Background: A previous CALGB trial (JCO2002;20:2429) showed a positive OS trend with AZA vs best supportive care (BSC) in MDS. The objective of this Phase III, international, multicenter, randomized, prospective trial was to demonstrate the superiority of AZA + BSC for prolonging OS vs CCR + BSC. Design: Higher-risk MDS patients (pts), FAB-defined as RAEB, RAEB-T, or CMML (10–29% marrow blasts) with an IPSS of Int-2 or High by central pathology/cytogenetic review, were enrolled. Before randomization, investigators preselected pts to 1 of 3 CCR: BSC only (transfusions, antibiotics, and G-CSF for neutropenic infection); low-dose ara-C (LDAC, 20 mg/m2/d x 14d, q 28d); or standard chemotherapy (Std CT: conventional induction/consolidation). Pts were stratified by FAB/IPSS and randomized to AZA (75 mg/m2/d x 7d, q 28d) or CCR. This trial did not allow erythropoietin. All analyses used the ITT population. Results: In all, 358 pts (70% male), were randomized at 79 sites to AZA (N=179) or CCR (N=179): BSC only (N=105, 59%), LDAC (N=49, 27%), or Std CT (N=25, 14%). Median age was 69 yrs (38–88) and per treatment (TX): AZA (69 yrs); BSC only (70 yrs); LDAC (71 yrs); and Std CT (65 yrs). The AZA and CCR groups were comparable for baseline (BL) parameters. At BL, 95% of pts were higher risk: RAEB (58%), RAEB-T/WHO AML (34%), CMML (3%), and other (5%). By IPSS, 87% were higher risk: Int-2 (40%), High (47%), and 13% indeterminate/other. AZA was administered for a median of 9 cycles; LDAC for 4 cycles. Median followup for the OS analysis was 21.1 months (mo). AZA demonstrated statistically superior OS vs CCR (stratified log-rank p=0.0001). AZA showed a median Kaplan-Meier (KM) OS time of 24.4 mo vs 15 mo with CCR (Figure). The hazard ratio (HR, Cox Model) was 0.58 (95% CI: 0.43, 0.77) for a 74% OS improvement. At 2 yrs, there was a 2-fold OS advantage: AZA (51%) vs CCR (26%), 95% CI: 13, 36%, p<0.0001. Differences in OS KM medians (HR; log-rank p) between AZA and BSC, LDAC, and Std CT, respectively, were 12.9 mo (0.55; p=0.0003), 9.1 mo (0.60; p=0.016), and 8.7 mo (0.69; p=0.19). Median OS per IPSS cytogenetic subgroup showed similar results (Table). The 1, 2, and 3-mo survival rates did not differ between AZA and BSC only (p>0.20). AZA was well tolerated with safety data consistent with previous reports. Conclusion: These data confirm and extend previous CALGB findings. This AZA trial is the first MDS clinical study to demonstrate a significant OS advantage, thus altering the natural disease course. AZA should now be considered first-line therapy for higher-risk MDS pts. OS Analyses per IPSS Cytogenetic Group Group % (n/N) Pts AZA Median (Months) CCR Median (Months) HR (95%CI) Log-rank p Good 46 (166/358) Not reached 17.1 0.61 (0.39, 0.96) 0.030 Intermediate 21 (76/358) 26.3 17.0 0.43 (0.21, 0.88) 0.017 Poor 28 (100/358) 17.2 6.0 0.52 (0.32, 0.87) 0.011 Figure Figure
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677 Background: Activating mutations of NRAS and KRAS (‘RAS’) are found in 10–30% of myeloid malignancies. Evidence of constitutive activation of the RAS-RAF-MEK-ERK pathway, however, is more ubiquitous. Trametinib is a potent, selective, allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A Phase I/II study of single, daily, oral dosing of trametinib in myeloid malignancies is ongoing. Here we report the results from Phase I/II patients receiving the recommended Phase II dose (RP2D) of 2 mg. Methods: Patient eligibility was limited to patients with relapsed/refractory myeloid malignancies and adequate hepatic, renal and cardiac function. There were no hematologic eligibility criteria. Patients were prospectively screened for KRAS mutations at amino acids 12, 13 and for NRAS mutations at amino acids 12, 13 and 61. Clinical response was assessed using International Working Group (2003 and 2006) criteria for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), respectively. Pharmacodynamic marker (pERK) analysis was conducted in phase II patients with patient paired (pre/during treatment) blood and bone marrow samples. Results: Eighty-seven (9 in Phase I and 78 in Phase II) patients received 2 mg of trametinib daily: AML (n=66), MDS (n=11), chronic myelomonocytic leukemia (CMML) (n=7) or other (n=3) (RAS mutations, n=57; RAS wild type, n=15 and RAS unknown, n=15). Median age was 68 years (range 21–87) and for close to half of the patients, trametinib was 3 3rd line of therapy. Trametinib exhibited a long effective half-life with small peak/trough ratios, and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Results of the pharmacodynamic analysis indicated an on-target effect of trametinib. Responses by RAS mutation status for Phase I/II subjects are summarized in Table 1. Responding patients have continued therapy for median of 16.9 weeks (range, 10.9 – 36.7). Drug-related grade 3/4 adverse events (AEs) were encountered in 31/87 (36%) of the Phase I/II patients and there was one grade 5 drug-related AE,cerebrovascular accident. Hepatic toxicities (9%), gastrointestinal disorders (7%) and rash (5%) were the most frequent grade 3/4 AEs. AEs possibly related to inhibition of MEK signaling were blurred vision (total,13%; grade 3, 1%) and decreased cardiac ejection fraction (total, 9%; grade 3, 6%); events were generally reversible. Conclusion: At the RP2D of trametinib (2 mg orally daily), trametinib has shown promising clinical activity and responses (CR/CRp/Marrow CR/MLFS/PR) were almost exclusively seen in patients with refractory myeloid malignancies characterized by somatic RAS mutations. Expansion of the CMML cohort for RAS positive subjects is ongoing. Disclosures: Borthakur: GlaxoSmithKline, Sigma-Tau, Eisai, XBiotech: Research Funding. Off Label Use: Trametinib, to report outcome of clinicla trial to audience at ASH meeting. Foran:GlaxoSmithKline: Research Funding. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding. Giagounidis:GlaxoSmithKline: Honoraria. Ottmann:GlaxoSmithKline: Clinical trial participation Other. Kadia:GlaxoSmithKline: Research Funding. Bauman:GlaxoSmithKline: Employment, Equity Ownership. Wu:GlaxoSmithKline: Employment. Liu:GlaxoSmithKline: Employment. Schramek:GlaxoSmithKline: Employment. Zhu:GlaxoSmithKline: Employment. Wissel:GlaxoSmithKline: Employment, Equity Ownership.
In acute promyelocytic leukemia (APL), the use of all-trans-retinoic acid (ATRA) as a differentiating agent induces complete remission in a high percentage of patients. In pregnancy, however, this drug bears the risk of severe teratogenicity to the child. We report the case of a 23-yr-old woman at 21 weeks' gestation suffering from APL. She was treated with ATRA (45 mg/m2) for 40 d and two courses of standard chemotherapy. The mother achieved complete remission within 22 d of treatment. Fetal development was normal, and a healthy premature girl was born in the 35th week of pregnancy. In a review of the literature we have identified 14 cases of APL in pregnancy treated with ATRA alone or in combination with chemotherapy. ATRA has been used as early as in the 3rd week of gestation and in no case have malformations or other teratogenic effects occurred. Side-effects, however, ranged from fetal cardiac arrhythmias to induction of labour. Although known to exhibit severe teratogenic effects during the first trimester of pregnancy, ATRA seems to be reasonably safe during the second and third trimesters in the treatment of APL. However, careful obstetric follow-up is mandatory regarding fetal cardiac complications.
Since the publication of this article it has been noted that there was an omission in the listing of conflict of interest. JM Bennett was listed as having no conflict of interest; however, the authors would like to correct this to read: 'JMB is a consultant for and has received honoraria and contract monies as a consulting hematomorphologist from the Celgene Corporation'.
298 The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies that are characterized by ineffective hematopoiesis resulting in peripheral cytopenias and a hypercellular bone marrow. Approximately 40% of patients with MDS will develop an acute myeloid leukemia. It is important to establish prognosis of MDS patients since the treatment options vary from supportive care to bone marrow transplantation. In order to determine the relationship of gene expression levels to prognosis and so identify new molecular markers, we have used gene expression profiling to study the transcriptome of the hematopoietic stem cells of 125 MDS patients with a minimum 12 month follow up. The CD34+ cells obtained from MDS patients and healthy individuals were analyzed using Affymetrix U133 Plus2.0 arrays. The patients were split randomly in a training set (n=84) and a test set (n=41). Supervised principal components analysis was used to identify genes correlated with survival. Using the 84 patients in the training set, the Cox scores were computed for each gene, and the principal components calculated on the genes with the highest Cox scores. The first of the principal components was then used to generate a regression model to predict the survival in the test set. Finally, for each probe set an importance score was calculated equal to its correlation with the supervised principal component predictor. This approach returned a list of 150 top ranked probe sets correlated with survival. Patients in the training set were split into tertiles based on the predictor (low, medium and high score) and patients in the test set were assigned to their predicted class, and Kaplan-Meier plots were generated for both training and test set. The differences in survival for both training and test set were statistically significant (Figure 1). Top ranked genes showing lower expression levels in patients with shorter survival include CDH1, LEF1 and AKAP12/Gravin. Top ranked genes showing higher expression levels in patients with shorter survival include IL23A, WT1 and PTHR2. Figure 2 shows survival of patients divided into tertiles of expression for the individual genes CDH1, LEF1 and WT1. It is probable that the genes identified in this study will become the first validated molecular markers for MDS prognosis. Multivariate analysis is currently being performed. Figure 1 Figure 1. Figure 2 Figure 2. Disclosure: No relevant conflicts of interest to declare.
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