Concept: Acute myeloid leukemia
Background Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. Methods We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. Results A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. Conclusions The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
The clinical importance of erythroid predominance in bone marrow of patients with acute myeloid leukemia (AML) is controversial. These cases represent a heterogeneous group of diseases that historically have been classified into different categories. We studied 313 AML patients and specifically compared the clinical, cytogenetic, and molecular features of cases of AML with erythroid predominance, arbitrarily defined as ≥50% erythroid precursors, to AML cases without erythroid predominance. We also assessed 51 patients with a high-grade myelodysplastic syndrome (MDS), refractory anemia with excess blasts (RAEB). All neoplasms were classified according to the World Health Organization classification. With the exception of therapy-related AML/MDS, the presence of erythroid predominance in variously classified categories of AML was associated with a survival advantage. In addition, AML with erythroid predominance had a lower frequency of cytogenetic abnormalities as well as a lower frequency of mutations involving NPM1, NRAS and FLT3 as compared with AML without erythroid predominance. We conclude that the clinical, cytogenetic, and molecular features of AML with erythroid predominance in the non-therapy-related setting are much closer to those of a high-grade myelodysplastic syndrome than they are to other types of AML.
Risk of Acute Leukemia and Myelodysplastic Syndromes in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS): a Population-Based Study of 17 315 Patients
- Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
- Published almost 5 years ago
The purpose of this study was to determine if there is an increased risk of acute leukemia and myelodysplastic syndromes (MDS) in persons with monoclonal gammopathy of undetermined significance (MGUS). We utilized a large population-based cohort of individuals systematically screened for the presence or absence of MGUS. MGUS status was then linked to the diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and MDS. 17 315 patients age 50 and older (605 MGUS and 16 710 controls) with a cumulative 435 021 person-years of follow-up were studied. MGUS patients had a significantly higher risk of developing MDS compared with controls, hazard ratio 2.4 (95%CI 1.08,5.32), P=0.031. There was no statistically significant increase in the risk of AML (RR 1.36 P=0.675), and no increased risk of developing ALL.Leukemia accepted article preview online, 5 February 2013; doi:10.1038/leu.2013.34.
A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213
- Annals of oncology : official journal of the European Society for Medical Oncology / ESMO
- Published over 4 years ago
BackgroundRituximab-hyper-CVAD alternating with rituximab-high-dose methotrexate and cytarabine is a commonly utilized regimen in the United States for mantle cell lymphoma (MCL) based on phase II single institutional data. To confirm the clinical efficacy of this regimen and determine its feasibility in a multicenter study that includes both academic and community-based practices, a phase II study of this regimen was conducted by SWOG.Patients and methodsForty-nine patients with advanced stage, previously untreated MCL were eligible. The median age was 57.4 years (35-69.8 years).ResultsNineteen patients (39%) did not complete the full scheduled course of treatment due to toxicity. There was one treatment-related death and two cases of secondary myelodysplastic syndrome (MDS). There were 10 episodes of grade 3 febrile neutropenia, 19 episodes of grade 3 and 1 episode of grade 4 infection. With a median follow-up of 4.8 years, the median progression-free survival was 4.8 years (5.5 years for those ≤65 years) and the median overall survival (OS) was 6.8 years.ConclusionsAlthough this regimen is toxic, it is active for patients ≤65 years of age and can be given both at academic centers and in experienced community centers.
Up to 30% of adults with acute myeloid leukemia fail to achieve a complete remission after induction chemotherapy - termed primary refractory acute myeloid leukemia. There is no universally agreed definition of primary refractory disease, nor have the optimal treatment modalities been defined. We studied 8907 patients with newly diagnosed acute myeloid leukemia and examined outcomes in patients with refractory disease defined using differing criteria which have previously been proposed. These included failure to achieve complete remission after one cycle of induction chemotherapy (RES), less than a 50% reduction in blast numbers with >15% residual blasts after one cycle of induction chemotherapy (REF1 ) and failure to achieve complete remission after two courses of induction chemotherapy (REF2). 5 year overall survival was decreased in patients fulfilling any criteria for refractory disease compared with patients achieving a complete remission after one cycle of induction chemotherapy: 9% and 8% in patients with REF1 and REF 2 versus 40% (p <0.0001). Allogeneic stem cell transplantation improved survival in the REF1 (HR 0.58 (0.46-0.74), p=0.00001) and REF2 (HR 0.55 (0.41-0.74), p=0.0001) cohorts. Utilization of REF1 criteria permits the early identification of patients whose outcome after one course of induction chemotherapy is very poor and informs a novel definition of primary refractory acute myeloid leukemia. Furthermore, these data demonstrate that allogeneic stem cell transplantation represents an effective therapeutic modality in selected patients with primary refractory acute myeloid leukaemia.
Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to co-repressors. We also observed large expansion of CFU-MKs derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton Cdc42 and RhoA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels.
Formaldehyde Exposure and Mortality Risks From Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute Cohort Study of Workers in Formaldehyde Industries
- Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine
- Published over 2 years ago
To evaluate associations between cumulative and peak formaldehyde exposure and mortality from acute myeloid leukemia (AML) and other lymphohematopoietic malignancies.
Background Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. Methods We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. Results Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. Conclusions The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535 .).
Background The majority of patients in need of a hematopoietic-cell transplant do not have a matched related donor. Data are needed to inform the choice among various alternative donor-cell sources. Methods In this retrospective analysis, we compared outcomes in 582 consecutive patients with acute leukemia or the myelodysplastic syndrome who received a first myeloablative hematopoietic-cell transplant from an unrelated cord-blood donor (140 patients), an HLA-matched unrelated donor (344), or an HLA-mismatched unrelated donor (98). Results The relative risks of death and relapse between the cord-blood group and the two other unrelated-donor groups appeared to vary according to the presence of minimal residual disease status before transplantation. Among patients with minimal residual disease, the risk of death was higher in the HLA-mismatched group than in the cord-blood group (hazard ratio, 2.92; 95% confidence interval [CI], 1.52 to 5.63; P=0.001); the risk was also higher in the HLA-matched group than in the cord-blood group but not significantly so (hazard ratio, 1.69; 95% CI, 0.94 to 3.02; P=0.08). Among patients without minimal residual disease, the hazard ratios were lower (hazard ratio in the HLA-mismatched group, 1.36; 95% CI, 0.76 to 2.46; P=0.30; hazard ratio in the HLA-matched group, 0.78; 95% CI, 0.48 to 1.28; P=0.33). The risk of relapse among patients with minimal residual disease was significantly higher in the two unrelated-donor groups than in the cord-blood group (hazard ratio in the HLA-mismatched group, 3.01; 95% CI, 1.22 to 7.38; P=0.02; hazard ratio in the HLA-matched group, 2.92; 95% CI, 1.34 to 6.35; P=0.007). Among patients without minimal residual disease, the magnitude of these associations was lower (hazard ratio in the HLA-mismatched group, 1.28; 95% CI, 0.51 to 3.25; P=0.60; hazard ratio in the HLA-matched group, 1.30; 95% CI, 0.65 to 2.58; P=0.46). Conclusions Our data suggest that among patients with pretransplantation minimal residual disease, the probability of overall survival after receipt of a transplant from a cord-blood donor was at least as favorable as that after receipt of a transplant from an HLA-matched unrelated donor and was significantly higher than the probability after receipt of a transplant from an HLA-mismatched unrelated donor. Furthermore, the probability of relapse was lower in the cord-blood group than in either of the other groups.
Childhood leukemia may be associated with traffic-related environmental exposure to benzene, and additional data are needed. The Géolocalisation des Cancers Pédiatriques (GEOCAP) Study, a nationwide French case-control study, was designed to avoid selection bias due to differential participation and misclassification. The study compared the 2,760 childhood leukemia cases diagnosed in France between 2002 and 2007 (including 2,275 cases of acute lymphoblastic leukemia (ALL) and 418 cases of acute myeloblastic leukemia (AML)) with 30,000 contemporaneous child population controls. The residence addresses were precisely geocoded, and 3 indicators of residential proximity to traffic were considered. Estimates of benzene concentrations were also available for the Île-de-France region (including Paris). A 300-m increase in major road length within 150 m of the geocoded address was significantly associated with AML (odds ratio = 1.2, 95% confidence interval: 1.0, 1.4) but not with ALL (odds ratio = 1.0, 95% confidence interval: 0.9, 1.1), and the association was reinforced in the Île-de-France region when this indicator was combined with benzene estimates. These results, which were free from any participation bias and based on objectively determined indices of exposure, showed an increased incidence of AML associated with heavy-traffic road density near a child’s home. The results support a role for traffic-related benzene exposure in the etiology of childhood AML.