Chinese Acute Myeloid Leukemia Patients Research Articles

IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders

Frequent mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) have been identified in gliomas and acute myeloid leukemia (AML). Our aim is to assess whether IDH mutations were presented in Chinese patients with various hematological disorders. In this study, we screened the IDH1 and IDH2 mutations in a cohort of 456 Chinese patients with various hematological malignancies and disorders. We found three missense (p.R132C, p.R132G, and p.I99M; occurred in five patients) and one silent mutation (c.315C>T; occurred in two patients) in the IDH1 gene and two missense mutations (p.R140Q and p.R172K; occurred in four AML patients) and one silent mutation (c.435G>A) in the IDH2 gene. Except for one non-Hodgkin lymphoma (NHL) patient harboring IDH1 mutation p.R132C, all IDH1 and IDH2 missense mutations were observed in patients with AML. Intriguingly, the IDH2 mutation p.R140Q and novel IDH1 mutation p.I99M co-occurred in a 75-year-old patient with AML developed from myelodysplastic syndromes (MDS). The frequency of IDH1 and IDH2 missense mutations in Chinese AML patients reached 5.9% and 8.3%, respectively. Our results supported the recent findings that IDH gene mutations were common in AML. Conversely, IDH mutations were rather rare in Chinese patients with other types of hematological disorders.

Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation

AbstractMutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genome-wide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P = .002), isolated monosomy 8 (P = .043), NPM1 mutation (P < .001), and French-American-British M1 subtype (P < .001), but inversely associated with French-American-British M4 subtype (P = .030) and expression of HLA-DR, CD13, and CD14 (P = .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during follow-ups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution.

A Multicentre, Randomized Study of FLAG Treatment in China(CHORT).

Introduction: Adult de novo patients with acute myeloid leukemia (AML) may achieve 70%-80% of clinical remission after induction treatment, but unfortunately some proportion of them will get relapse, and the prognosis in these patients is quite poor. Clinicians have been devoted themselves to exploring new effective strategies to re-induce remission in these kind of population including FLAG, which containing fludarabine, cytosine arabinoside (Ara-C), plus granulocyte colony-stimulating factor (G-CSF). FLAG was proved to be one of the most effective salvage treatments in relapsed or refractory AML patients. Our study was designed to assess the efficacy and safety of FLAG in Chinese AML patients and further to compare the clinical efficacy and safety between different dosage of Ara-C in FLAG treatment.Methods: This is multicentre, open-label, randomized clinical trial. Relapsed or refractory non-M3 AML patients were randomly assigned to 2 treatment group. Group A: 30mg/m2/d of fludarabine intravenous infusion through d1-d5, plus G-CSF 300μg/d, starting 24 hours before treatment and continuing to d5, 1.0g/m2 of Ara-C intravenously infusion from day 1 through 5, abbreviated as FLAG 1.0. Group B: fludarabine and G-CSF were used as same as those in Group A, but dosage of Ara-C increased to 2.0g/m2 daily from d1-d5, named as FLAG 2.0.Results: Between 2006 and 2008, 398 cases of patients from 72 medical centers in China were enrolled into the study with informed consent. 177 cases were entered into analysis, with median age of 39 yrs (range 16–80) and male: female ratio of 1.7:1. 97 cases were assigned into FLAG 1.0 whereas 80 in FLAG 2.0. 73 (41.7%) of patients were diagnosed as M2, 33(18.9%) in M4, 33 (18.9%) in M5, and the other 38 in other subtype of leukemia. And 52/177 cases (29.4%) were in first relapse, while 51 (28.8%) in multi-relapse and 74 (41.8%) in refractory disease. Totally 120 out of 177 patients achieved response remission (67.8%) including 88 (49.7%) in complete remission (CR) and 32 (18.1%) in partial remission (PR). 18 cases (10.2%) had stable disease, 20 (11.3%) had progressive disease, 10 (5.6%) in non-response, and 9 cases died. Among these 9 cases, 8 suffered from serious infection and fatal bleeding during bone marrow suppression and another 1 died due to psychological obstacles. The main side effect during treatment were neutropenia (77.4%, with neutrophil ≤ 0.5×109/L ) , thrombocytopenia (73.4%, with platelet count ≤ 50×109/L), nausea and vomiting (41.8%), and infection (54.8%), but most of them were moderate and the patients got recovery by using supportive treatment. Patients in first relapse had better RR (81.2%) when compared to those in multi-relapse or in refractory disease (55.8% and 64.8%, p=0.004). And, M2 patients had higher RR (76.8%) than those in M4 (58.9%) and similar to the response in M5 patients (76.5%). More of interest, among 80 patients who received FLAG 2.0 treatment, 42 (52.5%) achieved CR, while 45 out of 97 (46%) got CR in FLAG 1.0. And most important, the side effect including the hematological or non-hematological toxicities were comparable between two groups except the neutropenia (82.8%: 71%, p=0.019) and oral ulcer (27.5%:15%, p<0.001).Conclusion: FLAG was proven to have good clinical efficacy in refractory or relapsed Chinese AML patients with well tolerated toxicities. Enhanced Ara-C dosage (FLAG 2.0) had better clinical response although it didn't reach to the statistical difference, with comparable and manageable side effects, when compared to those in FLAG1.0 treatment. Long-term follow-up were warranted to properly evaluate the efficacy of FLAG treatment, and to compare the therapeutic benefit between FLAG 1.0 and FLAG 2.0 treatment in these relapsed or refractory AML patients.

Correlation between MDR1 genetic polymorphism and prognosis in acute myeloid leukemia

To assess the correlation of the multidrug resistance-1 (MDR1) gene single nucleotide polymorphisms (SNP) C1236T, G2677T/A and C3435T with the outcome of induction chemotherapy in patients with de novo acute myeloid leukemia (AML). A total of 44 AML patients were enrolled in this study. Genotype of MDR1 C1236T, G2677T/A and C3435T were analyzed with PCR/PFLP assay. Bone marrow smear was made at the end of the first induction chemotherapy to estimate whether complete remission (CR) has been achieved with the clinical characteristics. The Hardy-Weinberg equilibrium for the MDR1 C1236T, G2677T/A and C3435T were tested using a chi(2) analysis. Frequencies of genotype and allele in MDR1 C1236T, G2677T/A and C3435T were compared using a chi(2) test or Fisher's test in terms of the clinical characteristics or achievement of CR. There were significant differences among ethnicities in exon 12, 21, 26, but which were not between healthy chinese volunteers and AML patients. The CR rate of the group with the number of white blood cells (WBC) < 10 x 10(9)/L were significantly higher than that of the group with WBC > 10 x 10(9)/L (chi(2) = 7.207, P = 0.007). There was no correlation between the MDR1 C1236T and C3435T and CR rate (P = 0.349, P = 0.074), but MDR1 G2677T/A genetic polymorphisms were strong associated with the probability of CR (chi(2) = 6.214, P = 0.045). In addition, the CR was lower in G/G genotype at -2677 than non G/G genotype (chi(2) = 6.142, P = 0.013), and was lower in C/T genotype at -3435 than non C/T genotype (chi(2) = 3.991, P = 0.046), even lower than T/T genotype (chi(2) = 5.134, P = 0.023). With important prognostic significance, MDR1 genetic polymorphisms, such as G2677T/A can predict whether complete remission can be achieved after the first course of induction chemotherapy.