ALBERT

Description: Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after

Description: Background: We have previously shown that the survival of patients with AML who fail to achieve complete remission (CR) with 7+3 has improved since the 1980s. However, although CR rates with 7+3 have improved over the last four decades, we have not previously evaluated how outcomes for patients who achieve a CR1 with 7+3 has changed over time. Here we evaluate if either length of first CR (CR1) after 7+3 or of survival after relapse from CR1 has changed over the last four decades. Patients and Methods:We analyzed 1247 patients randomized to 7+3 arms from 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocols gave 7+3 per existing standard, which changed over time. In S8600, S9031, and S9033 the ara-C and daunorubicin doses were 200mg/m2and 45mg/m2, in S0106 100mg/m2and 60mg/m2, and in S1203 200mg/m2and 90mg/m2. CR was defined morphologically. To account for censoring in the dataset, we used landmark analyses. To evaluate patterns in length of CR1, among patients achieving CR1 and alive at 2 and 3 years, we calculated the proportion of 2 (or 3) years spent in CR1. To evaluate survival after relapse, among patients who achieved CR1 but who relapsed in next 2 (or 3) years we calculated the proportion of patients alive at least 1 year after relapse. To account for changing patient characteristics over time, multivariate linear and logistic regression models were fit. Results:Overall survival has improved dramatically over the last 4 decades (Figure 1). Additionally, among patients who achieved CR1 and were alive 2 years later, the proportion of those 2 years spent in CR1 has significantly improved over the last 4 decades (Figure 2) from a median of 58% to a median of 96% (p

Description: Background: Relapse remains the most common cause of treatment failure after intensive induction and consolidation (CONS) therapy in older adults with AML. We therefore performed a prospective randomized phase II study to determine the safety and impact on DFS (relapse or death) and OS of DAC maintenance using an abbreviated 3-day schedule administered every 4 weeks for 1 year (per Lubbert et al, Haematologica 97:393, 2012) vs. Observation (OBS) after intensive AML therapy, conducted in the large multi-center E-A E2906 Phase III trial in patients (pts) age ≥60 yrs. Methods: The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior OS following 'Standard' 7&3 (Daunorubicin 60mg/m2) induction and intermediate dose Ara-C consolidation (CONS) vs. single agent Clofarabine (CLO, provided by SANOFI), despite similar CR/CRi (CR with incomplete CBC recovery) and induction mortality rates. All CR/CRi pts after induction (n=311) were assigned to 2 cycles CONS with either Ara-C (1.5g/m2 x 12 doses; 6 doses if age 〉/=70 yrs), or single agent CLO, based on induction randomization. Ongoing CR/CRi after recovery from CONS was confirmed with restaging BM biopsy, and eligible pts offered participation in the 'Step 3' maintenance study, a 1:1 randomization (stratified by induction therapy, cytogenetic risk group, age

Description: Older age is a poor prognosis factor in acute myeloid leukemia (AML). This double-blind trial was designed to test the hypothesis that granulocyte colony-stimulating factor (G-CSF) used as supportive care could improve the treatment of elderly AML patients. Two hundred thirty-four patients 55 or more years of age with a morphologic diagnosis of de novo or secondary AML, French-American-British (FAB) M0-M7, excluding M3, were randomly assigned to a standard induction regimen (daunorubicin at 45 mg/m2 intravenously [IV] on days 1 through 3 and Ara-C at 200 mg/m2 IV continuous infusion on days 1 through 7) plus either placebo or G-CSF (400 μg/m2 IV over 30 minutes once daily). Results are reported here for 211 centrally confirmed cases of non-M3 AML. The two groups were well balanced in demographic, clinical, and hematological parameters, with median ages of 68 years in the G-CSF and 67 years in the placebo groups. The complete response (CR) rate was not significantly better in the G-CSF group: 50% in the placebo and 41% in the G-CSF group (one-tailedP = .89). Median overall survival was also similar, 9 months (95% confidence interval [CI], 7 to 10 months) in the placebo and 6 months (95% CI, 3 to 8 months) in the G-CSF arms (P = .71). We found a significant 15% reduction in the time to neutrophil recovery in the G-CSF group (P = .014). G-CSF had no impact on recovery from thrombocytopenia (P = .80) or duration of first hospitalization (P = .27). When infection complications were evaluated, G-CSF had a beneficial effect on the duration but not on incidence of infection. G-CSF patients had fewer days with fever and shorter duration of antibiotic use. However, there was no difference in the frequency of total documented infections or in the number of fatal infections (19% placebo v 20% G-CSF). In this study of elderly AML patients, G-CSF improved clinical parameters of duration of neutropenia and antibiotic use, but did not change CR rate or survival or shorten hospitalization.

Description: Introduction: Glutathione S-transferase (GST) P1-1 binds to and inhibits Jun kinase (JNK), a key regulator of cellular proliferation, differentiation and apoptosis. TLK199, a glutathione analog, binds selectively to GSTP1-1 fostering dissociation from JNK, kinase activation and the promotion of growth and maturation of hematopoietic progenitors in preclinical models, while promoting apoptosis in human leukemia cell lines. The intravenous study with liposomal TLK199 resulted in hematologic improvement (HI) in MDS patients (pts); this trial utilizes an oral formulation of TLK199 in MDS pts. Methods: The objectives of this study were to determine the safety and pharmacokinetics (PK) of TLK199 Tablets given b.i.d. at total daily doses ranging from 200 mg to 6000 mg for the first 7 days of each 3-week cycle. The design was a standard 3 by 3 (3 pts per dose level) dose escalation. Patients were treated until MDS progression or unacceptable toxicity up to a maximum of 8 cycles. Six pts underwent fed-fast PK analysis to determine the effect of food absorption. The PK was evaluated over the dose range for TLK199, and metabolites TLK236, TLK235, and TLK117. Results: 44 MDS pts (32 M/12 F), (9 RA, 11 RARS, 3 RAEB/RAEB-1, 1 RAEB-II, 7 RCMD, 2 RCMD-Rs, 2 CMML, 5 MDS-U, 4 Unknown); IPSS risk-low 14 (32%), INT-1 27 (61%), and INT-2 3 (7%); median age 72 years (range 53–84), received total 206 cycles, median 4.5 (range 1–9) cycles/pt. Ten pts (23%) completed the intended 8 cycles of therapy. Two pts had dose reductions and 4 pts had dose delays (2 due to adverse event (AE) and 2 for scheduling difficulty) at single cycle. Twenty-seven pts (61%) were red cell transfusion (tx) dependent and 5 pts (11%) were platelet tx dependent. Sixteen pts (36%) had abnormal karyotypes. Most common treatment-related AEs were non-hematologic: There were no Grade 3 or 4 toxicities; Grade 2 toxicities were diarrhea and nausea in 2 pts each (5%). Grade 1 toxicities were nausea (43%), diarrhea (25%), vomiting (18%), abdominal pain (7%) and constipation (7%). Three pts (7%) experienced pill-induced dysphagia and reflux esophagitis. Two pts (5%) had Grade 4 neutropenia and 1 pt had febrile neutropenia. There were no DLTs reported. The plasma concentration of the primary active metabolite, TLK236, increases with TLK199 Tablets dose with a mean t1/2 = 2.5 h (range 1.5–4); Cmax = 4.5 uM (range 0.4–6.3). There was no difference seen in the fed vs. fasted patients. By IWG criteria, 15 individual cell line HI responses were observed at the various dose levels of 1000–6000 mg/day with 9 HI responses at dose levels 4000–6000 mg/day. These HI responses were characterized as 1 HI-E major and 4 HI-E minor, 1 HI-N major and 2 HI - N minor, 1 HI-P major and 6 HI-P minor. One bilineage response was reported at 5000 mg/day and 2 trilineage responses at 6000 mg/day. These responses were accompanied by clinical symptoms improvement. Conclusions: TLK199 Tablets are well tolerated and HI responses in all three cell lines were observed with oral TLK199 short-course schedule. These data support the Phase 2 development of extended schedules of oral TLK199 in MDS.

Description: Recruitment of histone deacetylases and DNA hypermethylation of promoter regions of specific genes are two mechanisms of transcriptional repression and gene silencing which have been linked, and are implicated in differentiation block in AML. We hypothesized that the histone deacetylase inhibitor (HDI) depsipeptide could result in transcriptional de-repression, upregulation of specific target genes and differentiation of the leukemic clone in AML. Eighteen patients (pts), median age 60 years (range 25–77) with relapsed or refractory AML were enrolled on a multicenter Phase II study of depsipeptide in AML. Patients were stratified into 2 groups on study entry: Group A (n=14) included patients without specific chromosomal abnormalities known to recruit histone deacetylases. Group B (n=4) included patients with chromosomal aberrations such as the t(8;21), inv 16 and t(15;17) known to recruit histone deacetylases. Depsipeptide was administered intravenously at a dose of 18mg/m2/d on days 1, 8 and 15 of a 28 day cycle. Peripheral blood mononuclear cells were obtained prior to (hour 0), and after 4 (hr 4) and 24 hrs (hr 24), on days 1 and 8 of the first cycle of therapy for evaluation of histone acetylation by flow cytometry, and gene re-expression by REAL-time RT-PCR. Target genes of interest include MDR1, a target of HDI mediated upregulation, and p15INK4B (p15), a target of DNA hypermethylation in AML. MDR1 and p15 copy numbers are expressed as a normalized quotient of MDR1 and p15, respectively, to the housekeeping gene ABL. The drug has been well tolerated. The most common adverse effects noted included grade 1/2 nausea, vomiting and fatigue. No objective evidence of response (CR or PR) or other evidence of antileukemic activity has been seen in group A. In contrast, 2 of 4 pts (50%) in Group B, have had a disappearance of bone marrow blasts (blast percentage 〈 5%) in the setting of a normocellular marrow, with concomitant recovery of near-normal hematopoiesis following 1 and 2 cycles of therapy respectively. This anti-leukemic effect was short-lived, with both pts developing an increase in bone marrow blasts within 30 days of the initial response. Both of these patients also had translocations involving the AML1 gene {1 had t(8;21) and the other had a novel translocation t(4;21)}. Interestingly both of these responding pts and one other pt (75%) in cohort B demonstrated an increase in H3 acetylation at 4 and/or 24 hrs, in contrast to 4 of 14 pts (28%) in cohort A. There was an overall mean increase of 41% in MDR1 expression at hr 4 on days 1 and 8 (p=0.04). p15 expression was also upregulated at hr 4 on days 1 and 8 (91% mean increase, p=0.01). We conclude that the HDI, depsipeptide, may have anti-leukemic activity in specific cytogenetic subsets of AML known to recruit histone deacetylases, and this is associated with a concomitant increase in histone acetylation. In addition, upregulation of specific target genes occurred in patient derived mononuclear cells, following depsipeptide treatment. The study remains open to accrual for pts with specific chromosomal abnormalities known to recruit histone deacetylases.

Description: DNA hypermethylation of promoter-specific CpG islands is a well known mechanism of epigenetic silencing, and has been implicated in the pathogenesis and progression of disease in MMM. We are evaluating 5-aza-2′deoxycytidine (Decitabine), a potent DNA methyltransferase inhibitor in a Phase II trial in patients (pts) with MMM. Decitabine was administered subcutaneously at a dose of 0.3mg/kg/d on days 1–5, and days 8–12 and cycles were repeated every 6 weeks, in the absence of dose limiting toxicities. Response was determined every 12 weeks, and defined as an improvement in cytopenias and/or splenomegaly. Pts who had no response after 2 cycles were eligible for dose escalation to 0.4mg/kg/d. Elevated levels of circulating CD34+ cells are associated with advanced stage and evolution to the blast phase of the disease in MMM. Therefore, CD34+ cells were measured in peripheral blood at baseline, and at days 1, 5 and 12 of the first 2 cycles of therapy as a surrogate marker of disease activity. Seven pts (5 males, 2 females) have been enrolled, median age 71 (range 42–89), median baseline absolute CD34+ cell count 27× 106/L (11–4959), Dupriez score of 2, 1 and 0 in 72%, 14% and 14% respectively. Median number of cycles administered was 4 (range 1–7). Median WBC and platelet (plt) count at baseline were 3.6K/uL (range 1.5–29), and 188K/uL (range 62–446K/uL) and 3 pts were red cell transfusion dependent. Grade 4 neutropenia (ANC) occurred in all pts, and grade3/4 thrombocytopenia in 5 pts. Nadir ANC and plts occurred at a median of 31 days (range 24–44) and 23 days (range 17–31) respectively. Recovery to ANC 〉0.5K/uL and plts 〉50K/uL occurred at a median of 43 (range 35–58) and 26 days (23–36) respectively. Two pts required a dose reduction for prolonged myelosuppression, and in 1 pt the dose was escalated to 0.4mg/kg/d for lack of a response after 2 cycles. Two pts have developed febrile neutropenia; one of these pts had a documented infection. Grade 3–4 non-hematologic toxicities were rare and include a variceal bleed in a patient with baseline portal hypertension, occurring in the setting of a platelet count of 486K/uL. There have been no injection site reactions. Five pts are evaluable for response. Of these, two pts have had a response including 1 pt with a CR (normalization of blood counts including transfusion independence). One pt in the blast phase of the disease has had a hematological improvement as evidenced by a normalization in platelet counts (from 62K/uL to 200K/uL) associated with a significant decrease (from 2.58K/uL to 0.03K/uL) in peripheral circulating blasts. The other 3 pts have had stable disease; 2 of these remain on treatment and have received 4 and 7 cycles of treatment, respectively. A trend towards a decrease in spleen size has been observed in 3 of 4 patients with palpable splenomegaly at baseline. Overall, there was a significant reduction in circulating CD34+ levels, with a mean decrease of approximately 70% at day 12 of cycles 1 and 2 (p=0.01) We conclude that low dose decitabine administered subcutaneously is feasible in MMM and is associated with minimal non-hematologic toxicity. Myelosupression is significant, though reversible and requires close monitoring. To our knowledge this is the first report demonstrating the potential clinical activity of decitabine in MMM. This observation requires confirmation in a larger group of patients, and accrual is ongoing to this multi-center Phase II study.

Description: Background: Induction therapy with daunorubicin (Dauno) & cytarabine (Ara-C) [DA] has been the standard of care for eligible older adults (age ≥ 60 years) with newly diagnosed acute myeloid leukemia (AML) for over 2 decades. Single agent Clofarabine (CLO) induction & consolidation (Consol.) therapy has demonstrated important clinical activity in this age group in large phase II studies. Lower induction mortality (IM) & similar reported complete remission rate (CR) & overall survival (OS), as well as notable activity in those with higher risk disease features [including unfavorable cytogenetics, therapy-related AML (t-AML) & prior antecedent hematologic disorder (AHD)] raises the possibility that a non-Ara-C-based regimen could achieve similar or superior OS with lower toxicity. Methods: We performed a randomized United States Intergroup Phase III trial of single agent CLO [30mg/m2 x 5 days induction; 20 mg/m2 re-induction (if indicated) & 2 cycles Consol.] vs. standard DA therapy [Dauno 60mg/m2 D1-3 & Ara-C 100mg/m2 D1-7 induction x 1-2 cycles; 2 cycles Consol. with Ara-C (1.5g/m2 Q12hrs D1-6 age 60-69; once daily if age 70+)] in patients (pts) age ≥ 60 yrs with newly diagnosed AML. Patients with serum creatinine 〉1.0 (or GFR 3 (PS〉2 if age 70+ yrs) were excluded. Randomization was stratified by age (60-69 vs. 70+), t-AML, & AHD. Pts with HLA-matched donor were eligible for allogeneic transplantation (AlloHCT) after induction, and those completing Consol. were eligible for randomization #2 (R#2) to maintenance decitabine [20mg/m2 x 3D, monthly x 1 year] versus observation. With a target accrual of 747, E2906 was powered to determine non-inferiority [and possible superiority] of CLO vs. standard DA, and primary endpoint was OS. A weighted statistical analysis was performed to account for confounding impact of R#2. AlloHCT patients were censored at transplant in this analysis. Responses & cytogenetics were confirmed centrally and OS & CR rates were monitored by an independent Data Safety Monitoring Committee (DSMC) at pre-specified time points. Results: As of Feb 23, 2015, 727 pts were randomized. Median age was 68 years (range 60-86); 57% were male, and 38% were age ≥70 yrs. Treatment arms are well balanced for all baselineclinical & AML characteristics, & 30% had unfavorable cytogenetics. Of 659 with complete treatment information reported, 30.4% on DA vs. 40.1% on CLO received 2 cycles of induction (p=0.006). Median follow-up of surviving patients is 7.6 months. Table 1. shows early treatment results (CR, toxicity) for the 686 pts randomized as of Dec 23, 2014 (2 months prior to study end, & excluding 90 with ongoing response evaluation). DA CLO p-value CR/CRi 43.8% 42.8% p=0.87 30-day mortality 8.5% 7.9% p=0.89 60-day mortality 14.9% 13.1% p=0.58 Gr 4-5 Non-Heme Tox.Induction 27% 19% p=0.02 Gr 4-5 Non-Heme Tox.Consol. 20% 7% p=0.001 374 pts have died (174, DA; 200, CLO) & significantly inferior OS was observed for CLO vs. DA [Hazard Ratio (HR) 1.41 (95% CI 1.12-1.78)] (Fig. 1). Planned subgroup analyses were performed (Table 2) demonstrating significant differences in OS after CLO for patients age 60-69 yrs, without AHD, & with intermediate risk cytogenetics; but not for those with Unfav. Cytogen. (Fig. 2) or t-AML. Based on the primary weighted analysis, DSMC recommended suspension of new accrual to E2906 on Feb 23, 2015 & all active patients on CLO were transitioned to DA Arm. Table 2.NHR CLO/Standard (95% CI)*Weighted OS7271.41 (1.12-1.78)Unweighted OS7271.23 (1.00-1.50)Age 60-694491.48 (1.10-1.99)Age 70+2781.34 (0.93-1.93)Intermed. Risk Cytogen.3781.77 (1.27-2.47)Unfav. Risk Cytogen.2160.96 (0.65-1.43)No AHD6041.46 (1.13-1.89)AHD1231.22 (0.74-2.00)De novo AML6271.52 (1.18-1.96)Therapy-related AML1000.94 (0.54-1.61) Conclusions: Despite similar CR & IM, OS after single agent CLO is inferior to standard DA therapy for pts age ≥60 years with newly diagnosed AML who are fit for intensive therapy, and DA remains the standard of care. However no difference in OS was observed after CLO in some pre-specified high risk AML subgroups. R#2 & AlloHCT arms continue in E2906 for pts already enrolled. Embedded prospective minimal residual disease study at CR is being performed to identify pts at higher risk after CLO & DA. Figure 1. Weighted Kaplan-Meier Curves for OS Figure 1. Weighted Kaplan-Meier Curves for OS Figure 2. Unfavorable Cytogenetics OS by Therapy Figure 2. Unfavorable Cytogenetics OS by Therapy Disclosures Off Label Use: Use of clofarabine in AML, and maintenance therapy with decitabine in AML. Claxton:Medimmune: Research Funding; BMS: Consultancy; Astellas: Research Funding; Cyclacel: Research Funding; Merck: Research Funding; Ambit: Research Funding. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Altman:Seattle Genetics: Consultancy; BMS: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Al-Kali:Novartis: Research Funding.

Description: Abstract 2737 Synonymous SNPs may directly impact gene function through various translational or post-translational mechanisms. Further, such “silent” SNPs in the mutational hotspots of AML-associated genes have recently been reported to carry prognostic impact. We aimed to determine the prevalence, clinical associations, and prognostic significance of a known SNP in exon 4 of IDH1, near the location of the frequently-mutated R132 codon. Diagnostic marrow specimens from 253 pediatric AML patients (treated on the COG trial AAML03P1) and 274 adult AML patients (treated on SWOG trials S9031, S9333, or S9500) were analyzed for the presence of SNP rs11554137 via direct sequencing. In the pediatric cohort (median age 9.8 years), SNP rs11554137 was present in 27 of 253 (10.7%) patients. SNP+ pediatric patients did not differ significantly from wild-type patients in terms of sex, racial distribution (African American patients accounted for 23% of SNP+ patients vs. 14% of wild-type patients, P=0.24), bone marrow blast percentage, or age distribution, except in patients aged 0–2 years, who accounted for 44% of SNP+ patients vs. 23% of wild- type patients (P=0.013). Recurrent cytogenetic abnormalities occurred with similar frequencies in both the SNP+ and wild-type pediatric populations, as did FLT3/ITD, NPMc, and CEBPA mutations. Miscellaneous cytogenetic abnormalities accounted for 33% of SNP+ patients vs. 14% of wild-type patients, P=0.033. IDH1 SNP status had no prognostic impact on survival in the pediatric cohort, as SNP+ and wild-type patients had similar rates of five-year overall survival (OS, 76% vs. 63%, P=0.50), disease-free survival (DFS, 48% vs. 53%, P=0.97), and relapse rate (RR, 39% vs. 39%, P=0.94). In the adult cohort (median age 63 years), the IDH1 SNP was present in 30 of 274 (10.9%) patients. A slight female predominance for the SNP (63% vs. 37%, P=0.052) occurred among adult patients. The SNP was more prevalent in African American patients, who accounted for 30% of the SNP+ patients vs. 7% of wild-type patients, P=0.0046. SNP+ patients also had somewhat higher diagnostic bone marrow blast percentages (medians 80% vs. 70%, P=0.025). The normal karyotype subset accounted for similar proportions of SNP+ vs. wild-type patients (42% vs. 46%, P=0.83). Notably, SNP rs11554137 was not present in adult core-binding factor AML. Miscellaneous cytogenetic abnormalities were significantly more common in SNP+ patients (46% vs. 22%, P=0.022). SNP status was not significantly associated with FLT3/ITD status when all adult patients were considered (P=0.14). However, within the normal karyotype subset, FLT3/ITD was present in 90% of SNP+ patients vs. 59% of wild-type patients (P=0.0053). SNP+ patients had somewhat poorer 5 year OS (10% vs. 18%, hazard ratio [HR]=1.17) though this difference was not statistically significant (P=0.44). Among the 142 patients who achieved complete remission (CR), however, 5-year relapse-free survival (RFS) was significantly worse for SNP+ patients (0% vs. 25%, HR = 2.89, P=0.0014). Of the 14 SNP+ patients who achieved CR, 13 relapsed and the 14th patient died of sepsis in remission after 61 days. In multivariate analysis, after adjusting for the effects of age and cytogenetic group, SNP rs11554137 retained an independent prognostic effect (P=0.0062) regarding RFS. Notably, when FLT3/ITD status is included in multivariate analysis, SNP positivity loses independent prognostic significance (HR=1.72, P=0.18). Genome-wide expression profiling was performed on 134 pediatric AML specimens in whom IDH1 SNP status was known. By comparing SNP+ patients with wild-type patients, we derived a distinct gene-expression signature for patients with SNP rs11554137. Among the most upregulated probe sets in the SNP+ cohort were those representing PEX6 and NFYA, both of which interact with the TGF-beta/SMAD signaling network; the retinoid × receptor beta gene RXRB; and the FER gene, a tyrosine kinase critical to FLT3 signaling. The IDH1 SNP rs11554137 is present in approximately 11% of pediatric and adult AML patients, and gene expression profiling data suggests that leukemia in SNP+ patients may have unique biologic features. The SNP was an independent predictor of decreased RFS in adult AML in univariate analysis, but not in multivariate analysis when adjusting for FLT3/ITD status. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2590 Background FLT3-internal tandem duplication (ITD) is found in about 30% of patients with acute myeloid leukemia (AML) at diagnosis and confers a high risk of relapse. Thus allogeneic hematopoietic transplant (HCT) is recommended for these patients in first complete remission (CR) and after HCT they become candidates for trials of FLT3-ITD inhibitors (such as quizartinib) to prevent relapse. However at referral to tertiary centers after reaching CR, FLT3-ITD status at diagnosis is often unknown, complicating decisions about HCT. FLT3-ITDs are known to be associated with a normal karyotype (NK), translocation 6;9 and a high white blood cell (WBC) count, and we hypothesized that assessment of likely FLT3-ITD status at diagnosis in patients presenting in CR not tested at diagnosis would be improved by examining these covariates simultaneously. Methods Our initial analysis included 434 adult patients with newly diagnosed AML (excluding APL) treated on three SWOG trials (S9031, S9333, and S0106) in whom FLT3-ITD status (positive/negative) was established at diagnosis. Univariate and then multivariate analyses were used to identify covariates independently associated with FLT3-ITD positivity. The relative abilities of these to predict FLT3-ITD positivity were quantified using the area under the receiver operator characteristic curve (AUC); an AUC of 1.0 denotes perfect prediction, whereas an AUC of 0.5 is analogous to a coin flip. The log odds ratios (ORs) from the multivariate models were used to assign a score to each covariate and scores were summed; such that the higher the score, the greater is the likelihood of the FLT3-ITD positivity at diagnosis. We tested the performance of the scoring system in 2 newly-diagnosed populations that had not contributed to the system's development and in whom FLT3-ITD status at diagnosis was known: (a) 210 patients treated at FHCRC (Fred Hutchinson Cancer Research Center) and (b) 1,401 patients treated at MDACC (M.D. Anderson Cancer Center). Covariates examined were: age, sex, performance status (PS), WBC count, platelet count, bone marrow blast percentage, secondary AML, and cytogenetic risk (using SWOG/Eastern Cooperative Oncology Group criteria). Results FLT3- ITD was present in 101 of the 434 SWOG patients (23%) in the scoring system development population. The log OR were rounded to the nearest half point to create the scoring system. Only WBC 〉 20,000 (reference, WBC 〈 20,000) and cytogenetics (reference, normal) had non-zero scores, which are summarized below: Scores less than −0.5 were called low, ≥−0.5 and