Acute Myelogenous Leukemia Pts Research Articles

Outcome of Allogeneic Stem Cell Transplantation in FLT3-TKD-Mutated AML - a Study on Behalf of the Acute Leukemia Working Party of the EBMT

Introduction The overall prognostic impact of point mutations in the tyrosine-kinase domain 1 of FLT3 (FLT3-TKD mut) in patients (pts) with acute myelogenous leukemia (AML) remains controversial. Furthermore, co-occurrence of FLT3-TKD mut and mutated nucleophosmin-1 (NPM1 mut) was shown to have a favorable prognostic impact on AML pts receiving conventional chemotherapy. However, little is known about the outcome of AML pts with FLT3-TKD mut with or without co-occurring NPM1 mut treated with allogeneic stem cell transplantation (alloSCT). Patients and Methods This is a retrospective study of the acute leukemia working party (ALWP) of the European Society for Blood and Marrow transplantation (EBMT) investigating the outcome of adult AML pts with FLT3-TKD mut with or without NPM1 mut after first alloSCT using matched sibling (MSD), unrelated (UD) or haploidentical (haplo) donors between 2005 and 2022. All patients were in first or second complete remission (CR1 of CR2). Information on cytogenetic risk was necessary for inclusion. No ex-vivo T-cell depletion (TCD) was allowed. The primary endpoint was leukemia-free survival (LFS) at two years after alloSCT. Secondary endpoints were overall survival (OS), cumulative incidence of relapse (RI), non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) and GVHD-free, relapse free survival (GRFS). One hundred and eighty-two adult AML pts with FLT3-TKD mut were identified, of which 74 (40.7%) had a co-occurring mutation in NPM1. Median age was 55.1 years (range 18.6-79.1) and 46.7% were male. Median follow-up was 21.4 months [IQR 13.6-28.1]. 78% of the pts were in CR1. Cytogentic risk was favorable, intermediate and adverse in 12.6%, 75.3% and 12.1% of pts, respectively. Additional FLT3 internal tandem duplication (FLT3-ITD) was present in 25.8% of pts. Information on measurable residual disease (MRD) was available for 68.7% of pts, being positive in 48% of these. Karnofsky performance score was < 90% in 21.1%, and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was >=3 in 28.1% of pts. 69.6% of pts were cytomegalovirus (CMV) positive. Conditioning was myeloablative in 52.8% and reduced intensity in 47.2% of pts. Stem cell donors were MSD, UD and haplo in 25.8%, 55.5% and 18.7% of cases. Stem cell source was bone marrow in 10.4%, peripheral blood in 87.4% and both in 2.2%. In-vivo TCD was performed in 59.2% of pts. GVHD prophylaxis was calcineurin inhibitor-based in 92.2% of pts. Results Engraftment was achieved in 99.4% of pts with a day-60 absolute neutrophil count (ANC) >0.5 x 10 9/L of 97.7% [95% CI: 93.7-99.2]. Day-180 rates of acute GVHD (aGVHD) grade II-IV and grade III-IV were 26.2% (95% CI:19.9-32.9) and 8.1% (95% CI:4.6-12.8), respectively. At two years, rates of total chronic GVHD (cGVHD) and extensive cGVHD were 30% (95% CI: 22.5-38) and 16.6% (95% CI:10.6-23.7), respectively. Two-year LFS and OS were 66.1% (95% CI: 57.6-73.2) and 74% (95% CI: 65.4-80.8), respectively. Two-year RI, NRM and GRFS were 22.5% (95% CI:16-29.8), 11.4% (95% CI: 7-17), and 51.1% (95% CI: 42.4-59.1), respectively. Cause of death was original disease in 47.5%, infection in 27.5%, GVHD in 22.5% and non-SCT related in 2.5% of cases. In univariate analysis the only factor with significant impact on LFS was donor type (haplo [n=34] vs. others, p=0.006). For GRFS, patient CMV negativity (p=0.014) and in-vivo TCD (p=0.01) were significant. Interestingly, co-occurring mutations in FLT3 (FLT3-ITD) or NPM1 were not identified as having a significant impact on LFS or GRFS. Moreover, MRD status before alloSCT was also not shown to have a significant impact on these outcomes. In multivariate analysis of LFS and GRFS, only donor type (haplo [n=34] vs. others) was shown to be significant for both endpoints, hazard ratio (HR) 2.54; 95% CI: 1.4-4.6; p=0.002, and HR 2.01; 95% CI: 1.18-3.41; p=0.01, respectively. Conclusion Acknowledging the limitations of our retrospective study in this rare entity results are encouraging given the high-risk population (median age 55.1 years, CR2 in 22%, co-occurring FLT3-ITD in 25.8%, positive MRD in 48%, HCT CI >=3 in 28.1%). LFS, OS and GRFS rates were 66.1%, 74% and 51.1%, respectively, and both RI and NRM were comparably low with rates of 22.5% and 11.4%, respectively. No positive prognostic impact of co-occurring mutations in FLT3-TKD and NPM1 was detected, unlike what was found for conventional chemotherapy.

Prediction of Sinusoidal Obstructive Syndrome after Allogeneic Stem Cell Transplantation Using Liver Stiffness Measurement By Fibroscan

Background: Sinusoidal Obstructive Syndrome/ Veno-Occlusive Disease (SOS/VOD) is a potentially life-threatening complication post allogeneic transplantation (HSCT) with an incidence of ~ 10% in adults. The sensitivity of SOS symptoms (hyperbilirubinemia ≥2 mg/dl, weight gain>5%, painful hepatomegaly and ascites) is good, but the specificity is relatively low because other conditions such as infections, GvHD, and exacerbation of previous liver disease may cause similar symptoms. Transient elastography (TE) using FibroScan has been implemented as a non-invasive assessment of post-sinusoidal portal hypertension (PHTN) one of the hallmarks of SOS. We aimed to assess TE's applicability in predicting and diagnosis of SOS. Methods: This single-center study was conducted between January 2021 and June 2023. Twenty-seven patients (pts) underwent TE, 11 before HSCT (group 1) due to high risk of developing SOS in order to guide subsequent treatment, and 17 after HSCT (group 2) (1 pt was in both groups) due to an elevation of bilirubin ≥2 mg/dl. SOS was defined using the EBMT criteria. Results: Eleven pts were included in the 1 st group (M 5, F 6). The median age was 43 (22-65) years. 7 pts had acute myelogenous leukemia (AML) -4/7 secondary AML (sAML), and 4 pts had myelofibrosis (MF). 5/7 AML pts received a median of 4 (2-5) lines of chemotherapy before HSCT; 2/4 sAML pts got azacytidine/ venetoclax and all 4 MF pts received Ruxolitinib before HSCT. Two pts had chemotherapy for antecedent malignancy. Donors were HLA-matched siblings (n=5), matched unrelated (n=2), or haploidentical (n=4). Risk factors for developing VOD included: active disease (n=9), multiple lines of chemotherapy (n=7), elevated serum ferritin (n=5), splenomegaly (n=5 including 1 pt with overt PHTN), severe liver toxicity during previous treatment (n=4), age ≥60 (n=3), second transplantation (n=3), pre-existing liver disease including fatty liver (n=3, including 1 pt with liver cirrhosis), severe obesity (n=2), prior treatment with GO (n=2), baseline liver enzymes elevation (n=2), and alcohol abuse(n=1). The conditioning regimen included total body irradiation (n=1), busulphan (BU) alone (n=5), or double alkylating agents (DAC, n=5), respectively. Four patients had myeloablative conditioning (MAC). Most pts had several risk factors for VOD median 5 (3-8). This group had a median liver stiffness measurement (LSM) of 10.1 kPa (range, 3.3-28.3). In 6/11 pts with LSM ≥7.2 kPa, the conditioning was modified; Treosulfan was given instead of BU (n=3), non-DAC instead of DAC protocol (n=3), reduced intensity instead of MAC (n=4), methotrexate was omitted (n=2). One pt received Defibrotide prophylaxis. With these modifications only 2 pts developed SOS (1 died). The second group included 17 pts (M 10, F 7), median age 49 (32-62) years with AML/myelodysplastic syndrome (n=7), acute lymphoblastic leukemia (n=5), MF (n=4), and lymphoma (n=1). Ten had MAC, and 5 had DAC. Five had active disease at HSCT. Three had prior liver disease. All pts had bilirubin elevation ≥2 mg/dl after HSCT but only 10 fulfilled additional criteria for the diagnosis of SOS based on the EBMT criteria. Pts who developed SOS had significantly higher LSM compared to those who did not; 10.7 kPa (IQR, 7.5-25.2) versus 5.9 kPa (IQR, 5.1-7.4), respectively (p=0.007) (Figure 1A). There was a positive correlation between the diagnosis of SOS and LSM levels, with a correlation coefficient of 0.6 (p= 0.04) as determined by the Spearman correlation test. LSM was able to diagnose SOS with an AUC of 0.89 (p=0.008) (Figure 1B). The cut-off value for SOS diagnosis was 7.5 kPa, with a sensitivity of 80% and specificity of 88%. Pts with severe VOD were treated with defibrotide and none of them died .of VOD. Conclusions: Pts with a high risk for VOD may have a high baseline LSM. In these pts, modifying the planned conditioning and GVHD prophylaxis regimens to less hepato-toxic ones may reduce the incidence of subsequent VOD. LSM elevation after HSCT should increase awareness of SOS, while pts with hyperbilirubinemia and low LSM usually suffered from other causes of liver toxicity. High LSM could support the diagnosis of VOD in borderline cases. Therefore, LSM may be an additional diagnostic tool in diagnosing SOS after HSCT, but more studies are needed to confirm these findings.

Allogeneic Stem Cell Transplantation for Patients with Acute Myelogenous Leukemia (AML) in Second Complete Remission (CR2) Transplanted from Unrelated Donors with Post Transplant Cyclophosphamide (PTCy). a Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background:Post-transplant cyclophosphamide (PTCy) has been shown to significantly reduce transplant related mortality (TRM) post hematopoietic stem cell transplantation (HSCT) and is being increasingly used for acute myelogenous leukemia (AML) patients (pts) undergoing HSCT including from unrelated donors (UD). These publications mainly include pts transplanted in first complete remission (CR1). We recently reported outcome in 1879 AML pts transplanted in second CR (CR2) with conventional graft-versus-host disease (GVHD) prophylaxis (Leukemia 2020). Results may differ in transplantation with PTCy as GVHD prophylaxis, eliminating proliferating alloreactive T cells, and upregulating T regulatory cells while suppressing host natural killer (NK) cells immediately after transplantation, changing the biology and characteristics of the transplantation.Methods: The study aim was to assess outcome of adult AML pts, aged ≥18 years in CR2 undergoing HSCT from a 9-10/10 UD with PTCy, in 2010-2019.Statistics included multivariate analysis (MVA) adjusting for potential confounding factors was performed using a Cox's proportional-hazards regression model for main outcomes.Results: In total, 127 pts were included. Median follow-up was 19.2 (95% CI, 14.7-28) months (mos). Median age was 45.5 (range, 18.2-71.3) years. 54.3% were male. Cytogenetic risk (MRC classification) was favorable, intermediate, and adverse in 15.7%, 55.9%, and 5.5% of pts, respectively (missing data-22.8percentage) Median year of transplantation was 2017. Time from diagnosis to transplantation was 20.4 (range, 4.1-182.4) months. All pts were at CR2 at time of transplantation. Donors were 10/10 and 9/10 UD in 60.6% and 39.4% of pts, respectively. 77.8% and 47.2% of the pts and donors, respectively, were cytomegalovirus (CMV) seropositive. Conditioning was myeloablative in 50.4% and reduced intensity in 49.6%. The most frequent (61.4%) conditioning consisted of busulfan and fludarabine. All pts received PTCy as anti GVHD prophylaxis in combination with immunosuppression, which was cyclosporine A /mycophenolate mofetil (MMF) in 21.3% and MMF/tacrolimus in 23.6%. 33.9% of the pts received In vivo T-cell depletion. Grafts were peripheral blood in 93.7% and bone marrow in 6.3% of transplants. Karnofsky performance score (KPS) was > 90 in 71.2% and the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was zero in 61.5% of the pts. Engraftment was achieved by 97.6% with day (d) 60 absolute neutrophil count (ANC) > 0.5 x 10 9/L in 96.8%, and d 180 incidence of acute (a) GVHD II-IV and III-IV was 26.2% and 9.2%, respectively. The 2-year total and extensive chronic (c) GVHD was 34.3% and 13.8 %, respectively. The 2-year non-relapse mortality (NRM) was 17.2%. The 2-year relapse incidence (RI) was 21.1%. RI was the main cause of death in 41% of pts who died, followed by infections (23.1%) and GVHD (20.5%). The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) was 61.7%, 65.2% and 49.3%, respectively (Figure). In MVA time from diagnosis to transplant was significant prognostic factor for RI, LFS, OS and GRFS hazard ratio (HR) =0.19 (95% CI 0.07-0.48, p<0.001), HR=0.3 (95% CI 0.16-0.56, p<10-3) and HR=0.31 (95% CI 0.15-0.61, p< 0.001), HR=0.40 (95% CI 0.24-0.69, p<0.001), respectively. Year of transplant significantly predict GRFS and aGVHD HR =0.87 (95% CI 0.78-0.97, p<0.009) and HR=0.84 (95% CI 0.73-0.98, p=0.027), respectively. Age was prognostic factor for NRM and good risk cytogenetics for OS HR=1.83 (95% CI 1.24-2.69, p=0.002) and HR=0.21 (95% CI 0.05-0.91, p=0.036), respectively. Finally, female to male combination and RIC were prognostic factors for cGVHD HR=0.15 (95% CI 0.03-0.64, p=0.011), and HR=3.74 (95% CI 1.52-9.18, p=0.004), respectively.Conclusions: Outcome of AML pts undergoing HSCT from a 9-10/10 MUD in CR with PTCy as GVHD prophylaxis, are similar to previous reports using conventional GVHD prophylaxis with 26% of pts developing aGVHD ,34% cGVHD and NRM of 17%. These results are also similar to those we previously observed in pts undergoing HSCT from UD with PTCy while in CR1. [Display omitted] DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Kulagin: X4 Pharmaceuticals, Alexion, Apellis, Biocad: Research Funding; Novartis, Generium, Sanofi, Roche, Johnson & Johnson, Pfizer: Speakers Bureau. Blaise: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Clinical Characteristics and Prognosis of Thirty-Three Patients with Myeloid Neoplasms and DDX41 Mutation: Mayo Clinic Experience

Clinical Characteristics and Prognosis of Thirty-Three Patients with Myeloid Neoplasms and DDX41 Mutation: Mayo Clinic Experience

Thiotepa-Busulfan-Fludarabine in Comparison to Busulfan-Cyclophosphamide As Myeloablative Conditioning Regimen Pre Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background. Busulfan plus Cyclophosphamide (BuCy) is the traditional myeloablative conditioning (MAC) regimen pre allogeneic stem cell transplantation (SCT) for acute myelogenous leukemia (AML). The Thiotepa, Busulfan, Fludarabine (TBF) protocol was initially developed for cord blood SCT and subsequently employed in haploidentical SCT; however, there is limited data assessing the TBF regimen in SCT from sibling (MSD) and unrelated donor (URD) for AML and no comparison between the two preparative protocols has been performed.Patients and methods. We analyzed transplantation outcomes of 2523 adult patients (pts) with AML in remission (CR1, CR2+) aged 18-50 years that underwent a first SCT from MSD or URD between 2007 and 2015 and reported to the ALWP of the EBMT. One hundred and three patients received TBF and 2370 pts received BuCy. Pts who received oral busulfan, manipulated grafts, or transplant from <=8/10 HLA-matched donor were excluded. All pts received MAC regimen (defined by Busulfan dose>=9.6 mg/kg). As compared to BuCy, the TBF group included significantly older pts, who were transplanted more recently, had longer interval from diagnosis to transplant, and were more likely to have received BM as stem cell source and URD as donor type. In order to minimize the bias due to differences in pts characteristics, a 1:3 pair-matched analysis was performed. One hundred and forty-six pts receiving TBF were compared with 438 pts receiving BuCy; matching factors included age, year of SCT, disease status at SCT, interval from diagnosis to SCT, donor type, CMV serostatus of both the donor and patient, stem cell source, GVHD prophylaxis and use of anti-thymocyte globulin.Results. With a median follow-up of 22 months, incidence of grade II-IV and III-IV aGVHD after TBF vs BuCy was 29% vs 23% (p=0.23) and 15% vs 8% (p=0.04), respectively. The 5-year cumulative incidence of cGVHD and severe cGVHD was 36% vs 43% (p=0.66) and 16% vs 22% (p=0.72) for TBF vs BuCy, respectively. The 1-year and 5-year non-relapse mortality (NRM) rates were 10% and 22% for TBF vs 9% and 13% for BuCy, respectively (p=0.36). The 1-year and 5-year relapse incidence (RI) rates were 17% and 25% for TBF vs 21% and 37% for BuCy, respectively (p=0.32). No significant difference was observed in leukemia-free survival (LFS), being the 1-year and 5-year LFS rates 73% and 53% for TBF vs 70% and 50% for BuCy, respectively (p=0.56). Overall survival (OS) was also similar, being 80% and 54% for TBF vs 79% and 59% for BuCy, respectively (p=0.88). The composite endpoint graft-vs-host disease-free, relapse-free survival (GRFS) at 5 years was 48% for TBF and 40% for BuCy (p=0.48). Notably, when the analysis was restricted to pts in CR1, a significant difference in RI rate was observed (1-year and 5-year RI: 10% and 18% for TBF vs 20% and 38% for BuCy, respectively, p=0.003) leading to a trend for better LFS for TBF as compared to BuCy (1-year and 5-year LFS: 78% and 57% for TBF vs 72% and 50% for BuCy, respectively, p=0.07), with no difference in OS. When examining separately pts receiving SCT from MSD or URD, no significant difference was observed between TBF and BuCy regimens in terms of transplant outcome. In multivariate analysis, TBF was associated with lower RI compared to BuCy (HR 0.6, p=0.02), while no difference was observed in terms of NRM, LFS, OS and GRFS (HR 0.8, p=0.12 for GRFS). TBF was also associated with lower incidence of cGVHD (HR 0.7, p=0.04) and a trend for lower incidence of severe cGVHD (HR 0.6, p=0.1); on the contrary we observed a trend for higher incidence of grade III-IV aGVHD following TBF as compared to BuCy (HR 1.79, p=0.06).Conclusions. These results suggest that TBF is a valid myeloablative conditioning pre MSD or URD SCT for AML pts < 50 years of age and in remission, with similar transplantation outcome as compared to the traditional BuCy preparative regimen. These data may serve as the scientific background for a well designed randomized two arm study comparing TBF to BuCy as MAC pre SCT in AML pts below the age of 50 years in CR. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau.

Optimizing the Pretransplant Regimen for Autologous Stem Cell Transplantation in Acute Myelogenous Leukemia : Better Outcomes with Busulfan and Melphalan Compared with Busulfan and Cyclophosphamide in High Risk Patients Autografted in First Complete Remission

▪INTRODUCTIONAutologous stem cell transplantation (ASCT) is a relevant clinical option to consolidate some adult patients(pts) with acute myelogenous leukemia (AML) of the good and intermediate risk category in first complete remission (Bone Marrow Transplant. 2015;50:1495). It is still proposed in the 2017 ELN guidelines as consolidation for intermediate-risk genetics AML (Blood. 2017;129:424). Furthermore, the overal role of ASCT and the optimal conditioning pre ASCT for AML may need to be revisited due to the recent developments in the field including effective techniques for minimal residual disease (MRD) monitoring, new drug formulations and others. We have shown previously over the period from January 2005 to december 2015 (Cancer 2017 123:824), better outcomes following the combination of Busulfan and melphalan (BUMEL): in 225 pts who received BUMEL and 724 BUCY within 6 months after diagnosis, BUMEL compared to BUCY was associated with lower RI (34% versus 51%) higher LFS (62% versus 46%) and better OS (79% versus 65% ).In an effort to better study prognostic factors, we designed a larger study including all pts autografted from January 2000 to December 2016 with available cytogenetics. Since the availability of Melphalan remains an issue in some countries, we also wished to investigate whether some subgroups might specifically get benefit from BUMEL.METHODSPatients: All patients with available cytogenetics, autografted in the study period, in first complete remission, following either BUMEL or BUCY, were included. Busulfan was administered p.o. at the dose of 16 mg/kg or intravenously at the dose of 9.6 or 12.8mg/kg. Melphalan was given at the dose of 120 or 140 mg/m2. 1137 pts received BUCY and 512 BUMEL. The median follow up was 43 months for BUCY and 59 months for BUMEL pts.Statistics: Endpoints were relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS) and overall survival (OS). Variables considered were age, sex and Karnofsky score, Cytogenetics risk groups, year of transplant, time from diagnosis to transplant, source of stem cells, pretransplant conditioning. All factors differing between the 2 conditioning were introduced in multivariate analyses. All interactions between conditioning and other prognostic factors were tested.RESULTSPrimary analysis in the overall population:The distribution of the characteristics of patients receiving BUCY and BUMEL was even except for the duration of the interval from diagnosis to transplant which was longer in the BUMEL group (5.5 months versus 4.7 months, p< 10-4). Cytogenetics were similar in BUCY and BUMEL. 117 pts (10%) in the BUCY group and 27 (5%) in the BUMEL group were reported as FLT3-ITD positive. We found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation.Separate analysis of the poor risk group (poor cytogenetics and/or FLT3-ITD mutation):176 patients received BUCY and 62 BUMEL. The distribution of the characteristics of patients receiving BUCY and BUMEL was even except for the duration of the interval from diagnosis to transplant. By multivariate analysis, BUMEL was associated with a lower RI (HR: 0.52 (0.34-0.78); p= 0.002), a better LFS (HR: 0.54 (0.36-0.80); p=0.002) and a better OS (HR: 0.61 (0.40-0.94); p=0.02). At five years, the RI post BUMEL versus BUCY was 53% versus 69%, the LFS 42% versus 25%, the OS 54% versus 36% (figure).Separate analysis of the non poor risk group (good or intermediate cytogenetics, FLT3 wild type):961 BUCY and 450 BUMEL patients belong to this group. At five years for BUCY and BUMEL respectively, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60%, with no significant difference. By multivariate analysis, age, year of transplant and good versus intermediate cytogenetics were significant prognostic factors, but not the nature of the conditioning regimen.CONCLUSIONIn the current study, we demonstrated the superiority of BUMEL over BUCY in poor risk AML pts. It is conceivable that BUMEL is more cytoreductive than BUCY even in high risk pts more chemoresistant. This study and others confirms that ASCT may still be an option to consolidate patients with AML in CR1 at a time when maintenance post transplant including immune therapies may offer an alternative to allogeneic transplantation with a better quality of life in a carefully selected patient population. [Display omitted] DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

Outcomes of Acute Myelogenous Leukemia Patients Undergoing Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide: Impact of Total Body Irradiation Versus Chemotherapy-Based Myeloablative Conditioning

<h3>Background</h3> Optimal myeloablative conditioning (MAC) in the setting of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is unknown. We studied the outcomes of total body irradiation (TBI) vs. chemotherapy (CT) based MAC regimens in acute myelogenous leukemia (AML) pts undergoing haplo-HCT and reported to EBMT. <h3>Methods</h3> The study included 1008 AML pts who underwent haplo-HCT during 2010-2018, following TBI (n=89, 9%) or CT (n=919, 91%) based MAC. Regimen intensity was defined by EBMT criteria and the cases with busulfan dose <9 mg/kg or TBI dose ≤6 gray were excluded. Fludarabine-TBI (78%) and Thiotepa-busulfan-fludarabine (56%) were the most common MAC regimens in TBI and CT-cohorts, respectively. Pts in TBI cohort were more likely to be younger (median age, 38 vs. 47 yrs, p<0.01) and receive BM graft (57% vs. 43%, p-0.01) Other pt, disease and transplant characteristics were similar in both groups. Median follow up for TBI and CT cohort were 25.4 and 20.7 months, respectively. <h3>Results</h3> In univariate analysis, day 100 incidence of acute GVHD (aGVHD) II-IV and III-VI was 22% vs. 27% (p-0.44) and 12% vs. 12% (p-0.92) in TBI and CT cohorts, respectively. Two-yr total and severe chronic GVHD (cGVHD) incidence were 42% vs. 27% (p<0.01) and 9% vs. 12% (p-0.33) in TBI and CT cohorts, respectively. Graft failure was reported in 2 (2%) and 65 (7%)(p-0.08) pts who received TBI and CT-based MAC, respectively. Three (1%) pts died due to graft failure in CT-group. Death from veno-occlusive disease was reported in 1(3%) TBI pt and 11(3%) CT pts. Death due interstitial pneumonitis was reported in 1 (3%) TBI and 8(2%) CT pts. One pt died from a second malignancy in each group. In multivariate analysis, TBI was associated with higher incidence of overall cGVHD [HR=1.81, 95% CI:1.14-2.87, p-0.01] compared to CT. There was no difference in other outcomes such as extensive cGVHD[HR=0.34, p-0.07], relapse incidence(RI) [HR=1.32, p-0.22], nonrelapse mortality(NRM) [HR=0.82, p-0.52] and leukemia free survival(LFS) [HR=1.09, p-0.62], overall survival(OS) [HR=1.07, p-0.71] and GVHD free relapse free survival (GRFS) [HR=1.02, p-0.92]. 2-yr LFS and OS of TBI and CT cohort were 45% vs. 49%,p-0.98 and 50% vs. 55%,p-0.79, respectively (figure 1). Factors impacting OS were pt age (per 10yrs, HR=1.1, p-0.02), KPS≥90 (HR=0.55,p<0.01) and advanced disease status before haplo-HCT (HR=2.35, p<0.01). In a subgroup analysis of pts <40 yrs old and pts with pre-HCT disease status CR2 or advance disease, no interaction was observed between type of MAC and RI, NRM, LFS, OS and GRFS. <h3>Conclusions</h3> In this large relatively homogenous cohort of AML patients who received haplo-HCT with PTCy, TBI based MAC was associated with higher incidence of overall cGVHD without impacting other transplant outcomes compared to CT based MAC. A prospective study is needed to validate these findings.

Center Effects on Outcomes in the Treatment of Acute Myelogenous Leukemia (AML): A Multilevel, Community-Based, Case-Controlled Study

Background As with other complex therapies, treatment of AML varies among centers (ctrs) due to differences in patients (pts), infrastructure and care delivery models. Variation in ctrs practices, experience and resources may influence pt outcomes. Few studies have examined the association of ctr characteristics and survival in AML. Previous research offers conflicting results regarding outcomes of AML pts treated in National Cancer Institute Comprehensive Cancer Centers (NCICCC) versus community settings; neither study investigated ctr-level differences other than volume. We sought to compare AML outcomes in any of the HCA Healthcare (HCA) network of 131 community hospitals from 2011-18 with those reported in the Surveillance, Epidemiology, and End Results (SEER) database. We then examined pt, disease and center-related characteristics influencing outcomes in HCA hospitals. Methods We identified pts with AML (excluding APL) &gt; 18 yrs treated between 10/31/11 and 10/31/18 in an HCA hospital (N = 4,882) and obtained pt level data from electronic medical records. A comparative population treated was developed from the most recent SEER database (2011-15; N = 19,349). We used coarsened exact matching to control for as many potential biases as possible. We compared mortality at 30, 90 and 120-days and overall survival curves between HCA and SEER . A Cox regression model was used to investigate differences in hazard rates among HCA facilities while simultaneously assessing the impact of patient characteristics and facility characteristics. Of the HCA patients, 1339 were treated in 6 hospitals that meet defined metrics of infrastructure, staffing, processes and volume as part of certification to participate in the Sarah Cannon Blood Cancer Network (SCBCN). Results Matching for age, gender and race, HCA pts were found to have significantly lower mortality than SEER at 30, 90 and 120 days (p&lt;.001) as well as significantly better survival (p&lt;0.001; fig.1). We next investigated how pt and facility characteristics interact to predict outcomes for HCA patients (table 1). Elevated White Count at diagnosis (HR=1.3), Charlson index (HR=1.1), older age (HR= 1.04), and receiving treatment at a hospital with larger bed count (HR=1.26) were associated with significantly worse survival. Commission on Cancer (COC) accreditation status, Socio-economic status (SES), distance to facility, and gender did not significantly impact risk. Being treated in the SCBCN (HR=0.68) and African American race (HR= 0.66) were associated with improved survival Conclusions Previous research utilizing registry data demonstrated better survival for pts with AML treated in higher volume centers but provides conflicting information about survival for pts treated in a NCICCC versus a community setting. Neither study examined center characteristics beyond NCI designation. This report examines a large pt cohort treated in community hospitals across the US. Pts treated in these hospitals had significantly better survival than a matched cohort from the SEER database. We validate the importance of age, acuity and Charlson index as adverse factors. Analysis of facility characteristics demonstrated that qualification as a member of SCBCN was associated with improved survival underscoring the importance of infrastructure, quality systems and volume in achieving improved outcomes. Disclosures Lemaistre: HCA: Employment. Chao:HCA: Employment. Cruz:1. Daiichi Sankyo advisory board: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Speakers Bureau. Eghtedar:Verastem Oncology: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Holder:Sarah Cannon: Employment. Malik:Kite Pharma: Honoraria. Rotta:Kadmon Corporation, LLC: Consultancy; Jazz: Speakers Bureau.

Survivorship in AML - Outcomes of Acute Myelogenous Leukemia (AML) Patients (pts) after Maintaining Complete Remission (CR) for at Least 3 Years (yrs)

Survivorship in AML - Outcomes of Acute Myelogenous Leukemia (AML) Patients (pts) after Maintaining Complete Remission (CR) for at Least 3 Years (yrs)

TP53 Mutations Determine Outcome of Patients (pts) with High-Risk Myelodysplastic Syndrome (HRMDS) and Acute Myelogenous Leukemia (AML) Regardless of Karyotype and ELN Risk Stratification

Background: Cytogenetic and molecular abnormalities are the backbone of risk stratification for pts with AML/MDS. Yet, the current stratification systems still fail to identify some pts at high risk for treatment failure. TP53 mutations have been linked to poor outcome and treatment resistance in many malignancies. We conducted a retrospective case-control study of pts with HRMDS and AML with TP53 mutations (TP53 m) to define disease characteristics, response, and outcome after transplant (HSCT).Methods: Twenty-one consecutive pts with HRMDS or AML were treated between January 2014 and March 2016 who wereTP53 m. The pts were compared to a control cohort of 46 pts with wild type TP53 (TP53 wt). Mutation analysis was performed using next generation sequencing. All AML pts were treated with a standard 3+7 induction protocol. Pts were excluded for incomplete cytogenetic and molecular data.Results: A total of 21 patients were identified with TP53 m (14 HRMDS, 11 AML). The median age of the 21 pts was 64 years (range 32-84). Pts with TP53 m were older (median age 64 vs 55 years, p=.0256) and exhibited a higher rate of adverse cytogenetics (71% vs 30.4%, p=.043) when compared to TP53 wt. Secondary AML was also more common with TP 53 m (57% vs 31%, p=.05). Pts with TP53 m were less likely to achieve CR (33% vs 74%, p=.009). Three pts with TP53 m proceeded to transplant (2 with HRMDS and 1 with AML).With a median follow up of 3.4 months (range 0.3-73) the estimated PFS and OS at 18 months was superior in TP 53 wt compared to TP 53 m (17% vs 69%, p=.037 and 17% vs 50%, p=.0095 respectively). HSCST was associated with a 70% reduction in mortality, but this was not statistically significant (p=.067).Conclusion: TP 53 mutations in pts with HRMDS and AML are associated with advanced age, high risk cytogenetic abnormalities, and secondary AML. Our findings demonstrate that TP53 m in HR MDS and AML is associated with poor clinical outcome including lower CR rates, and lower PFS and OS. Different treatment strategies need to be devised for these pts. DisclosuresMcCloskey:Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Koprivnikar:Alexion: Consultancy, Speakers Bureau. Depadova:Amgen: Speakers Bureau. Stanislaus:Novartis: Consultancy, Speakers Bureau. Goldberg:COTA Inc: Employment; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership; Novartis: Consultancy; Pfizer: Honoraria. Faderl:Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Amgen: Speakers Bureau.

Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia.

7007Background: Treatment options for older patients (pts) with acute myelogenous leukemia (AML) unfit for intensive chemotherapy are limited. Expected complete remission rates for low-dose cytarabine (LDAC) are about 10% in this population. Targeting the pro-survival molecule BCL-2 has demonstrated clinical efficacy as a therapeutic strategy in various hematologic malignancies. Venetoclax (VEN), a selective BCL-2 inhibitor, shows synergy with cytarabine in several AML cell lines and primary samples. Methods: This is a non-randomized, open-label phase 1/2 dose-escalation/expansion study of VEN + LDAC, in treatment-naive AML pts ≥ 65 years not eligible for intensive chemotherapy. Pts receive oral VEN once daily (QD) on days 1‒28 and subcutaneous LDAC 20 mg/m2 QD on days 1‒10 of each 28-day cycle. VEN dose escalation follows a 3 + 3 design; dose-limiting toxicities (DLTs: grade 4 toxicity, platelet count < 25,000/μL, or absolute neutrophil count < 500/μL within 14 days of last VEN dose) areassessed during c...

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy

T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HCT) For Adult Patients With Acute Myelogenous Leukemia (AML) In First and Second Remission: Long-Term Disease Free Survival(DFS) With a Significantly Reduced Risk Of Graft-Versus-Host Disease(GvHD)

IntroAllogeneic-HCT is recommended for AML patients (pts) in CR2, in CR1 with poor-risk cytogenetics, and should be considered for those in CR1 with intermediate-risk. Non-relapse mortality (NRM) and GVHD remain major causes of treatment failure. Ex vivo TCD can prevent GvHD but large case series have not been published. MethodsA retrospective chart review was conducted to evaluate 178 pts with AML in CR1 and CR2 undergoing TCD-HCT between 2001 and 2011. All pts received myeloablative-conditioning. The majority received ATG for graft rejection prophylaxis. Acute (A) and chronic(c) GVHD were assessed by standard criteria. No GVHD prophylaxis was administered post-transplant. Soybean agglutination+sheepRBC rosetting (sRBCR) was used for BM TCD. CD34+ selection +/- sRBCR was used for PBSC TCD. Pt characteristics were compared using Pearson's chi-squared and Fisher's exact tests. Prognostic factors relating to overall survival (OS) and DFS, including age, gender, leukemia etiology, cytogenetic-risk group, donor-type, TCD-method, conditioning-regimen, HLA match grade, HCT-specific comorbidity index and immune reconstitution were evaluated using log-rank test statistics. Differences in cumulative incidence (CI) rates were evaluated using Gray's test. Cox proportional-hazards regression was used to further adjust for pt risk factors for OS and DFS. ResultsPt characteristics and outcomes are summarized in Tables 1 and 2. Median follow-up of survivors is 52 mo (12-134). 177 pts engrafted. One died pre-engraftment, 7 developed late graft-failure (GF), and 3 are alive after a 2nd HCT. One yr incidence of aGVHD was low (grade 2-4 13%, 3-4 3%). Only 1 pt developed cGVHD by NIH consensus criteria. Univariate association between CR status (1 vs 2), OS and DFS was not statistically significant (p=0.17 and 0.16, respectively). After adjusting for HLA status, age, sex, cytogenetic risk, and regimen, CR2 pts had an increased risk of death (HR: 1.90 (1.14-3.16), p= 0.014). In CR1 pts, cytogenetics was associated with relapse incidence (p=0.003) and was highest in patients with adverse cytogenetics (31%, 95%CI 16-48) and <10% in intermediate I-II risk pts. Overall CI relapse at 1 and 2 yrs was 13% and 16%, respectively. Causes of death were: relapse (n=29), infection (n=25), GVHD (n=7), organ toxicities (n=5), GF (n=2) and other (n=7).Female gender was significantly associated with decreased OS and DFS (p<0.002 and 0.003, respectively). Two yr estimates of OS and DFS in females vs males was 51% vs. 71% and 49% vs. 69%, respectively. These differences were due to a higher NRM in females receiving the chemotherapy based regimen (p<0.001). Gender difference was not observed in pts receiving TBI-based regimens (p=0.599). This difference persisted after adjusting for other common prognostic factors in a multivariate model. For the entire group, 2yr OS and DFS was 67% and 62%, respectively. For CR1 pts, 2 yr OS and DFS was 70% and 64%, respectively (Fig.1). ConclusionThese results support the use of TCD HCT in AML pts in CR. Durable DFS and long-term OS can be achieved with low rates of GVHD without compromising the graft-vs-leukemia effect. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Survivorship In AML - Outcomes Of Acute Myelogenous Leukemia (AML) Patients (pts) After Maintaining Complete Remission (CR) For At Least 3 Years

▪ IntroductionApproximately 80% of younger patients and 50% of older patients with newly diagnosed AML achieve CR after induction chemotherapy. The majority of patients who achieve CR eventually relapse, with most relapsing within the first 3 years. Long-term outcomes in pts maintaining 1st CR for at least 3 years (AML survivors) remain largely unknown. The purpose of this study was to investigate long-term outcomes in this subset of pts. MethodsWe performed a chart review of pts with AML treated at our institution who achieved CR for at least 3 years after their initial chemotherapy ± allogeneic stem cell transplant (ASCT) to analyze their long-term outcomes. Results1792 pts with AML were treated between 2000 and 2010 at our institution. 1081 (60%) pts achieved CR. Among them, 266 (25%; 15% of all treated) maintained 1st CR for at least 3 years. The 1st 200 pts are described in this analysis: 33 after ASCT and 167 after chemotherapy (chemo) alone. Median time to CR from initiation of induction chemotherapy was 34 days (range, 19-115) for pts who received ASCT and 28 days (17-104) for chemo only. Characteristics of AML survivor pts at time of diagnosis were as follows: hypertension (HTN) was present in 25% of the pts; cardiac disease in 7%; hypothyroidism in 5%; diabetes (DM) in 7%; depression in 6%; osteoporosis in 2%; chronic obstructive disease (COPD) or asthma in 4%. Median number of medications per pt at baseline was 1 (0-7). Relapses after maintaining CR for ≥3 years (i.e., late relapses) were noted in 12% of the pts: 9% of the pts treated with ASCT and 12% of pts with chemo alone. The median CR duration for those who relapsed was 4 years (3-10) and 4.8 years (3-12), respectively. At relapse, karyotype was different from the karyotype at the time of diagnosis in 47% of the cases: 100% after ASCT and 41% after chemo alone. Mutational status changes at relapse were noted in 31% of the pts. New Flt3 ITD mutations were the most common change, noted in 75% of pts who had a mutational status change. A 2nd complete remission (CR2) was achieved in 52% of pts, including 33% of pts that had received ASCT and 56% of pts treated with chemo alone. The median CR2 duration was 5 months and 10 months (3-30) respectively. The median survival after relapse was 13 months (1 to 42). Four pts with relapsed disease who initially were treated with chemo only underwent ASCT; no patient received a 2nd ASCT. New medical problems that were present at the 3 year mark included: HTN in 10% of pts; cardiac disease in 4%; hypothyroidism in 4%; depression in 4%; renal insufficiency in 3%; pulmonary disease in 2%; DM in 3%; hematological disorders, including anemia, thrombocytopenia, monoclonal gammopathy of undetermined signigicance (MGUS), systemic mastocytosis & Waldenstorm's macroglobulinemia, in 5%. Pulmonary disorders (e.g., bronchiolitis obliterans and COPD) occurred in 6% of pts who underwent ASCT and 2% of pts who treated with chemo alone. Renal insufficiency was noted in 9% of pts who underwent ASCT and in 2% of pts treated with chemo alone. The median number of medication per pt 3 yrs from initial CR was 3 (range, 0-11). New medical problems that developed at time of last follow up included: HTN in 12% of pts, cardiac disease in 6%, hypothyroidism in 5%, depression in 7%, renal insufficiency in 4%, pulmonary disease in 3%, DM in 5%, hematological disorders in 6%. Cardiac problems, including the development of coronary artery disease, myocardial infarction, congestive heart failure and arrhythmias were noted in 3% of pts who underwent ASCT and in 6% of pts treated with chemo alone. The median number of medications per pt at last follow up was 3 (0-14). Second malignancies occurred in 10% of pts. The most common 2nd malignancies were colorectal carcinoma, breast cancer, prostate cancer and lymphoma, each occurring in 2% of pts. At median follow up of 4.2 years (3.2-10.2) and 4.9 years (3.2-12) respectively, 94% and 80% of pts are alive. In descending order, the most common causes of death included AML relapse, second malignancy and myocardial infarction. ConclusionAML pts who achieved CR for at least 3 years have a low incidence of late relapses. New medical problems including heart disease and second malignancies may occur but most pts are still currently alive. AML pts who maintain 1st CR for at least 3 years require ongoing medical care and long-term surveillance. Disclosures:No relevant conflicts of interest to declare.

Survival Advantage of Cell Therapy Over Cytotoxic Therapy Alone in Adult Patients with Relapsed AML After Allogeneic Hematopoietic Stem Cell Transplantation

AbstractAbstract 1994 Background:The prognosis of acute myelogenous leukemia (AML) relapsing after allogeneic hematopoietic stem cell transplantation (allo HCT) remains poor and the treatment options are limited. There is no standard of care for these patients (pts) and treatment primarily aimed towards rapid tapering of immunosuppressant medications to induce graft versus leukemia effect. Salvage chemotherapy alone post allo HCT for relapsed AML is seldom curative with the overall survival (OS) at 2 years 9% as reported by the European Blood and Marrow Transplant Group (EBMT). The addition of cell therapy, such as donor lymphocyte infusion (DLI) or stem cells (second transplant) may improve response rate however, long term survival rate remains poor. Methods and Patients:To asses the factors contributing to outcomes after relapse post allo HCT; we conducted a retrospective analysis of 85 adult pts with relapsed AML from 2004 to 2011 at our institution. Our study was designed to evaluate the efficacy of different therapies with focus on an intent-to-treat analysis. Therapy groups were defined as: cytotoxic therapy, including hypomethylating agents (HMA) or other forms of chemotherapy (CH); cell therapy (CT), including chemotherapy followed by DLI or CD34+ stem cells; and supportive care. The median time from transplant to relapse was 4.3 (range: 0.6–45) months (m) and the median post HCT follow up was 9 (range: 2–85) m. Patient Characteristics:The median age was 50 (range: 19–69) years, 39 were females and 45 males. 41 (47%) pts had secondary AML, 44 (51%) with de novo AML. At diagnosis 31 (36%) pts were positive for adverse cytogenetics, 33 (38%) pts had intermediate-1(INT-I), 17 (20%) pts had INT-II and 4 (5%) pts with favorable cytogenetics. CIBMTR Risk stratification: 35 (41%) low, 24(28%) intermediate and 26 (30%) high. At time of HCT 55 (64%) pts had bone marrow (BM) blasts < 5%, 7 (12%) pts with minimal residual disease; 30 (35%) had BM blasts > 5% and 4 pts (13%) had BM blasts > 30%. Eighty three (97%) received mobilized CD34+cells from peripheral blood, 36 (42%) pts previously received HCT were from matched related donors, 34 (40%) from matched unrelated donors and 14(16%) from a mismatched unrelated donors. At relapse post HCT, 28 (32%) pts received cytotoxic therapy (HMA or CH), 21 (24%) pts received CT. Thirty-six (42%) pts received supportive care only. Results:In pts who received salvage therapy the complete remission (CR) rate was 43%. For the CT group 71% achieved CR compared to 21% who received cytotoxic therapy (p=0.002). No significant difference was noted in the CR rate between HMA or CH group 31% versus 9% respectively (p=0.27). The median time to relapse after achieving CR for all pts was approximately 13 m with 14%, 40% and 70% relapsed by 6, 12 and 24 months respectively. The median time of survival from time of relapse post HCT for all pts was 3.7 m with the best outcome noted in the CT group at 10.2 m compared to 4.7 m and 2.6 m for those received HMA and CH respectively. The OS at 1 year from the time of relapse post allo HCT was 24% for all pts, 43% for CT, 29% for cytotoxic therapy (HMA 31%, CH 27%) and 8% for those received supportive care (P<0.001). Conclusions:These data suggest that pts who are able to receive CT preceded by cytotoxic therapy have the best chance of prolonged OS. Cytotoxic therapy alone does not improve survival over supportive care. Our findings suggest that future approaches should focus on giving cytotoxic therapy followed by CT to achieve maximal response for AML pts after relapse post HCT. Disclosures:No relevant conflicts of interest to declare.

Leukapheresis (WBC Depletion) Treatment for Patients with Acute Leukemia and Blast Crisis Can Enable a High Percentage of Patients to Undergo Induction Chemotherapy

Abstract 4281 Introduction:Several retrospective, cohort studies have demonstrated that leukapheresis (WBC depletion) treatment in patients (pts) with acute leukemia and concurrent hyperleukocytosis and blast crisis decreases short-term mortality rate, but does not increase overall survival. However, pts selected in these studies for leukapheresis treatment are often sicker and have a higher underlying mortality rate (than pts who do not receive such treatment). No randomized controlled trials assessing the efficacy of leukapheresis in this subset of pts with acute leukemia have been performed. Methods and Clinical Presentation:Between January, 2006 and June, 2010, Apheresis Care Group (ACG) treated 1,636 pts performing 13,587 therapeutic apheresis treatments (txs). Of this patient cohort, 126 (7.7%) pts had acute leukemia with clinical and/or laboratory evidence of blast crisis and received leukapheresis treatment. 77 pts had acute myelogenous leukemia (AML) and received 174 leukapheresis txs; 49 pts had acute lymphoblastic leukemia (ALL) and received 158 txs. AML pts presented with median WBC 204 × 109/L (range 66–418 × 109/L) and 87% pts had blast crisis (defined as blast percent >75% or blast count >100 × 109/L). Median age was 54 years (6.5–85 years); 61% pts were male. Of CNS or pulmonary symptoms (sxs) of leukostasis (CNS sxs defined as: headache, lethargy, confusion, or visual abnormalities; pulmonary sxs defined as: shortness of breath, hypoxia, or chest x-ray infiltrates without evidence of pneumonia), 13% pts had no sxs, 52% pts had 1 sx, and 35% pts had 2 sxs. ALL pts presented with median WBC 338 × 109/L (104–736 × 109/L) and 82% pts had blast crisis. Median age was 22 years (4–80 years); 64% pts were male. Of sxs of leukostasis, 25% pts had no sxs, 63% pts had 1 sx, and 12% pts had 2 sxs. Treatment:All pts received a course of leukapheresis (Lp) with the following objectives: 1) decreasing the risk of thrombotic and hemorrhagic complications related to leukostasis, and 2) stabilizing pts for induction chemotherapy. WBC treatment goals were defined as: WBC count (ct) <55 × 109/L for AML pts, and WBC ct <80 × 109/L for ALL pts. AML pts received a median of 2 Lp txs (range 1–5 txs); ALL pts underwent a median of 2 Lp txs (1–7 txs). Results:Outcomes were evaluated by the percentage of pts who: 1) reached the WBC treatment goal and, 2) received induction chemotherapy. “Improved” outcome was defined as pts who reached their WBC treatment goal during leukapheresis therapy; “stabilized” was defined as pts who achieved >50% reduction in WBC ct, but did not reach their WBC goal; and “unchanged” was defined as pts who achieved neither. In the AML cohort, 76% pts improved, 23% pts stabilized, and 1% pts were unchanged. In the ALL cohort, 63% pts improved, 34% pts stabilized, and 3% pts were unchanged. For AML pts, the median final WBC ct was 53 × 109/L (range 17–133 × 109/L) and 92% pts received induction chemotherapy. For ALL pts, the median final WBC ct was 76 × 109/L (range 30–294 × 109/L) and 98% pts received induction chemotherapy. 7 (9%) AML pts and 1 (1%) ALL pt expired within 1–4 days after completing course of leukapheresis. Of the 8 expired pts, 75% had both blast crisis and 2 sxs of leukostasis; 38% had intracranial hemorrhage or CVA; and 88% were hypotensive, receiving mechanical ventilation, and unable to tolerate induction chemotherapy. Conclusion:Carefully selected patients with acute leukemia and evidence of impending thrombosis may benefit significantly from leukapheresis therapy. A limited number of treatments (median of 2 treatments) can enable a high percentage of patients to receive induction chemotherapy and may improve short-term clinical outcomes. Leukapheresis treatments are considered emergency procedures as they are often life saving. Disclosures:Hofmann: Fresenius Medical Care: Consultancy. Kiprov:Fresenius Medical Care: Employment.

Oral Azacitidine (AZA) Activity in Patients with Acute Myelogenous Leukemia (AML)

Abstract 1546 Background:When administered subcutaneously (SC), the cytidine nucleoside analog azacitidine (AZA) has been shown to significantly improve overall survival in patients (pts) with low-blast count (20%–30%) AML compared with conventional care regimens (Fenaux, JCO, 2010). An oral AZA formulation would be more convenient for pts, increase access to treatment, allow extended dosing schedules, and may improve efficacy. An initial study of oral AZA administered once daily on a 7-day schedule demonstrated it to be bioavailable, safe, and clinically active in pts with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) (Garcia-Manero, JCO, 2011). Purpose:To present results of a multicenter phase I study of the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and preliminary hematologic response rates in pts with AML receiving varying dose regimens of oral AZA. Methods:Pts aged ≥ 18 years with AML who were not candidates for other therapies (but who may have failed prior treatment) were included. In Part 1, pts received an initial cycle of SC AZA 75 mg/m2 QD x 7 days of a 28-day cycle. Thereafter, oral AZA (120–600 mg QD) was given for 7 days of repeated 28-day cycles. In Part 2, pts received only oral AZA, in 1 of 4 extended dosing schedules: 300 mg QD or 200 mg BID, each for 14 or 21 days of 28-day cycles. Oral AZA was continued until disease progression or withdrawal for other reasons. PK was assessed during the first cycle of oral AZA treatment and DNA methylation was assessed during cycles 1 and 2 of oral AZA (Infinium Methylation27 BeadArray). Pts were monitored continuously for adverse events (AEs) and assessed for treatment response (Cheson, JCO, 2003; Cheson, JCO, 2006) at the end of every second cycle. Results:In all, 23 pts (median age 68 years [range 44–85], 13 male/10 female) with AML (13 de novo, 10 transformed from MDS) have received oral AZA on 7-day QD (n=8), 14-day QD (n=4), 21-day QD (n=4), 14-day BID (n=4), or 21-day BID (n=3) treatment schedules. At baseline, 14 (61%) and 8 (35%) pts were red blood cell (RBC) or platelet transfusion dependent, respectively; 13 pts (57%) had prior AML treatment, primarily intensive chemotherapy. Eight pts had unfavorable and 12 pts had intermediate cytogenetics (data not available, n=3). At baseline, median (range) hematologic measures were WBC = 1.5 K/μL (0.4 − 21.2), ANC = 0.2 K/μL (0 − 3.5), platelets = 34.0 K/μL (6.0 − 102), and % BM blasts = 28.0% (2.0 − 92.0). Median duration of oral AZA (any regimen) was 4 cycles (range 1–14). Seven pts (30%) received ≥ 6 cycles of oral AZA and 16 pts discontinued before completing 6 cycles (Figure). PK results were consistent with recently published data (Garcia-Manero, JCO, 2011). Following a single 300 mg dose (n=8), AUC0-∞ = 230 ± 210 ng*hr/mL, Cmax = 150 ± 114 ng/mL, t1/2 = 0.54 ± 0.21 hr, and median Tmax = 0.8 hr. There was no accumulation following multiple doses. Compared with extrapolated cumulative exposure of SC AZA administered for 7 days per the approved dosing regimen, extrapolated cumulative exposures of oral AZA with extended dosing schedules ranged from 55% for 300 mg QD × 14 days to 104% for 200 mg BID × 21 days. Overall, hematologic improvement (HI) was achieved by 5 pts (22%) (Table). One pt receiving 7-day QD oral AZA achieved a CRi. Responses were seen in 3/13 pts with de novo AML and 3/10 with secondary AML (Figure), and in 2/13 pts with prior AML treatment and 4/10 pts without prior treatment. DNA methylation levels in whole blood were reduced after oral AZA in 4/7 tested pts. The most common AEs (any severity) were gastrointestinal. Most common grade 3–4 AEs were febrile neutropenia (35%), pneumonia and syncope (17% each), nausea (13%), and thrombocytopenia, diarrhea, fatigue, dehydration, headache and mental status changes (9% each). Two pts died due to causes related to AML, and 2 pts discontinued (treatment failure, withdrew consent), within the first 60 days on-study. Conclusions:Oral AZA treatment was well tolerated in this AML population of pts who were not candidates for other therapy. The oral formulation showed biological activity by reducing DNA methylation. Oral AZA also showed clinical activity in these AML pts, many of whom had complex cytogenetics and/or had failed prior therapy before study entry. [Display omitted] [Display omitted] Disclosures:Gore:Celgene Corporation: Consultancy, Equity Ownership, Research Funding. Off Label Use: Oral formulation for Azacitidine in AML patients. Cogle:Celgene Corporation: Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene Corporation: Employment, Equity Ownership. Shi:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Giordano:Celgene Corporation: Employment, Equity Ownership.

Prevalence of venous thromboembolism (VTE) among patients (pts) with acute leukemia (AL) prior to treatment.

6595 Background: Cancer and cancer treatment increases the risk of VTE. However, the association of AL and VTE is unknown. Methods: We performed a retrospective chart review to determine the prevalence of VTE prior to treatment and recurrence of VTE. Medical records of 1295 pts [299 acute lymphoblastic leukemia (ALL) pts and 996 acute myelogenous leukemia (AML) pts] at MD Anderson Cancer Center between November 1999 and May 2005 were reviewed and analyzed. All computations were conducted using Stata version 11. Results: Of the 1295 pts with AL, the overall prevalence of VTE was 1.6% (22 VTE cases, median age: 63.5 yrs). The prevalence was 2.3 % (7/299) and 1.5% (15/996) among ALL and AML patients, respectively. Two of 14 AML pts were M3-AML. In the ALL group, 1 pt had VTE approximately 1 month prior to ALL diagnosis (dx), and 6 pts developed VTE at the time of ALL dx. In the AML group, 3 pts had VTE prior and 12 pts developed VTE at AML dx. Pulmonary embolism occurred in 4 pts [3 had associated lower extremity (LE) deep venous thrombosis (DVT)]. Nine pts (7 AML, 2 ALL) had upper extremity DVTs, and 9 pts (6 AML, 3 ALL) had LE DVTs. Recurrent VTE occurred in 5/22 (23%) pts. In a univariate model, pts with baseline platelet (plt) count ≤ 50 x 109/L or 50-99 x 109/L had a protective effect on VTE development, with 69% and 85% less likely to develop VTE than pts who had plt count 100-349x 109/L, respectively. Pts with prior history of VTE were 17.8 times (95%CI: 6.3-49.27) more likely to develop a VTE than pts without a prior VTE history. Pts with phlebitis were 4.8 times (95%CI: 1.07-21.9) more likely to develop VTE than pts without phlebitis. In a multivariate model, significant predictors of VTE were baseline plt count and prior history of VTE. Overall survival did not differ between pts who developed VTE prior to treatment versus others. Conclusions: Acute leukemia pts have a high prevalence of VTE. Occurrence of VTE prior to initiation of chemotherapy was not associated with poor prognosis. Further studies should be conducted to establish guidelines for the prevention and management of VTE in pts with leukemia.

Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

AbstractAbstract 186Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML TherapyF is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below.Age# < 50Secondary AMLAdverse GeneticsMDS/MPDt-AMLSingleComplexFlt3ARM A (n = 36)59ü(24–78)31956133Total 24/36 = 67%Total 22/36 = 61%ARM B (n = 34)58ü(20–73)51698105Total 25/34 = 74%Total 23/34 = 68%Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures:No relevant conflicts of interest to declare.

Value of Low Dose IL-2 as Maintenance Following Consolidation Treatment or Autologous Transplantation in Acute Myelogenous Leukemia (AML) Patients Aged 15-60 Years Who Reached CR After High Dose (HD-AraC) Vs Standard Dose (SD-AraC) Cytosine Arabinoside During Induction: Results of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups.

Abstract 791The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, were randomized (891 by EORTC-LG and 1114 by GIMEMA) and 104 (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. After 1 or 2 courses of induction, CR was achieved in 1377 patients. Between 4/2000 and 5/2008 550 (230 EORTC, 320 GIMEMA) were randomized for the IL-2 question: 276 in IL-2, 274 Observation (Obs) arm; the remaining patients were not randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The 2 groups were well balanced with respect to the stratification factors, age, sex, WBC counts and history of the disease. Currently, maintenance/observation period has been documented for 144 IL-2 and 144 Obs patients. The patients received a median of 30 s.c. injections (range 3-60) of IL-2. In more than 75% of patients, the mean dose was 6 × 106 IU per injection. Grade 3-4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (4.2% vs 0%), fatigue (9% vs 1.4%), rigor/chills (4.2% vs 0%), arthralgia/myalgia (3.5% vs 0%). A total of 32 patients (22.2%) out of 144 stopped IL-2 prematurely based on patient refusal or medical decision due to toxicity. In the Obs arm, 4 (2.8%) patients out of 144 went off study due to toxicity. Maintenance/observation period has not yet been documented for 132 IL-2 and 130 Obs patients. Among them 28 (21.2%) vs 13 (10%) respectively went off-study due to toxicity of the previous treatment (autoSCT or consolidation), 41 vs 45 due to early relapse, 9 vs 11 due to protocol violation, 9 vs 5 due to other reason. For the total of 550 patients, the median follow-up from the 2nd randomization was 3.6 years. As of July 2009, a total of 269 DFS events were reported: 132 (IL-2 arm) vs 137 (Obs arm); among them 242 relapses (121 vs 121) and 27 deaths without relapses (11 vs 16). The DFS from 2nd randomization was similar in the 2 groups: the 3-yr DFS rate was 44.1% (IL-2) vs 42.0% (Obs), hazard ratio (HR)=0.93 (95% CI 0.74-1.19), p=0.57. A total of 106 patients died in each treatment group. The 3-yr overall survival rate was 54.1% (IL-2) vs 55.9% (Obs), HR=1.01 (95% CI 0.77-1.32), p=0.94. The initial treatment received/randomized did not impact the treatment outcome after the 2nd randomization. This evaluation of the second randomization (IL-2 vs Obs) of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3.6 years, low dose IL-2 maintenance does not lead to a higher DFS and overall survival. Disclosures:Muus:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.