Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).
The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
Iron deficiency anemia (IDA) has reached epidemic proportions in developing countries and has become a major global public health problem, affecting mainly 0–5-year-old children and young women of childbearing age, especially during pregnancy. Iron deficiency can lead to life-threatening loss of red blood cells, muscle function, and energy production. Therefore, the pathogenic features associated with IDA are weakness and impaired growth, motor, and cognitive performance. IDA affects the well-being of the young generation and the economic advancement of developing countries, such as India. The imbalance between iron intake/absorption/storage and iron utilization/loss culminates into IDA. However, numerous strategic programs aimed to increase iron intake have shown that improvement of iron intake alone has not been sufficient to mitigate IDA. Emerging critical risk factors for IDA include a composition of cultural diets, infections, genetics, inflammatory conditions, metabolic diseases, dysbiosis, and socioeconomic parameters. In this review, we discuss numerous IDA mitigation programs in India and their limitations. The new multifactorial mechanism of IDA pathogenesis opens perspectives for the improvement of mitigation programs and relief of IDA in India and worldwide.
Introduction: FLT3-ITD mutations are among the most common molecular abnormalities in AML, occurring in ≈ 25% of pts. These driver mutations are associated with high leukemic burden and poor prognosis, eg, high risk of relapse, decreased response to salvage therapy, and shorter overall survival (OS). Pts with R/R FLT3-ITD AML have a worse prognosis and represent a population with high unmet medical need. Q is a once-daily, oral, highly potent and selective FLT3i shown in phase 2 trials to have promising single-agent antileukemic activity and a manageable safety profile. QuANTUM-R was the first global, phase 3, randomized controlled trial (NCT02039726) to show that an FLT3i prolonged OS compared with salvage chemotherapy (SC) in pts with R/R FLT3-ITD AML. Final efficacy and safety data from this pivotal phase 3 trial are reported. Methods: Pts aged ≥ 18 years with FLT3-ITD AML refractory to or relapsed (duration of first remission ≤ 6 mo) after standard AML therapy, w/wo hematopoietic stem cell transplant (HSCT) were randomized 2:1 to receive Q (60 mg [30-mg lead-in]) or 1 of 3 preselected investigator's choice (IC) SC: low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; Q and LoDAC were given until lack of benefit, unacceptable toxicity, or HSCT. Prior therapy with midostaurin was allowed, but all other FLT3i were not. Pts receiving HSCT in the Q arm could resume Q after HSCT. Primary and secondary endpoints were OS and event-free survival (EFS), respectively. Sensitivity analyses for OS and EFS were conducted: (1) using the per-protocol set (randomized and treated patients without major protocol deviations), (2) censoring at HSCT, (3) censoring at the use of other postbaseline FLT3i (for OS only). Predefined subgroup analyses of OS were also performed. Exploratory endpoints included response rates, duration of CRc, and transplant rate. Results: 367 pts were randomized; 245 to Q and 122 to IC SC (LoDAC, n=29; MEC, n=40; FLAG-IDA, n=53). Four pts randomized to Q and 28 pts randomized to SC did not receive therapy. Median follow-up was 23.5 mo. Six pts were still on initial Q treatment at data cutoff vs 0 in the SC arm. Treatment groups were well balanced for baseline characteristics, including age, response to prior therapy, transplant history, and FLT3-ITD allelic burden. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; stratified log-rank test, 1-sided P=0.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo, with an estimated 12-mo OS probability of 27% vs 20% in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; stratified log-rank test, 1-sided P=0.1071); median EFS was 6.0 (95% CI, 0.1-8.3) vs 3.7 (95% CI, 0.4-5.9) wk, respectively. Sensitivity analyses of OS and EFS all supported benefit of quizartinib compared with SC, as did OS analyses across subgroups, including varying allelic ratio, prior HSCT, AML risk score, and response to prior therapy (Tables 1 and 2, Figure). CRc was 48% (95% CI, 42%-55%) and 27% (95% CI, 19%-36%) in Q and SC arms (nominal P=0.0001), respectively. Duration of CRc was 12.1 (95% CI, 10.4-27.1) vs 5.0 (95% CI, 3.3-12.6) wk. Transplant rate was 32% and 12% in Q and SC arms (nominal P<0.0001), respectively; of 79 eligible pts, 49 (62%) resumed single-agent Q after HSCT (15 ongoing Q treatment at data cutoff). Median duration of post-HSCT Q was 129 d. Rates of treatment-emergent adverse events (TEAEs) were comparable between the 2 arms, despite higher total drug exposure in Q vs SC arms (101.9 vs 3.7 patient-years [pt-y], respectively). Exposure-adjusted TEAEs were 2.3 vs 25.2 per pt-y, respectively. Most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Only 2 pts discontinued Q due to QTcF prolongation. QTcF >500 ms (grade 3) by central laboratory was 3% in the Q arm; no grade 4 QTcF occurred. Q-treated pts post-HSCT had a similar AE profile to those overall. Conclusions: This report confirms the survival benefit observed with single-agent Q compared with SC in pts with R/R FLT3-ITD AML and the favorable Q safety profile, providing evidence of meaningful clinical benefit in pts who have few options. These results are paradigm changing in the R/R FLT3-ITD AML treatment setting. Disclosures Cortes: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Khaled:Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Perl:Arog: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ganguly:Amgen: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau. Russell:Daiichi Sankyo: Consultancy; Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kramer:Daiichi Sankyo: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Dombret:Daiichi Sankyo: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding; Agios: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma: Honoraria, Research Funding; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria. Jonas:Accelerated Medical Diagnostics: Research Funding; Incyte: Research Funding; Esanex: Research Funding; LP Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Kalobios: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche: Research Funding; Glycomimetics: Research Funding; Tolero: Consultancy; Amgen: Consultancy; Forma: Research Funding. Leung:Novartis: Speakers Bureau; Daiichi: Research Funding. Mehta:Daiichi Sankyo: Honoraria. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Radsak:Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Other: Travel grant; TEVA: Consultancy; Daiichi Sankyo: Honoraria, Other: Travel grant; Gilead: Other: Travel grant; Celgene: Honoraria, Other: Travel grant; Takeda: Consultancy. Arunachalam:Daiichi Sankyo: Employment. Holmes:Daiichi Sankyo: Employment. Kobayashi:Daiichi Sankyo: Employment. Namuyinga:Daiichi Sankyo: Employment. Ge:Daiichi Sankyo: Employment. Yver:Daiichi Sankyo: Employment. Zhang:Daiichi Sankyo: Employment.
BackgroundHealth state (HS) utility values for patients with acute myeloid leukemia (AML), a hematological malignancy, are not available in the United Kingdom (UK). This study aims to develop clinically sound HSs for previously untreated patients with AML and to assign utility values based on preferences of the general UK population.MethodsThis study was conducted in the UK and comprised 2 stages. During the first stage, AML HSs were drafted based on evidence from a literature review of AML clinical and health-related quality-of-life studies (published January 2000–June 2016) and patient-reported outcome measures previously used in this population. A panel of UK hematologists with AML experience validated the clinical relevance and accuracy of the HSs. During the second stage, validated HSs were valued in an elicitation survey with a representative UK population sample using the time trade-off (TTO) method. Descriptive statistics and bivariate tests were obtained and performed.ResultsA total of eight HSs were developed and clinically validated, including treatment with chemotherapy, consolidation therapy, transplant, graft-vs-host disease (GvHD), remission, relapse, refractory, and functionally cured. In total, 125 adults participated (mean age, 49.6 years [range, 18–87 years], 52.8% female). Mean (95% confidence interval [CI]) TTO preference values (n = 120), ranked from lowest (worst HS) to highest (best HS) were as follows: refractory − 0.11 (− 0.21 to − 0.01), relapse 0.10 (0.00–0.20), transplant 0.28 (0.20–0.37), treatment with chemotherapy 0.36 (0.28–0.43), GvHD 0.43 (0.36–0.50), consolidation 0.46 (0.40–0.53), remission 0.62 (0.57–0.67), and functionally cured 0.76 (0.72–0.79). Mean (95% CI) visual analog scale preference values followed the same rank order, ranging from 0.15 (0.13–0.17) for refractory to 0.71 (0.68–0.73) for functionally cured.ConclusionsTo our knowledge, this is the first study to report utility values for AML from the UK societal perspective. Participants were able to distinguish differences in severity among AML HSs, and preference values were consistent with clinical perception of HS severity. HS preference values observed in this study may be useful in future evaluations of treatment benefit, including cost-effectiveness analyses and improved patient well-being.
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