Newly-diagnosed Acute Myeloid Leukemia Research Articles

A Randomised Comparison of the Sequential Addition of the FLT3 Inhibitor Lestaurtinib (CEP701) to Standard First Line Chemotherapy for FLT3-Mutated Acute Myeloid Leukemia: The UK Experience

Activating mutations of the receptor tyrosine kinase FLT3 are seen at diagnosis in one-third of younger adults with acute myeloid leukemia (AML) and are associated with an increased risk of relapse. FLT3 remains the subject of intense clinical interest as a therapeutic target. To date FLT3-targeted monotherapy has produced only transient clinical responses with no prospective trial producing an overall survival benefit. Here we report the results of the first randomised trial of a FLT3 inhibitor (Lestaurtinib, CEP701) given sequentially to chemotherapy as first line treatment for newly-diagnosed AML. FLT3-mutated patients entering the UK MRC AML15 and UK NCRI AML17 trials between January 2007 and October 2012 were randomised to receive either oral Lestaurtinib 80mg bid, or placebo, for up to 28 days after each of 4 courses of chemotherapy. Based on early pharmacokinetic data provision was made for dose reduction to 40mg bid for patients on concomitant azole anti-fungal drugs.500 patients were randomised (175 AML15, 325 AML17). Median age was 49yrs (5-68, only 5 were <16yrs.). 94% patients had de novo AML, 5% secondary AML and 1% high risk MDS. The majority of patients (89%) had cytogenetically intermediate risk disease with 6% favourable and 5% adverse risk. Median presenting WBC was 28.0x109/l (0.2-363); 381 patients (74%) had FLT3-ITD mutations, 127 (23%) FLT3-TKD point mutations and 12 (2%) both types; 207 patients (41%) had concomitant mutated NPM1. All characteristics were balanced between the arms.Results: No difference in remission rate was seen between the arms (CR/CRi: Lestaurtinib 92% vs Control 94%. OR 1.37 [0.68-2.78] p=0.4). The respective 5-year RFS was 40% vs 37%, HR 0.87 (0.68-1.12) p=0.3; cumulative incidence of relapse 52% vs 54%, HR 0.87 (0.67-1.13) p=0.3 and OS at 5 years 46% vs 43%, HR 0.89 (0.68-1.13) p=0.3 did not differ between arms. [Display omitted] 43% of patients were transplanted in both Lestaurtinib and control arms (130/300 and 85/200 respectively); 133 transplants were in CR1, 63 in CR2; 188 were allografts. When the data were censored at SCT the lack of difference in clinical outcome persisted (HR 0.97 [0.71-1.33] p=0.8).Stratified analyses involving age, sex, diagnosis (de novo/secondary/MDS), cytogenetic group, performance status, ITD vs TKD, ITD allelic %, NPM1 status, Gemtuzumab ozogamicin (GO) or not in induction and concomitant use of azoles were undertaken to identify evidence of subgroup benefit with Lestaurtinib. No significant interactions were seen, with some evidence of survival benefit in patients receiving GO (p=0.09 for interaction). In patients receiving concomitant azole treatment there was a significant survival benefit with Lestaurtinib (HR 0.57 (0.36-0.92) p=0.02) although the test for interaction was not significant (p=0.2). Course 1 day 14 plasma trough Lestaurtinib levels were significantly higher in azole-treated patients than in those not receiving azoles (median 4517 vs 3085ng/ml, p=0.03). In AML17 patients treated with GO and azoles, survival with Lestaurtinib at 4 years was 61% compared to 28% in the control arm (p=0.02)Minimal difference in toxicity was seen between the 2 arms, with the exception of slight excess nausea/diarrhea with Lestaurtinib in course 2. Supportive care requirements were slightly increased with Lestaurtinib with a borderline-significant 1-day increase in median time to platelet recovery following course 2 (p=0.05).Conclusion: Lestaurtinib may be safely combined with intensive chemotherapy in younger patients with newly-diagnosed FLT3-mutated AML. No overall clinical improvement was seen with Lestaurtinib, although there was a suggestion of benefit in patients also receiving GO in induction: in Lestaurtinib-treated patients receiving both GO and azoles, survival was 61%. The potential clinical benefit of GO with adequate FLT3 inhibition requires prospective validation.(We are grateful to Cephalon for the provision of Lestaurtinib for this study) DisclosuresKnapper:Cephalon: Consultancy, Research Funding. Off Label Use: Tyrosine kinase inhibitor Lestaurtinib (CEP701) used off-label in a randomised controlled trial in FLT3-mutated acute myeloid leukemia.

Primacy of resistance rather than toxicity in determining outcome of therapy for AML.

Less intense therapies are currently attracting much interest in the treatment of newly-diagnosed acute myeloid leukemia (AML). Although "less intense" often goes undefined, I understand it to mean a therapy that very likely causes less treatment-related mortality than does the standard remission induction regimen of 3 days of either daunorubicin or idarubicin and 7 days of ara-C, referred to as "3+ 7." The primary appeal of less intense therapy is the potential for less toxicity. However, in this article I will make the point that for most patients, including many in their 70s if not 80s, the fundamental obstacle to curing AML is lack of efficacy not excess toxicity.

Tumor suppressor DYRK1A effects on proliferation and chemoresistance of AML cells by downregulating c-Myc.

Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults. We reported here DYRK1A expression level was reduced in the bone marrow of adult AML patients, comparing to normal controls. Overexpression of DYRK1A inhibited the proliferation of AML cell lines by increasing the proportion of cells undergoing G0/G1 phase. We reasoned that the proliferative inhibition was due to downregulation of c-Myc by DYRK1A, through mediating its degradation. Moreover, overexpression of c-Myc markedly reversed AML cell growth inhibition induced by DYRK1A. DYRK1A also had significantly lower expression in relapsed/refractory AML patients, comparing to newly-diagnosed AML patients, which indicated the role of DYRK1A in chemoresistance of AML. Our study provided functional evidences for DYRK1A as a potential tumor suppressor in AML.

Elevated Th22 Cells Correlated with Th17 Cells in Peripheral Blood of Patients with Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a hematological tumor in which progress T helper (Th) subsets including Th22, Th17, and Th1 cells play a pivotal role. However, the role of T helper (Th) subsets in the immune pathogenesis of AML remains unclear. Here, we investigated frequencies of Th22, Th17, pure Th17, and Th1 cells in the peripheral blood (PB) of AML patients. We demonstrated that Th22, Th17, and pure Th17 in newly-diagnosed (ND) and non-complete remission (Non-CR) AML patients and plasma IL-22 in ND AML patients were significantly increased. Retinoid-related orphan receptor C (RORC) expression was significantly elevated in CR and Non-CR AML patients. However, Th1 in ND AML patients and IL-17 in ND, Non-CR or CR AML patients was significantly decreased compared with controls. Moreover, Th22 and IL-22 showed positive correlation with pure Th17, but Th22 showed negative correlation with Th1 in ND AML patients. RORC showed positive correlation with Th22 and approximately positive correlation with pure Th17 in Non-CR patients. PB blast cell showed positive correlation with Th22 and negative correlation with Th1 in ND AML patients. Our results indicate that Th22 and pure Th17 cells conjointly contribute to the pathogenesis of AML and might be promising novel clinical index for AML.

Imprinted Non-Coding RNA Genes, H19 and ZNF215, Are Potential Markers For Two-Year Survival For Acute Myeloid Leukemia Patients With Normal and Abnormal Karyotypes

Studies in large-scale genome sequencing have shown that only 2% of the mammalian genome encodes mRNAs, but the most part is transcribed as long and short non-coding RNAs (ncRNAs). The ncRNAs with gene regulatory functions are starting to be seen as a common feature of mammalian gene regulation. Genomic imprinting is a form of epigenetic regulation and imprinted genes are silenced in a parental-specific manner. Although the exact mechanism how imprinted ncRNA regulates gene expression remains largely unknown, it is general accepted that imprinted ncRNAs binds to chromatin modifying complexes, such as PRC2, TRX, and G9a, and generates specific silencing of genomic loci both in cis and trans. Imprinting is associated with many human diseases or syndromes (e.g. Prader-Willi, Angelman, Beckwith-Wiedemann, Retts, and Silver-Russell syndromes) and various cancers (e.g. breast, prostate, and colorectal cancers), but its role in leukemogenesis remain elusive. In this present study, the expression of a panel of 24 human imprinted ncRNA genes (AMPD3, C15orf2, COPG2, CPA4, GABRB3, H19, IGF2, IMPACT, INPP5F, L3MBTL, NR3251, NR3252, PEG3-AS, PPP1R9A, PRIM2, RASGRF1, RTL1, SFMBT2, SLC22A3, SNURF, TCEB3C, TSPAN32, ZNF215, ZNF264) and a panel of 66 human histone modifying enzymes (HME) genes was investigated in 68 newly-diagnosed acute myeloid leukemia patients with chromosome normal (AML-CN), 115 AML patients with chromosome abnormal (AML-CA), and 85 healthy individuals using real-time quantitative RT-PCR. Altered expression of 9 imprinted ncRNA genes (C15orf2, COPG2, H19, IGF2, IMPACT, PEG3-AS, PRIM2, SLC22A3, ZNF215) and 16 HME genes were observed. In AML-CN, patients' survival days are correlated with the expression levels of H19 (p < 0.01), IMPACT (p < 0.05), DNMT3L (p < 0.05) and AURORA (p < 0.01). In AML-CA, patients' survival days are correlated with the expression levels of PGE3-AS (p < 0.01), PRIM2 (p < 0.01), SLC22A3 (p < 0.05), and ZNF215 (p < 0.01). Multiple linear regression analysis further revealed the expression level of H19 and ZNF215 can be used as predictors for 2-year survival for AML-CN patients (p = 0.002) and AML-CA patients (p = 0.040), respectively. Cox proportional hazard model was used to analyze the hazard ratio (HR) for H19 (HR=0.868, 95.0% Confident Interval: 0.797-0.945, p = 0.001) and ZNF215 (HR=0.904, 95.0% Confident Interval: 0.821-0.995, p =0.040). In addition to survival, analysis has also been performed to correlate patients' clinical parameters and expression levels of these altered genes and to correlate the expression levels between imprinted ncRNA genes and HME genes (results will be presented at the meeting). From our preliminary results, it is reasonable to hypothesize that loss imprinting of imprinted ncRNA is critical for the leukemogenesis of AML and under CN or CA conditions different ncRNAs are activated and affect different imprinted gene expression and thus leading to different clinical outcomes. Based on our findings, we will further perform in vitro functional analysis to elucidate the functions and mechanisms of these imprinted ncRNAs in AML tumorigenesis. Updated results of these analyzes will be presented at the meeting. Disclosures:No relevant conflicts of interest to declare.

Improving Survival in Acute Myeloid Leukemia: Pick the Best Subjects?

Improving Survival in Acute Myeloid Leukemia: Pick the Best Subjects?

Probability of Eventual CR After Course 1 of Induction Therapy for Newly-Diagnosed AML As a Function of Platelet and Neutrophil Recovery.

AbstractAbstract 2598 Background:After initial induction chemotherapy for acute myeloid leukemia (AML), it is commonplace that reinduction or intensified therapy is not indicated if the bone marrow has <5% blasts, even despite persistently low neutrophil (ANC) and/or platelet counts. This practice suggests that complete remission (CR), i.e. ANC >1000/μl and platelet count >100,000/μl per standard criteria (Cheson BD, et al. J Clin Oncol. 1990;8(5):813-9), might still occur and that the lack of blood count recovery may not bear prognostic significance. However, the time to CR after the first induction has been shown to be inversely related to subsequent duration of disease-free survival (DFS) and survival (OS), independent of age, treatment, and cytogenetics (Estey EH, et al. Blood. 2000;95(1):72-7). Additionally, the level of ANC and platelet recovery at time of CR is prognostic, with significantly better DFS among patients with higher counts (Yanada M, et al. Leuk Res. 2008;32(10):1505-9). Newly-diagnosed AML patients often present with below normal neutrophil and platelet counts, suggesting that persistence of such cytopenias after induction may be a clinical indicator of minimal residual disease (MRD) in the marrow. We therefore examined whether blood count recovery affected the probability of subsequent CR in patients with <5% bone marrow blasts. Methods:We included 85 patients who, by day 21 or thereafter of induction therapy for newly-diagnosed AML, had not met blood count criteria for CR despite a bone marrow in the prior week with <5% blasts by morphology. Patients were classified by type of induction therapy based on cytarabine dosing. G-CSF was not systematically administered. Marrows were planned for day 21 after chemotherapy and/or weekly thereafter to assess for disease status and evidence of marrow recovery. Because patients were often managed as outpatients, counts and marrows were not uniformly available and thus “day 28” included days 21–28, “day 35” included days 29–35, etc. If a patient had more than one marrow evaluation after day 21, we included only the first one. Results:Overall cohort CR rate was 64%. Eventual CR rate was significantly affected by platelet count, with 44% eventual CR for patients with platelets <30,000, 66% CR for platelets 30,000–100,000, and 95% CR for platelets >100,000. The effect of ANC recovery on eventual CR was less dramatic, with an OR 0.4 (0.2–1.0, p=0.049), for ANC <0.1 vs. >0.1 in the univariate analysis. By day 28, patients with either ANC or platelet recovery were significantly more likely to obtain CR than patients with neither count recovery (89% vs. 51%), OR 8.05 (2.2–30, p=0.002). In the multivariate analysis, (a) lack of platelet recovery to >30,000 was associated with significantly lower incidence of CR, OR 0.26 (0.1–0.8, p=0.02), and was independent of cytogenetic risk, antecedent hematologic disorder, and induction regimen, and (b) there was a suggested association between earlier count recovery and CR (>28 days vs. day 21–28), OR 0.31 (0.1–1.0, p=0.051). Conclusion:Persistence of low peripheral blood counts, despite the presence of <5% bone marrow blasts, is predictive of low eventual CR rates after induction chemotherapy. These results suggest that initiation of further and possibly different therapy, rather than continued observation, should be investigated in this setting.DemographicNo.No. CR, %Patients, No.8554 (64%)Median age, years54 (range 20-81)CytogeneticsInv16 or t(8;21)87 (88%)Intermediate4425 (57%)Monosomal karyotype1710 (59%)Other unfavorable1612 (75%)Type of AMLDe novo AML4431 (70%)Secondary AML4123 (56%)Induction RegimenLow-dose cytarabine40Standard-dose cytarabine5637 (66%)High-dose cytarabine1813 (72%)Treatment without cytarabine74 (57%)Day of marrow <5% blastsPlatelets <30, CR(%)Platelets 30-100, CR(%)Platelets >100, CR(%)ANC <0.1, CR(%)ANC 0.1-0.5, CR(%)ANC 0.5-1.0, CR(%)ANC >1.0, CR(%)Total Patients, CR(%)21-2815,7 (47%)12,9 (75%)15,15 (100%)18,10 (56%)14,13 (93%)3,2 (67%)7,6 (86%)42,31 (74%)29-3514,6 (43%)12,5 (42%)4,3 (75%)17,8 (47%)8,3 (38%)1,0 (0%)4,3 (75%)30,14 (47%)36-424,1 (25%)5,5 (100%)03,2 (67%)3,3 (100%)03,1 (33%)9,6 (67%)>423,2 (67%)01,1 (100%)2,1 (50%)1,1 (100%)1,1 (100%)04,3 (75%)Totals36,16 (44%)29,19 (66%)20,19 (95%)40,21 (53%)26,20 (77%)5,3 (60%)14,10 (71%)85,54 (64%) Disclosures:Becker:Sanofi: Research Funding.

Outcomes and Prognostic Factors for Patients with Acute Myeloid Leukemia Admitted to the Intensive Care Unit

AbstractAbstract 3613 AimPatients with acute myeloid leukemia (AML) receiving intensive chemotherapy commonly experience life-threatening complications requiring intensive care unit (ICU) support. Limited information is available regarding which patients are likely to benefit from an ICU admission and their subsequent outcomes. The present study has considered a more homogenous patient population than the majority of previous reports of ICU outcomes in AML, as patients were only included if they were within an induction or consolidation chemotherapy cycle for recently-diagnosed AML. MethodsThis is a retrospective study of 505 consecutive adult patients with newly-diagnosed AML who were treated at the Royal Brisbane or Princess Alexandra Hospitals with intensive chemotherapy between 1st January 1999 and 31st December 2010. Hematology and ICU databases were cross-referenced to identify patients admitted to ICU in the setting of intensive induction or consolidation chemotherapy attempting to achieve or maintain complete remission 1 (CR1). Statistical analyses were undertaken to identify risk factors for ICU admission, short- and long-term outcomes, and prognostic factors predicting survival following ICU admission. ResultsEighty-three patients (16.4%) were identified who had required a total of 92 ICU admissions, complicating 9.4% of induction and 6.7% of consolidation chemotherapy cycles. The median age of patients admitted to ICU was 53 years. Neutropenia was present in 70.7% of patients on admission to ICU, with a median duration of 13 days. The primary indication for ICU admission was hemodynamic instability in 46.7% of patients and respiratory impairment in 40.2% of patients; the underlying pathology was most commonly infection (75.0%). Vasopressors were required in 67.4% of admissions, mechanical ventilation in 58.7%, and hemodialysis in 15.2%. Median APACHE III score was 89 and SOFA score was 11.There were no baseline characteristics found to be associated with an increased likelihood of ICU admission during chemotherapy. Survival to ICU discharge, hospital discharge, 6 months, and 12 months were 67.4%, 60.9%, 48.9%, and 38.6%, respectively. Patients admitted to ICU had worse overall survival than patients not requiring ICU admission (median OS = 0.7 years vs 3.5 years, 5 year OS = 24.3% vs 46.0%, respectively; P < 0.0001) (Figure 1). The increased mortality was predominantly the result of early deaths, as ICU patients surviving to hospital discharge had a similar long-term survival to other patients who survived chemotherapy (median OS = 6.7 years vs 4.1 years, 5 year OS 38.0% vs 47.8%; P = 0.83) (Figure 2). Leukemia-free survival from the time of CR1 was not significantly different between groups (P = 0.054). Multivariate analysis identified independent prognostic factors predicting mortality prior to hospital discharge to be mechanical ventilation use and higher fibrinogen, and mortality at 12 months to be associated with mechanical ventilation use and AML cytogenetic risk group. Notably, survival in patients admitted to ICU was not significantly influenced by the AML status (active disease vs CR1), whether the patient was receiving an induction or consolidation cycle, or the dose of cytarabine used. ConclusionsAdmission to ICU is associated with an increased mortality rate compared to those patients not requiring ICU admission. However, a substantial proportion of patients recover from the acute event, and subsequently experience long-term survival. Prognostic factors predicting short-term survival tend to be related to the acute illness, while longer-term survival is more significantly affected by characteristics of the underlying AML. No factors predicted an outcome sufficiently poor to indicate futility of ICU care. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Size of the Dendritic Cell Population At Diagnosis Worsens Prognosis in Acute Myeloid Leukemia – Bigger Is Not Better

Abstract 4870 Background:Dendritic cells (DC) are a heterogeneous population of lineage-negative antigen-presenting cells derived from CD34+ hematopoietic progenitors, present in tissue, blood and bone marrow (BM), where plasmacytoid DC (pDC) are a normal finding, representing 0.2 ± 0.1% of cell populations (Matarraz et al, 2010).DC neoplasms include solid tumors (such as DC sarcomas) and an entity classified by the World Health Organization (2008) as an acute myeloid leukemia (AML)-related precursor neoplasm: blastic pDC neoplasm/leukemia, an aggressive disease with poor prognosis, with no clinical trials to orient consensus regarding the most effective treatment; it is usually chemo-resistant, although some cases respond to AML-like regimens and allogeneic hematopoietic stem cell transplant.It is not clear if the presence of an increased DC population in non-DC AML confers pDC neoplasm-like biological characteristics to the former. Aims:This study aims to evaluate whether an increase in the size of DC populations in newly-diagnosed non-DC AML affects the latter's biological behavior, as represented by the overall survival (OS) of patients with the disease. Methods:We reviewed all AML diagnosed in our Hospital between January 1st 2008 and December 31st 2010, identifying 146 patients. We excluded 9 patients who had no flow cytometry immunophenotyping (IP) performed, and 7 whose first IP was performed after treatment was instituted. In that time frame, we also diagnosed 4 pDC neoplasms.Of the 130 patients included, 91 had their presenting IP performed on BM aspirate, while the remaining 39 were phenotyped on blood samples. The size of the DC populations and blastic DC maturation were determined on these samples.Patients were classified into 2 groups according to the size of the DC component; one (the Non-DC Group) had a DC component of up to 0.3% (in practice, the highest value in this group was 0.2%); the other (DC Group) had a percentage over this limit (the lowest value being 1.0%).OS data was determined for both groups; special consideration was given to age strata, separating patients under 65 years of age (Under-65) from those 65 or older (Over-65) and etiology (distinguishing de novo AML from AML secondary to therapy, myelodysplasia or myeloproliferative diseases). The percentage of DC identified by IP did not influence nor alter the type of treatment instituted. Results:We found that the presence of a DC component above the normal BM interval (as determined by Matarraz et al) was associated with a significantly decreased OS, with patients with DC components over 0.3% presenting with a median OS of 2.4 months (mean: 6.4 ± 1.6) and those with a component under 0.3% with a median OS of 8.6 months (mean: 17.0 ± 1.9) (p = 0.033).In our series, patients Over-65 had a median OS of 2.9 months (mean = 6.9 ± 1.0) and those Under-65 a median of 21.3 months (mean = 22.5 ± 2.5), p < 0.001. The differences in OS according to DC component were attenuated in patients Over-65 (median = 1.8 vs. 3.9 months, p = NS), whereas in patients Under-65 the median survival was 2.7 months (mean: 8.7 ± 2.9) for the DC Group and 24.4 months (mean: 24.3 ± 2.7) for the non-DC Group (p = 0.035).The differences in OS were also significant for de novo AML (median = 2.4 vs. 16.0 months, mean = 4.7 ± 1.9 vs. 20.5 ± 2.6, p = 0.017), but not statistically relevant for secondary AML (median = 4.4 vs. 5.5 months, mean = 8.4 vs. 10.8, p = NS). Discussion:In this study, we found that an increase in the size of the DC component as determined by IP at diagnosis on newly-diagnosed AML had a negative impact on prognosis, with a significant decrease in median and mean OS in patients with a percentage of DC over the upper limit of the normal interval.We also determined that the decreased survival was primarily attributed to the better-prognosis groups (patients under 65 and with de novo AML), whereas the effect of the worsened prognosis was attenuated in those patients with a bad prognosis at the outset (patients over 65 and with secondary AML).If data from DC neoplasms could be extrapolated, we could suggest that AML with increased DC components are less chemo-sensitive, which would explain the OS differences found in the Under-65 group, as well as the no-difference found in the Over-65 Group, which is frequently undertreated due to comorbidities. Conclusion:Our study suggests that the size of the DC component at diagnosis as determined by IP is a new prognostic marker predictive of decreased survival. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Clinical Significance of CD33 Non-Synonymous Single Nucleotide Polymorphisms (SNPs) in Pediatric Patients with Acute Myeloid Leukemia Treated with Gemtuzumab Ozogamicin-Containing Chemotherapy,

Abstract 3489 Introduction:Acute myeloid leukemia (AML) remains a difficult-to-treat disease, and outcome with standard conventional chemotherapeutics is often poor. An emerging approach uses monoclonal antibodies as a means to deliver targeted therapy. The antigen currently most exploited is CD33, in particular with gemtuzumab ozogamicin (GO), an immunoconjugate with a toxic calicheamicin derivative that causes DNA strand breaks, apoptosis, and cell death. However, while efficacious in some patients with untreated or relapsed/refractory disease, clinical response to GO is heterogeneous, emphasizing the need for studies to determine the subsets of patients that will benefit from GO. Although response to therapy is generally multi-factorial in origin, there is often a significant contribution of host genetic factors. Since GO targets CD33, we sought to determine the clinical impact of CD33 single nucleotide polymorphisms (SNPs) in a larger cohort of pediatric AML patients enrolled on Children's Oncology Group (COG) AAML03P1 pilot Phase III study, which explored the safety of GO addition to standard induction chemotherapy for newly-diagnosed AML. Methods:We genotyped four CD33 SNPs [rs35112940 (G>A; Arg304Gly), rs12459419 (C>T; Ala14Val), rs2455069 (A>G; Arg69Gly), and rs1803254 (G>C; 3’UTR)] occurring with an allelic frequency greater than 10% in genomic DNA samples in 242 pediatric AML patients. These were treated on trial COG-AAML03P1, and determined the associations between CD33 SNPs with CD33 protein expression levels in diagnostic leukemic cells and clinical outcome. Results:CD33 coding SNPs, rs35112940 (G>A; Arg304Gly) and rs12459419 (C>T; Ala14Val), and the 3’UTR SNP rs1803254 demonstrated significant associations with outcome or CD33 expression levels. Specifically, among white patients (which consisted of the major group 166/242=68.6%) homozygous for wild-type allele (GG) for the SNP rs35112940, a lower 3-year relapse risk from the end of course 1 was observed as compared to other genotypes (GG vs. AG vs. AA; 24±9% vs. 41±17% vs. 67±38%; p=0.018 Figure. 1A). Similarly, the 3-year overall survival from end of course 1 for among white patients homozygous for G allele in complete remission was 84±8% versus 68±15% for other genotypes (p=0.036; Figure. 1B). Patients homozygous for variant allele (TT) for SNP rs12459419 had a 3-year overall survival of 88±13% compared to 69±6% for other genotypes (p=0.056). Among white patients, the homozygous TT genotype also had a lower mean CD33 expression compared to other genotypes at this SNP (mean fluorescence intensity, 42 vs. 145, p=<0.001). Additionally, we observed an increased proportion of patients homozygous for variant allele (TT) for rs12459419 in the favorable risk group compared to genotypes CC and CT (52% vs. 31 %, p=0.034). [Display omitted] Conclusion:In conclusion, our findings suggest that CD33 SNPs are associated with clinical disease features such as CD33 expression levels and risk group as well as outcome after GO-containing chemotherapy in patients with newly diagnosed AML. The recently completed COG-AAML0531 randomized Phase III trial will allow validation of our findings. If their usefulness as a prognostic marker for treatment outcome of GO-based therapy is confirmed in an independent cohort, CD33 SNPs may serve to optimize the clinical use of this immunoconjugate; by extrapolation, prognostic information provided by CD33 SNPs may also be applicable to novel, second-generation CD33-targeting immuno-conjugates that have entered preclinical and clinical testing. Disclosures:No relevant conflicts of interest to declare.

Outcomes of Patients with Newly-Diagnosed Acute Myeloid Leukemia Over the Last 5 Decades At M.D. Anderson Cancer Center

Abstract 2606 Background:For the last 40 years, cytosine arabinoside (ara-C) combined with anthracycline (at different dose schedules) has been considered standard therapy for AML. Multiple novel agents have been added to that combination in an attempt to improve AML outcomes. We evaluated the survival of patients with AML treated at our institution over the last 5 decades. Methodology:A total of 3,631 patients with newly-diagnosed non-APL AML, 294 CBF-AML, and 237 APL registered in the MDACC Leukemia Database (1965–2010) were evaluated. Patients were divided by decade of referral. Outcomes in specific AML subtypes were evaluated in patients enrolled in 80 different chemotherapeutic protocols used since 1985 when cytogenetic information was consistently available. Analyses comparing different regimens included only protocols that accrued a minimum of 30 patients. Results:Median overall survival (OS) per decade (1960 to 2010) was 2.1, 8.5, 8.5, 10.4, and 12.5 mos. 1-yr OS was 26%, 41%, 41%, 45%, 51% (Fig 1A). While the prognosis remains poor, incremental improvements in median OS were observed both in patients <60yr (3.7, 11.8, 13.8, 15.7, 19.4 mos; p<0.001) and ≥60yr (0.7, 1.6, 3.7, 5.8, 7.6 mos; p<0.001). As expected, cytogenetics predicted response to chemotherapy, with complete response (CR) rates of 90%, 66%, 58%, 38% for patients with core-binding factor (CBF) AML, cytogenetically-normal (CN) AML, complex cytogenetics, or -5/-7 abnormalities, respectively. The achievement of CR during induction remained a critical prognostic factor across decades; regimens that produced CR rates ≥60% rendered improved OS rates over those inducing CR rates in <60% of patients (53 vs 28wks; p=0.0001). Patients treated with regimens containing ≥1g/m2 versus <1g/m2 of ara-C per course rendered higher CR (65% vs 58%; p=0.0001), CR duration (67 vs 48wks; p=0.002), and median OS (55 vs 48wks; p=0.06) rates, with similar low early mortality (first 8wks) rates among patients <60yr (12% vs 13%) but higher early mortality among patients ≥60yr (30% vs 21%). When comparing idarubicin (12mg/m2x3) vs daunorubicin (45mg to 60m/m2×3) combined with equal ara-C doses, idarubicin-containing regimens induced higher CR (66% vs 52%; p=0.005) and OS (61 vs 46; p=0.06). Based on these data, we developed the AI regimen (ara-C: 1.5g/m2×3d and idarubicin: 12mg/m2×3d) in 1990’s for the treatment of newly diagnosed AML (n=486; CR, CR duration, and OS rates: 61%, 63wks, and 48wks). Four agents (sorafenib, SAHA, G-CSF and tipifarnib) improved CR, CR duration, and OS rates when added to the AI backbone (compared to AI alone) amongst patients with non-CBF, non-APL AML: 84%/58wks/NR, 74%/42wks/68wks, 76%/82wks/83wks, 61%/72wks/54wks, respectively. The addition of G-CSF to AI (AIG; n=137) appeared to improve CR, CR duration, and OS rates (77%/87wks/86wks) over the AI regimens, even after removing CBF-AMLs (n=22; 76%/82wks/83wks) but not when fludarabine was substituted for idarubicin (AFG; n=413; 57%/42wks/35wks). Fludarabine-based regimens designed in the 1990’s such as FA (n=290; 72%/NR/85wks) but not FAI (n=265; 54%/42wks/32wks) improved upon AI. However, when CBF-AMLs were removed, the outcomes with FA (n=159; 55%/47wks/34wks) and FAI (n=260; 54%/41wks/32wks) were both inferior to AI-based combinations (n=860; 65%/64wks/55wks). In the 2000’s, the FLAG-gemtuzumab regimen improved CR, CR duration, and OS (92%/NR/NR) compared with outcomes in the 80’s (89%/21mo/28mo) and 90’s (90%/22mo/35mo) (Fig 1B). Similarly, the use of ATRA+ATO+/−gemtuzumab improved outcomes in APL in the 2000’s (88%/NR/NR) compared with the 80’s (64%/18mo/18mo) and 90’s (71%/NR/126mo) (Fig 1C). Conclusions:Albeit modestly, AML outcomes have improved every decade since 1960 due to improvements in supportive care, the use of higher doses of ara-C and idarubicin (over daunorubicin). The addition of certain targeted agents to chemotherapy backbones (e.g. sorafenib, SAHA, G-CSF, tipifarnib) may further improve outcomes in non-APL, non-CBF AML. CBF-AML outcomes have improved remarkably with FLAG-gentuzumab and APL outcomes have done so with ATRA+arsenic+/−gemtuzumab. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Clinical Relevance of Acute Myeloid Leukemia Stem Cells

Abstract 240▪▪This icon denotes a clinically relevant abstractRelapse of acute myeloid leukemia (AML) is hypothesized to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs) - the rare, resistant cells presumed responsible for maintenance of the leukemia. These cells have generally been reported to have a similar phenotype to normal hematopoietic stem cells (HSCs). However, despite the considerable research on LSCs over the past two decades, the clinical significance of these cells remains uncertain. We hypothesized that any minimal residual disease (MRD) present after therapy would be enriched for LSCs and that such persistence of LSCs would predict relapse.CD34+ cell populations from 27 AML patients and 10 normal donors were analyzed by flow cytometry for CD38 expression and for aldehyde dehydrogenase (ALDH) activity by Aldefluor. A total of 16 AML patients who achieved morphologic complete remission (CR) after induction chemotherapy were followed throughout their treatment course, and the flow cytometric staining patterns of their CD34+ cells at follow-up intervals were correlated with clinical outcomes. Cell subpopulations were sorted and then analyzed by fluorescence in situ hybridization (FISH) for leukemia-specific cytogenetic abnormalities (when applicable) and by transplantation into NOD/SCID-IL2Rgnull (NSG) mice to determine their in vivo self-renewal capacity.Normal bone marrow CD34+CD38− cells consistently exhibited two, discrete subpopulations by ALDH activity: one with low ALDH activity levels (CD34+CD38−ALDHlow) and another with high levels (CD34+CD38−ALDHhigh). As few as 1000 CD34+CD38−ALDHhigh cells generated normal hematopoiesis after transplantation into NSG mice. An additional population of CD34+CD38− cells with intermediate (int) levels of ALDH activity was found in the AML patients, but not in any of the normal donors studied. When present, even in patients in cytogenetic CR, this CD34+CD38−ALDHint population was at least 89% leukemic by FISH; and 1000 of these cells generated AML when transplanted into NSG mice. The CD34+CD38−ALDHhigh cells were invariably present in small numbers in newly-diagnosed AML patients. These cells did not harbor the AML-specific FISH abnormality, and 1000 generated normal hematopoiesis when transplanted into NSG mice, consistent with a residual population of normal HSCs. In those AML patients who achieved CR, any detectable MRD was enriched for the CD34+CD38−ALDHint leukemic cells. This population comprised 34% (range 9–51%) of the total leukemic burden when detectable in patients in cytogenetic CR, as compared to just 3% (range 0.5–4%) at initial diagnosis (p=0.02). Six of the seven CR patients with a detectable CD34+CD38−ALDHint population ultimately relapsed; the lone exception underwent allogeneic transplantation in first CR. Conversely, all nine of the patients with a consistently undetectable CD34+CD38−ALDHint population have remained in CR (p<0.01), with a median follow-up of 688 days.Putative AML LSCs have a unique CD34+CD38−ALDHint phenotype, which distinguishes them from normal (CD34+CD38−ALDHhigh) HSCs. These LSCs appear to be more resistant to therapy than the bulk leukemic cells, as reflected by their relative enrichment in MRD after therapy. Furthermore, the persistence of these putative LSCs in patients after therapy was highly predictive of subsequent clinical relapse. Analysis of the ALDH activity of CD34+CD38− cells potentially offers a patient-specific means by which to clinically assess response at the level of the LSC. The ability to separate LSCs from normal HSCs within the same individual may also facilitate better identification of therapeutic targets and resistance mechanisms. These data provide some of the first evidence supporting the clinical relevance of LSCs. Disclosures:Sharkis:Aldagen: Patents & Royalties. Jones:Aldagen: Patents & Royalties.

Altered Regulation of Imprinted Non-Coding RNA Genes in Acute Myeloid Leukemia,

Abstract 3456Studies in large-scale genome sequencing have shown that only 2% of the mammalian genome encodes mRNAs, but the most part is transcribed as long and short non-coding RNAs (ncRNAs). The ncRNAs with gene regulatory functions are starting to be seen as a common feature of mammalian gene regulation. Genomic imprinting is a form of epigenetic regulation and imprinted genes are silenced in a parental-specific manner. Imprinted genes tend to occur in clusters and ncRNAs have been found at all well-characterized imprinted clusters. Although the exact mechanism how imprinted ncRNA regulates gene expression remains largely unknown, it is general accepted that imprinted ncRNAs binds to chromatin modifying complexes, such as PRC2, TRX, and G9a, and generates specific silencing of genomic loci both in cis and trans. Imprinting is associated with many human diseases or syndromes (e.g. Prader-Willi, Angelman, Beckwith-Wiedemann, Retts, and Silver-Russell syndromes) and various cancers (e.g. breast, prostate, and colorectal cancers), but its role in leukemogenesis remain elusive. In this present study, a panel of 24 human imprinted ncRNAs genes, including ampd3, cpa4, snuf, rasgrf1, slc22a3, lgf2, treb3c, gabrb3, c15orf2, sfmbt2, rtl1, copg2, h19, l3mbtl, ppp1r9a, tspan32, lnpp5f, impact, nr3251, nr3252, znf215, prim2, peg3as and znf264, has been mined using Bioinformatics approach. We investigated the expression of these imprinted ncRNA genes using real-time quantitative RT-PCR in 67 newly-diagnosed acute myeloid leukemia patients with normal karyotypes (AML-NK), 22 AML patients with abnormal karyotypes (AML-AK), and 39 healthy individuals. In AML-NK patients, the expression of lgf2, h19, slc22a3, copg2, and impact were significantly upregulated than in healthy individuals (p < 0.0001). In AML-AK patients, besides lgf2, h19 and impact genes, ampd3 and gabrb3 were also significantly upregulated than in healthy individuals (p < 0.0001). Expression of igf2 was almost undetectable in healthy individuals but drastically increased in all AML patients. Both lgf2 and h19 were significantly increased in both AML-NK and AML-AK patients. From our preliminary results, it is reasonable to hypothesize that loss imprinting of lgf2/h19 is critical for the leukemogenesis of AML and under NK or AK conditions different additional ncRNAs are activated and affect different imprinted gene expression and thus leading to different clinical outcomes. Based on our findings, we will further perform methylation analysis of promoter CpG sites in AML patients to investigate if hypomethylation is responsible for the upregulation of these imprinted ncRNAs. We will also carry out in vitro functional analysis to elucidate the functions and mechanisms of these imprinted ncRNAs in AML tumorigenesis. Updated results of these analysis will be presented at the meeting. Disclosures:No relevant conflicts of interest to declare.

The clinical development of FLT3 inhibitors in acute myeloid leukemia

Introduction:Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur at high frequency in acute myeloid leukemia (AML), being detected in > 30% of patients at diagnosis and carrying a profound negative prognostic impact. The development of effective small molecule inhibitors of FLT3 has been the focus of an intensive international research effort in recent years.Areas covered:The published results of the first decade of clinical trials of FLT3-targeted tyrosine kinase inhibitors are critically reviewed. Over this period, a first generation of compounds has followed an orderly progression from monotherapy studies through combination with chemotherapy and into advanced stage international trials in both relapsed and newly-diagnosed AML. Correlative laboratory studies performed alongside several of these studies have been highly illuminating, demonstrating close correlations between clinical activity and effective inhibition of FLT3, and highlighting potential drug resistance mechanisms.Expert opinion:Clinical responses to several of the early multi-targeted agents were hindered by unfavorable pharmacokinetics and lack of potency. Newer, more potent FLT3 inhibitors such as sorafenib and AC220 possess the ability to achieve more sustained in vivo inhibition of FLT3 and have shown highly promising activity in early clinical studies. As these agents enter advanced stage trials, they carry the potential to make a major clinical impact in this disease. In future, FLT3 inhibitors may be effectively used in combination with other molecularly targeted agents.

Combination Treatment of Flag with Non-Pegylated Liposomal Doxorubicin (MYOCET™) in Elderly Patients with Acute Myeloid Leukemia: A Single Center Experience

The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.

The Prevalence of Fanconi Anemia Among Patients with De Novo Acute Myelogenous Leukemia

AbstractAbstract 2232The diagnosis of acute myeloid leukemia (AML) was the first presentation in approximately one-third of published cases of Fanconi anemia (FA) that led to the diagnosis of FA. Our objective therefore was to estimate the number of undiagnosed patients with Fanconi anemia (FA) who may present with acute myelogenous leukemia (AML), in order to justify a universal screening strategy. The probability of having FA among patients with AML, using Bayes rule, was calculated as: P(FAüAML) = [P(AMLüFA) × P(FA)]/P(AML). Data from the Surveillance, Epidemiology and End Results (SEER) Program, published FA cohort studies, and the Fanconi Anemia Research Fund were used to estimate these probabilities. P(FAüAML) was then applied to data on the time to recovery of an absolute neutrophil count (ANC) above 1000/μL from 892 de novo AML patients enrolled on Children's Oncology Group treatment protocol CCG-2961 between 1997 and 2002. A derived, exact binomial distribution of a one-sided Fisher hypothesis test was used to estimate the number of patients with FA among newly diagnosed AML patients required to reject the null hypothesis stating that the prevalence of FA among patients newly diagnosed with AML is less than an arbitrarily chosen threshold of 1%. From the published FA cohort studies, we estimated P(AMLüFA) in patients less than 19 years old at 0.5%/yr. Assuming an FA allele frequency of 1/300, autosomal recessive inheritance and an 80% FA survival rate until age of 18 years, P(FA) in the US population less than 19 years of age was estimated to be 5 × 10-5. SEER data were used to estimate the age-adjusted P(AML) in persons 0–19 yrs at 0.73/100,000. The estimated probability that a newly-diagnosed AML patient has FA is therefore ∼3%. In CCG-2961, ANC recovery >1000/ μL after the first round of AML induction chemotherapy occurred in a mean of 40 +/− 9.6 days. Eighteen percent (165/892) of the patients never achieved an ANC >1000 and 22% (193/892) had no ANC recovery at 60 days (2 SD from the mean). Based on our estimate of 3% FA patients among de novo AML cases 27 FA patients (3% of 892) could represent at least 14% (27/193) of patients who had no ANC recovery at 60 days. Using the exact binomial distribution we estimate that a sample size of 375 newly diagnosed AML patients would have 80% power and a type I error rate of <0.05 to reject the null hypothesis that the prevalence of FA is less than 1% among those 375 AML patients. For this test, the critical value is 8 FA cases in 375 AML patients. In conclusion, we suggest that at least 3% of newly-diagnosed AML patients may, in fact, have FA. Identification of 8 or more FA cases among 375 newly diagnosed patients with AML would justify a universal screening strategy. FA screening in the evaluation of patients with newly-diagnosed AML would require the development of rapid FA screening techniques. This would permit timely adjustment of the chemotherapy regimen in order to minimize FA-related chemotoxicities. Finally, the remaining of those patients who never achieved ANC recovery might be accounted for by the toxicity of the AML treatment due to polymorphisms in genes involved in the metabolism of chemotherapy or to other, undiagnosed, AML-prone genetic syndromes. Disclosures:No relevant conflicts of interest to declare.

Etoposide and mitoxantrone in newly diagnosed acute myeloid leukemia patients with persistent leukemia after a course of induction therapy with cytarabine and idarubicin

7073 Background: The goal of induction chemotherapy in acute myeloid leukemia (AML) is complete remission with restoration of normal bone marrow. If residual leukemia is present after the first course of induction therapy, patients receive a second course identical to the first or receive a non-cross resistant antileukemic regimen. Methods: In a retrospective study of adult patients with newly-diagnosed AML treated at the University of Pittsburgh Cancer Institute between December 2002 and May 2008, we evaluated the efficacy and toxicity of mitoxantrone (10 mg/m2/d) and etoposide (100 mg/m2/d), both administered intravenously within 5 days as second course therapy of patients not responding to first-course induction therapy with cytarabine and idarubicin. Univariate and multivariate associations between patient characteristics and complete response (CR) were assessed by logistic regression, with overall- and relapse-free survival estimated by Kaplan-Meier analysis. Results: 74 AML patients (mean age 56 years, range: 18–73 years) completed treatment with etoposide and mitoxantrone; 29 (39%) achieved CR. Lower CR rate was associated with unfavorable cytogenetic risk status at diagnosis and higher percent blasts prior to treatment with mitoxantrone and etoposide. Ten (14%) patients died due to infectious complications. No grade 3 or 4 hepatic toxicities were observed. One patient developed grade 3 cardiac toxicity. Median duration of neutrophil recovery following therapy in patients achieving CR was 29 days. Median overall survival was 9.0 months (95% CI 5.8–14.9 months). The 29 patients who achieved CR received postremission therapy: 16 of these eventually relapsed, while 4 others died without evidence of relapse. Median duration of relapse-free survival in these 29 patients was 11.0 months (95% CI: 9.0–19.3 months). Conclusions: Our study suggests that the combination of etoposide and mitoxantorne is an active and well-tolerated regimen as second-course therapy in newly diagnosed AML patients who have persistent leukemia after a first course of induction therapy with cytarabine and idarubicin. No significant financial relationships to disclose.

A Homoharringtonine-Based Protocol Is Superior to Daunorubicin and Idarubicin-Based Protocols in Elderly Patients with Newly-Diagnosed Acute Myeloid Leukemia with Comparable Effects and Low Toxicities: Experience in a Chinese Center.

Homoharringtonine (HHT) is a plant alkaloid which has been used in China for the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia for over 30 years. We present here a retrospective analysis designed to compare the efficacy and toxicity of HHT with daunorubicin (DNR) and idarubicin for the treatment of AML in elderly patients. Fifty-three patients over 60 years with newly diagnosed non-M3 AML between January 1998 and December 2007 were treated with cytarabine (Ara-c, 100mg/m2/day for 7 days) in combination with HHT (2mg/m2/day for 7 days; HA group; n=19), or DNR (40mg/m2/d for 3 days; DA group; n=16), or idarubicin (8mg/m2/d for 3 days; IDA group; n=18). In the HA group, 42.1% (8/19) of patients achieved complete remission (CR), 26.3% (5/19) of patients had partial remission (PR). In the DA group, the CR and PR rates were each 18.8% (3/16). In the IDA group, 55.5% (10/18) of patients achieved CR, 5.9% (1/18) patients had PR. The CR and OR rates were not significantly different between the three groups. However, whereas in the IDA and DA groups the early death rate within one month after chemotherapy was 33.3% (6/18) and 23.5% (4/16) respectively, there was no early death in the HA group. The estimated OS (overall survival) times were 23.2±7.9 months, 7.6 ±2.1 months, 14.0±3.4 months in HA, DA, and IDA groups (HA versus DA, P = 0.048; HA versus IDA, P = 0.678). The estimated mean disease-free survival (DFS) time of those patients who achieved CR in the HA group (44.3±17.3) were also significantly higher than those in the DA group (7.8±2.7; P = 0.047), and comparable with those in the IDA group (18.0±4.2; P = 0.598). In summary, the response to HA induction therapy was at least equal to that of DA and IDA induction, with relatively mild extramedullary toxicity and lower myocardial toxicity. So HHT is a particularly suitable candidate for the treatment of elderly AML patients.

Impact of Weekend Admissions on Quality of Care and Outcomes in Patients with Acute Myeloid Leukemia (AML).

Background: Hospital services can be significantly reduced over the weekend. This was associated with higher mortality among patients with serious medical conditions in previous studies. It is unknown whether weekend admissions affect outcomes of AML patients, as delay in treatment or delay in obtainment of procedures (such as triple-lumen catheter [TLC] placement requisite for anthracycline delivery) may occur for weekend admissions. We investigated quality of care and clinical outcomes of newly-diagnosed AML patients treated with induction chemotherapy and hospitalized on weekends vs. weekdays.Methods: We conducted a retrospective review of all AML patients treated with cytarabinebased induction chemotherapy at Cleveland Clinic from 1994–2008. Data on known prognostic factors (age, WBC at diagnosis, cytogenetic risk groups [as defined by CALGB 8461] and AML etiology [de novo vs. secondary AML]) were collected and controlled for in multivariable analyses. Quality measures included time to TLC placement; time to induction chemotherapy (TTI); length of stay (LOS); early death (within 15 days of chemotherapy initiation); and 30-day mortality. Weekend admissions were defined as starting Friday, 5pm through Monday, 12am. Factors associated with quality of care and outcomes were assessed by the routines of linear, categorical, and survival analyses.Results: In all, 422 patients were identified. Median age was 61 years (range:17–81) and 47% were female. Median baseline WBC was 9.9/mcL (range:0.4–550); 4.7% had acute promyelocytic leukemia, and 30% had secondary AML. Cytogenetics risk distribution was: favorable (11.6%); intermediate (41.2%); adverse (24.2%); unknown/no growth (23%). In all, 24.4% (n=103) were admitted on the weekend. The complete remission (CR) rate was 66.6%; Median times to TLC was 2 days (range:0–27); TTI was 2 days (range:0–22); and LOS was 32 days (4–91). Early death rate was 3.1%, and 30-day mortality 10.4%. Compared to younger (<60 years) patients, older patients had higher 30-day mortality (14.7% vs. 5.8%, p=0.003), early death (4.9% vs. 1.1%, p=0.025), TTI rates (2.7 days vs. 2.1 days, p=0.02), but lower CR (62.9% vs. 77.8%, p=0.001) and overall survival (OS) rates (195 vs. 474 days, p<0.0001). In univariate analyses, time to TLC was delayed for weekend vs. weekday admissions (3.8 vs. 2.7 days, p<0.01), as was a trend for LOS (35.9 vs. 33.5 days, p=0.09). Surprisingly, weekend admissions had lower early mortality (0% vs. 4%, p=0.04) and 30-day mortality (3.9 % vs. 12.3%, p=0.02). There was no difference in TTI (2.5 vs. 2.4 days, p=0.6), CR rates (72% vs. 69%, p=0.6), or OS (258 vs. 273 days, p=0.2). In multivariable analysis, only time to TLC remained significantly longer for weekend admissions (p<0.001).Conclusions: Weekend admissions significantly delayed placement of TLC, and possibly LOS, without affecting other quality parameters or patient survival. This is likely due to immediate initiation of peripheral chemotherapy with cytarabine even prior to the placement of TLC for infusion of anthracyclines, and emphasizes the need to start chemotherapy promptly in AML patients.

Exclusion from Acute Myeloid Leukemia (AML) Clinical Trials of Patients Unlikely To Respond.

Introduction: Patients with newly diagnosed AML are increasingly being enrolled on industry-sponsored clinical trials. These trials routinely exclude patients with Zubrod performance status (PS) &gt;2, bilirubin &gt;1.9 mg/dL, or creatinine &gt;1.9 mg/dL; such patients are well-known to be relatively unlikely to respond (UTR). Here we quantify the effect of this practice on inclusion of UTR patients in clinical trials. Patients and Methods: Overall, 2323 adults with newly-diagnosed AML (no acute promyelocytic leukemia) were registered on clinical trials (industry-sponsored and other) from 1991–2006. Considering patients as UTR if they fulfilled any of the criteria noted above, we examined rates of enrollment of UTR patients over time: Results: Thus, while more patients are being enrolled on clinical trials, fewer UTR patients are being enrolled particularly over the last 5 years (p = .04) with a concomitant decrease in the proportion of such patients enrolled (p&lt;.0001 over the 16 years in question). Findings are qualitatively the same in older patients. Conclusion: Newer clinical trials may be less applicable to UTR patients than previous trials. There is a need for clinical trials specific to the UTR population, the group most in need of novel therapies. Rates of enrollement of unlikely to respond patients on clinical trials for newly diangosed AML Year No. of pts. treated on clinical trial (pts. age≥60 yrs) UTR pts. enrolled (pts. age≥60 yrs) % of UTR pts. enrolled (pts. age ≥60 yrs) 1991 101 (50) 17 (13) 17 (26) 1992 100 (48) 20 (14) 20 (29) 1993 96 (46) 18 (9) 19 (20) 1994 109 (41) 23 (13) 21 (32) 1995 102 (48) 20 (10) 20 (21) 1996 104 (63) 14 (10) 13 (16) 1997 145 (81) 30 (20) 21 (25) 1998 124 (63) 14 (8) 11 (13) 1999 164 (86) 26 (16) 16 (19) 2000 169 (96) 25 (19) 15 (20) 2001 187 (98) 30 (19) 16 (19) 2002 162 (91) 17 (11) 10 (12) 2003 195 (111) 4 (2) 2 (2) 2004 184 (109) 17 (11) 9 (10) 2005 185 (117) 15 (7) 8 (6) 2006 196 (109) 17 (12) 9 (11) Total 2323 (1257) 307 (194) 13 (15)