implementing large gene signatures in clinical settings. Accurate biomarkers are still needed to improve prognostic assessment in AML. Methods: We analyzed RNA sequencing data of 430 clinically annotated AML samples and identified HMGA2 asa new candidate prognostic marker. A RT-qPCR test was developed and validated in order to facilitate implementation in clinical laboratories. The association of HMGA2 expression with complete remission (CR), overall survival (OS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR), was studied in a training cohort of 358 diagnostic AML samples from intensively treated patients. Multivariable models were adjusted for age, white blood cell counts, cytogenetic risk, NPM1 and FLT3 -ITD mutations and, except for CR prediction, hematopoietic stem cell transplantation as a time-dependent variable. The prognostic value of the HMGA2 test was validated in an independent cohort of 260 diagnostic AML samples from patients enrolled in the UK National Cancer Research Institute (NCRI) AML17 trial. Results: In the training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. A high expression level of HMGA2 (H+) was associated with lower CR frequency (58.8% vs 83.4%, p Next, we investigated whether the HMGA2 test could improve prognostic assessment in AML patients classified according to the 2017 ELN genetic risk stratification (Dohner et al., Blood, 2017). We observed that a positive HMGA2 test identified 45 of 87 (51.7%) ELN adverse risk patients who were unresponsive to current treatments. Importantly, the HMGA2 test was also positive in 43.5% of intermediate risk patients who were negative for NPM1, FLT3 -ITD and biallelic CEBPA mutations, and in 66.7% of patients with TP53, RUNX1 or ASXL1 mutations. This finding is clinically relevant, especially if screening for TP53, RUNX1 or ASXL1 mutations is not available. Consistent with results in the training cohort, H+ was a good predictor of poor survival and a higher CIR in the validation cohort (Fig. C-D). Multivariable analyses also confirmed that H+ was strongly and independently associated with a higher risk of primary refractory disease (CR: aOR = 3.98 [1.36-11.65], p= 0.01), lower OS (aHR = 2.03 [1.36-3.03], p Conclusion: High HMGA2 expression adds significant independent prognostic value to known clinical and genetic prognostic factors in AML, and is predictive of poor clinical outcomes with standard AML therapies. The HMGA2 test can complement the current AML tests to improve treatment orientation and be integrated in ongoing and future prospective clinical trials studying innovative therapies to increase survival of HMGA2 positive AML patients. Download : Download high-res image (149KB) Download : Download full-size image Figure 1 . Disclosures Wei: Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fleming: Abbvie: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; MSD: Speakers Bureau. Schwarer: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Specialised Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sauvageau: ExCellThera: Other: Chief Executive Officer and Chief Scientific Officer.

Preferential In Vitro and In Vivo Induction of Endogenous Retrovirus Transcription from a Monoallelic Chromosome 7q in Decitabine (DAC) Treated AML Blasts

Background: Hypomethylating agents (HMAs) show an encouraging but not yet well-understood activity in AML/MDS patients (pts) with adverse cytogenetics, such as -7/7q-, often embedded in a complex, monosomal karyotype (Lübbert et al., Haematologica 2012). Integrative methylome/transcriptome studies have provided evidence for aberrant hypermethylation/silencing on monoallelic gene loci, including tumor suppressor genes (TSGs, Kotini et al., Nat. Biotechnol. 2015). Recently, an alternative mechanism of HMA action was described (Roulois et al., Chiappinelli et. al, Cell 2015): induction of silenced endogenous retroviral (ERV) dsRNA transcription, resulting in activation of an interferon-mediated, antitumor immune response (“viral mimicry”). To unravel in vivo HMA activity in different (cyto)genetic backgrounds, we hypothesized that in AML haploinsufficient for 7q, transcriptional repression of monoallelic genes in this region may be preferentially reversed by HMA treatment.Materials and Methods: For identification of genes induced by HMAs, two AML cell lines were selected, ELF-153 (ELF) and UCSD-AML1 (AML1): copy number variations were analyzed by Genome-Wide Human SNP Array 6.0 (Affymetrix), and revealed no monosomies but loss of 7p; in AML1 loss of one entire chromosome 7 was the only numerical aberration. Cells were treated with DAC at equitoxic and -effective concentrations for 4 days, harvested on day 5. Total RNA was depleted of ribosomal RNA (Ribo-Zero rRNA Removal Kit, Illumina) and cDNA libraries (strand-specific, 50 bp) were sequenced with ≥33 million paired-end reads, read quality checked with FastQC (≥95% >Q30). Alignment to the reference genome hg19 was performed with TopHat2, read-counting with HTseq, differential expression testing with DESeq2 (protein-coding transcripts only). Selected target genes were validated by RT-qPCR. Peripheral blood mononuclear cells (PBMC) were collected from 9 AML pts (5 pts with 7q-, 4 cytogenetically normal [CN] pts) treated with DAC (i.v. 20 mg/m2 for 5 days) within the DECIDER trial (NCT00867672). Leukemic blasts before treatment and at day 8 were isolated using automatic magnetic sorting of cells labeled with anti-human CD34 and CD117 MACS microbeads.Results: DAC treatment of AML1 and ELF cells resulted in massive transcriptome changes in both cell lines, with 1,704 genes induced in AML1 (total of 3,583) and 1,206 in ELF (total of 1,867; adjusted FDR <0.01). Comparing DAC-induced expression changes only of genes on 7q, we identified 43 genes significantly differentially expressed only in AML1 cells (up: 15), 24 only in ELF (up: 21), and 19 in both (up: 12). The 15 genes on 7q that were selectively upregulated in AML1 included 3 with TSG features: zyxin (ZYX; up 6.0-fold), homeodomain interacting protein kinase 2 (HIPK2; up 3.8-fold), and high mobility group box transcription factor 1 (HBP1, up 3.1-fold). However, the most heavily upregulated transcripts in AML1 were the endogenous retrovirus 3 group member 1 (ERV3-1 ; up 86.4-fold in AML1 vs 14.3-fold in ELF) and the neighboring zinc finger 117 (ZNF117; up 119.4-fold in AML1vs. 6.5-fold in ELF), both transcribed from the ERV3-1 promoter. ERV3-1 induction was accompanied by induction of the interferon type I response genes retinoic acid inducible gene I (RIG-I) and interferon regulatory factor 7 (IRF7) in both cell lines. Therefore, we next interrogated induction of these genes by DAC in vivo, utilizing serially sorted, matched primary AML blasts (purified before and 3 days after DAC administration). Stronger induction of ERV3-1 and RIG-I mRNA was seen in the 7q- pts compared to the CN pts: By qRT-PCR, median ERV3-1 and RIG-I expression was induced 1.5- and 1.4-fold, respectively, in the pts with 7q- (range: 1.1-2.1 and 1.0-3.2), 1.1- and 0.7-fold, respectively, in the CN pts (range: 0.8-1.7 and 0.3-0.9).Conclusions: We successfully developed an unbiased RNA-seq approach of AML cell lines either mono- or bi-allelic for 7q, demonstrating that DAC treatment preferential upregulates several monoallelic TSGs, and massively activates the ERV3-1 gene (implicated in “viral mimicry”). Induction of ERV3-1 and the dsRNA sensor RIG-I was validated in vivo, and preferentially seen in 7q- AML purified primary blasts. Thus, under clinically established treatment conditions, both the ERV and an interferon response gene can be activated by DAC, supporting a combination with immunotherapy. DisclosuresLübbert:Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding.

Molecular Profiling Defines Distinct Prognostic Subgroups in Chilhood Acute Myeloid Leukemia: A Report from the French ELAM02 Study Group

Introduction:Despite major treatment improvements over the past decades, pediatric acute myeloid leukemia (AML) is still a life-threatening malignancy with relapse rates up to 30% and survival rates below 75%. Moreover, most of investigations are based on the study of large cohorts of adult AML patients while genetic profiles are known to be quite different between adults and children with AML. In this context, a better description of the pattern of molecular aberrations in childhood AML remains a great challenge to refine prognostication and improve outcome in such patients. We report here the comprehensive molecular landscape of a large and well-annotated cohort of pediatric AML and propose a new prognostic molecular classifier in this particular group of patients.Patients and methods:We performed molecular analysis using both high-throughput sequencing focused on 36 genes recurrently mutated in myeloid malignancies and ligation-dependent RT-PCR detecting more than 50 recurrent gene rearrangements in 385 patients with AML of the 438 children enrolled in the prospective ELAM02 trial and we evaluated their prognostic significance.Results:The median age at AML diagnosis was 8.6 years (range: 0-18) and the median WBC count was 16.6×109/L (range: 0.40-575). The distribution in the cytogenetic subgroups was as follows: normal karyotype (n=101, 26.2%), CBF-rearranged (n=92, 24% including t(8;21): n=57 and inv(16)/t(16;16): n=35), KMT2A (MLL)-rearranged (n=79, 21%), adverse karyotype (n=40, 10% including complex karyotype: n=27, monosomy 7: n=9 and t(6;9): n=4) and other (n=73, 19%). 76% of patients had at least one driver mutation among the genes we screened. The most common class of mutations involved genes that control tyrosine kinase signaling (61% including CBL, FLT3, JAK2, KIT, KRAS, MPL, NRAS, PTPN11, SETPB1) followed by transcription factors (16%: CEBPA, ETV6, GATA1, GATA2, RUNX1), tumor suppressors (14%: PHF6, PTEN, TP53, WT1), NPM1 (9%), chromatin modifiers (9%: ASXL1, BCOR, BCORL1, EZH2), DNA methylation controllers (8%: DNMT3A, IDH1, IDH2, TET2), cohesin genes (5%: NIPBL, RAD21, SMC1A, SMC3, STAG2) and spliceosome (3%: SF3B1, SRSF2, U2AF1, ZRSR2). Moreover, a recurrent transcript fusion was detected in about a half of pediatric patients. Taken together, we identified at least one molecular aberration (mutations or fusion transcripts) in 344 (89%) out of 385 patients.In multivariate analysis, the presence of a NUP98 fusion is the sole variable associated with induction failure (50% CR, P=0.038). NUP98 -rearranged cases represented 2.6% of this cohort (10 patients/385 in which 5 had a normal karyotype). When studying OS, 5 factors revealed a negative impact : (1) WBC count higher than 30×109/L (P=0.001); (2) WT1 mutations (P=0.027); (3) RUNX1 mutations (P=0.043); (4) PHF6 mutations (P=0.038) and (5) adverse cytogenetics (P<0.001). On the other hand, 3 factors were shown to positively impact OS: (1) NPM1 mutations (P<0.001), (2) CEBPA dm (P=0.042) and (3) CBF-rearrangements (P<0.001).Considering results from multivariate analysis and strong molecular markers validated among studies, we defined a molecular classifier, refining the prognosis in childhood AML (see figure). Overall, CBF rearrangements, NPM1 and double CEBPA mutations represented 37% of the cohort and defined a favorable molecular subgroup (3-years OS: 92%) while NUP98 fusions, WT1, RUNX1 and PHF6 mutations (15% of the cohort) segregated into a poor molecular subgroup (3-years OS: 46%). Neither karyotype nor others gene mutations were able to discriminate patients into the intermediate molecular risk subgroup (3-years OS: 73%). KMT2A -rearrangements (21% of the cohort) were associated with an intermediate risk.Conclusion:Despite some overlaps, the spectrum of molecular aberrations and their prognostic significance differ between childhood and adult AML. These results have important implications to contribute in refining risk stratification of pediatric AML and show the need for further validations in independent pediatric cohorts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

The Synergy of Vitamin C with Decitabine Activates TET2 in Leukemic Cells and Significantly Improves Overall Survival in Elderly Patients with Acute Myeloid Leukemia

Background: Decitabine is widely used in the treatment of acute myeloid leukemia (AML) in elderly patients. Low-dose ascorbic acid (Vitamin C) has also been indicated to induce DNA demethylation at the cellular level. Our previous study demonstrated its combined effect and safety with low-dose decitabine prior to aclarubicin andcytarabine (DCAG) in elderly patients with AML, in which it appeared to achieve a complete remission (CR) rate of 76.3% and a median overall survival of 10 months. Pharmacological concentrations of Vitamin C (10-1,000μM) induced a time- and dose-dependent increase in 5-hmC. However, little is known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic. Methods: The effect of combined low-dose Vitamin C and decitabine on cell proliferation, the cell cycle, apoptosis and the expression level and activity of TET2 was investigated in HL-60 and NB-4 human leukemic cells. Additionally, we analyzed the clinical outcomes of 73 elderly AML patients who received A-DCAG (intravenous Vitamin C [IVC] plus DCAG [ n=39]) or DCAG (n=34) treatment. Patients received one of the two induction courses: DCAG or A-DCAG. DCAG consisted of 15mg/m2 of decitabine (intravenously, days 1-5) and 300 μg/day of granulocyte colony-stimulating factor (G-CSF, days 0-9) for priming its combination with 10 mg/m2 of cytarabine (q12h, days 3-9), 8 mg/m2 of aclarubicin (days 3-6, DCAG), or IVC (50-80 mg/kg/day, days 0-9; A-DCAG). The G-CSF priming was discontinued when white blood count (WBC) was ≥20×109/L. Results: We found that low-dose Vitamin C and decitabine has a synergistic efficacy on proliferation, apoptosis and TET2 activity, compared to drug-alone treatment in HL60 and NB4 cell lines in vitro . In clinic, feasibility and safety evaluations revealed that patients who received A-DCAG regimen have a higher complete remission (CR) rate than those who received the DCAG regimen (79.92 % vs. 44.11%; P=0.004) after one cycle of chemotherapy. IVC admission decision appeared to beat the discretion of attending physicians. The median overall survival (OS) was better in the A-DCAG group compared with the DCAG group (15.3 months vs. 9.3 months, P=0.039). Patients with adverse cytogenetics did benefit from CR. There was no clinically significant additional toxicity observed with the addition of IVC. Conclusion: On the basis of these results, the addition of IVC at low doses to DCAG appeared to improve CR and prolong OS, compared with DCAG, in elderly patients with AML. DisclosuresNo relevant conflicts of interest to declare.

Persistent Somatic Mutation at Remission Is Associated with Poor Survival and Higher Risk of Relapse in Patients with Acute Myeloid Leukemia

IntroductionMinimal residual disease (MRD) measured by multi-color flow cytometry has been associated with an increased risk of relapse in patients with acute myeloid leukemia (AML). There is also a strong interest in using somatic mutation as an MRD marker and persistence of NPM1 mutation after 2 cycles of induction therapy has been shown to increase the risk of relapse in AML (Ivey et al, NEJM 2016). However, only one third of AML patients carry NPM1 mutation and prognostic impact of persistent mutations in the context of other co-occurring mutations and association with flow cytometry measured MRD is not well understood.MethodsWe studied 95 patients with previously untreated AML who received frontline induction chemotherapy and subsequently achieved complete remission (CR). Paired bone marrow samples obtained at pre-treatment and CR (median day 31) were analyzed by targeted capture exome sequencing of 295 genes (median 309x coverage). Mutect and Pindel was used to call single nucleotide variants (SNVs) and small indels, respectively. We defined two levels of mutation clearance (MC) based on the variant allele frequency (VAF) of the detected mutations at CR: 1) MC2.5, if persistent mutation with VAF <2.5%, and 2) MC1.0 if persistent mutation with VAF <1%. Overall survival (OS), relapse free survival (RFS), event free survival (EFS), and cumulative incidence of relapse (CIR) considering non-relapse death as a competing event were calculated from the date of CR.ResultsOf 95 patients, 49 (52%) were male and 46 (48%) were female. The median age was 53 (range: 17-76). Conventional karyotyping showed one (1%) patient with favorable cytogenetics (CG), 70 (74%) with intermediate CG, and 21 (22%) with adverse CG (all defined by ELN criteria). Eighty nine (94%) patients had de novo AML and 6 (6%) had secondary AML. Thirty-nine (41%) patients underwent allogeneic stem cell transplant in first CR. In the pre-treatment samples of 95 AML patients, we detected 299 high-confidence somatic mutations (192 SNVs and 107 indels) in 60 genes in 85 (89%) patients. The most frequently mutated genes were NPM1 (31%) followed by DNMT3A (29%), FLT3 (18%), and IDH2 (18%). In the matching CR samples, 84 (28%) and 108 (36%) mutations persisted at the level of VAF ≥2.5% and ≥1%, respectively, which corresponded to 41 (48%) and 31 (36%) patients achieving MC2.5 and MC1.0, respectively. Pattern of MC was distinct between mutated genes and affected molecular pathways (Table1). Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), DNA methylation, and splicing had low rate of MC, whereas mutations in transcription factor genes or receptor tyrosine kinase (RTK) pathway had high rate of MC. With the median follow-up of 41 months (95% CI: 39-47), patients who achieved MC1.0 had significantly better RFS, EFS, OS and lower CIR than those without MC1.0, while there was no significant difference in any of the above outcomes by MC2.5 (Table 2). Flow cytometry-based MRD (flow-MRD) data were available in 92 (97%) patients at CR. Positive flow-MRD was associated with significantly worse RFS, EFS, OS and CIR (Table2). Among 61 patients with negative flow-MRD, 25 (41%) and 32 (52%) had persistent mutations with VAF ≥2.5% and ≥1%, respectively. Multivariable analysis considering mutations that were prognostic in univariable analysis (NPM1, IDH1), age, ELN-defined adverse cytogenetics, flow-MRD and MC revealed that MC1.0 was a significant prognostic factor for RFS (p = 0.03, HR 0.36, 95%CI: 0.14-0.91) and CIR (p = 0.03, HR 0.42, 95%CI: 0.19-0.92). MC1.0 in DNA methylation (2-year EFS: 85% (95% CI: 51-96) in MC1.0 vs. 40% (95% CI: 23-56) in non-MC1.0, p = 0.01; 2-year OS: 85% (95% CI: 51-96) in MC1.0 vs. 58% (95% CI: 39-72) in non-MC1.0, p = 0.03) or in chromatin-cohesin pathways (2-year EFS: 73% (95% CI: 37-90) in MC1.0 vs. 15% (95% CI: 3-39) in non-MC1.0, p < 0.01; 2-year OS: 82% (95% CI: 45-95) in MC1.0 vs. 39% (95% CI: 14-63) in non-MC1.0, p < 0.01) was associated with significantly better EFS and OS.ConclusionIn patients with AML treated with induction chemotherapy, persistent somatic mutation at CR with VAF >1% was associated with increased risk of death and relapse. Assessment of both mutation clearance and flow-based MRD at CR may help further risk stratification of AML. [Display omitted] DisclosuresDaver:Immunogen: Research Funding; Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Consultancy; Pfizer Inc.: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Kantarjian:Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Novartis: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

Real World Data on Decitabine Treatment in 296 Patients with Acute Myeloid Leukemia: Outcome and Impact of TP53 Mutations

Real World Data on Decitabine Treatment in 296 Patients with Acute Myeloid Leukemia: Outcome and Impact of TP53 Mutations

Outcomes after Third Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Acute and Chronic Leukemias

Background: A subset of patients with acute and chronic leukemia have received more than one allogeneic hematopoietic stem cell transplant (alloSCT) to achieve a durable remission. A very small proportion of these patients have received a third alloSCT (alloSCT3), and very little is known about their outcome.Methods: We identified 18 patients with acute or chronic leukemia who had relapsed or failed to engraft after their second alloSCT, and received alloSCT3 at our institution. Primary objectives were to evaluate relapse-free (RFS) and overall survival (OS). RFS was the time from SCT3 to relapse, death or censored at last follow up date. OS was defined as the time from alloSCT3 to death from any cause or censored at last follow up.Results: Eleven of the 18 patients, 11 (61%) had acute myeloid leukemia (AML). Patient characteristics are listed in Table 1. Sixteen (18%) patients were considered for SCT3 after disease relapse and 2 (11%) for SCT2 engraftment failure. Five of 11 (55%) AML patients had adverse risk cytogenetics prior to alloSCT3. In the entire cohort (n=18), seven (39%) were in complete remission (CR) at alloSCT3, and 6 patients with AML had active disease with a median bone marrow blast % of 16 [range, 7-40]. Neutrophil and platelet engraftment occurred in 94% and 83% of the cases, respectively. The most common preparative regimen was fludarabine + melphalan that was used in 10 (55%) patients. Other preparative regimens used were fludarabine + cyclophosphamide + rituximab, 2 (12%); decitabine, 2 (12%); others, 4 (23%). Ten (55%) alloSCT3 were from matched-related donors, 6 (33%) from matched-unrelated and 2 (11%) from umbilical cord blood. Median time for neutrophil and platelet count recovery was 18 and 21 days, respectively. Thirteen (72%) patients had a different donor from SCT2 to alloSCT3. Acute and chronic GVHD occurred in 3 (19%) and 5 (31%) of 16 evaluable patients, respectively. Nine of 15 (60%) evaluable patients relapsed after alloSCT3. Two patients, both with AML, experienced delayed relapses at extramedullary sites (breast at 9.5 months; skin at 11.5 months). At a median follow up of 7.5 (range, 0.8-678) months, one-year RFS and OS probabilities were 39% (Figure 1) and 38% (Figure 2), respectively. Both patients transplanted with umbilical cord blood graft experienced short remission durations lasting < 3 months from the receipt of transplant. Two patients (CML 1, CLL 1) are still alive and in remission, beyond 5 years post-alloSCT3.Conclusions: Our study results suggest that alloSCT3 is a feasible option in a small subset of patients with leukemia and can offer durable remissions in selected cases. [Display omitted] DisclosuresPemmaraju:novartis: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; roche diagnostics: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; cellectis: Research Funding. Kantarjian:Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; Novartis: Research Funding. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.