ALBERT

Description: Introduction: Essential thrombocythemia (ET) is a BCL-ABL1-negative myeloproliferative neoplasm (MPN), and is characterized by increased number of mature megakaryocytes (MKs) in the bone marrow and sustained thrombocytosis in the peripheral blood. We have reported that activated B cells are increased in patients with essential thrombocythemia, and can facilitate platelet production mediated by cytokines, such as interleukin-1beta (IL-1β) and interleukin-6 (IL-6) regardless JAK2 V617F mutational status (Thromb Haemost. 2014, 112: 537). Recently, Calreticulin (CALR) mutations were discovered in JAK2/MPL-unmutated essential thrombocythemia (ET) and primary myelofibrosis. Although CALR mutations may be associated with activated JAK-STAT signaling pathway, its exact molecular pathogenesis remains elusive in MPN. Interestingly, in vitro study has shown that CALR is capable of driving B cells activation through the toll-like receptor 4 (TLR4) pathway (J Immunol.2010; 185: 4561). Here we sought to evaluate the association between CALR mutations and B cell immune profiles in ET patients. Methods: Fifty-four patients diagnosed with ET based on the 2008 WHO classification were enrolled into this study. CALR mutations were screened by high-resolution melting analysis and nucleotide sequencing. JAK2 V617F and MPL mutations were screened by allele-specific PCR and nucleotide sequencing, respectively. B cell populations, granulocytes/monocytes membrane-bound B cell-activating factor (mBAFF) and CALR levels, B cells TLR4 expression and intracellular levels of IL-1β/IL-6 and the expression of CD69, CD80, and CD86 were quantified by flow cytometry. Serum BAFF and plasma CALR concentrations were measured by ELISA. Forty-eight healthy adults and 17 patients with reactive thrombocytosis were used for comparison. The association between clinical, laboratory and molecular characteristics were studied. Statistical significance was defined as a two-sided p value

Description: Background: Discontinuation of E. coli- asparaginase in patients with acute lymphoblastic leukemia (ALL) upon severe allergic reactions is unavoidable. We aimed to examine the outcomes following E.coli- asparaginase discontinuation upon severe allergic reactions in ALL. Patients and methods : In Taiwan Pediatric Oncology Group (TPOG)-2002-ALL protocol (enrolled 2002-2012), intramuscular E. coli- asparaginase (Kyowa Hakko, Japan) was given at 5000 IU/m2 per dose thrice weekly for 3 weeks during the remission induction therapy of high-risk (HR) and very-high-risk (VHR) groups. During the first 20 weeks of continuation therapy, HR patients received weekly intramuscular E. coli- asparaginase 10,000 IU/m2 per dose every week. They also received two reinduction treatments during which E.coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 3 weeks. Patients in VHR groups received one reinduction treatment during which E. coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 2 weeks. Patients in standard-risk (SR) group, received no E. coli- asparaginase in induction, but were randomized to receive one or two reinduction phases, during which E. coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 2 weeks. The scheduled cumulative doses of E.coli- asparaginase in each risk group were 30,000 IU/m2 or 60,000 IU/m2 in SR, 265,000 IU/m2 in HR and 75,000 IU/m2 in VHR group. We evaluated outcome of children enrolled in TPOG-2002-ALL protocol who had E. coli- asparaginase discontinued due to severe allergic reactions (marked swelling and redness at the injection site or anaphylaxis) between 2002 and 2012, and compared outcomes between those who with Erwinase continued and those who without after the discontinuation of E. coli- asparaginase. The distributions of the Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) were compared using log-rank test. Chi-square test was used to compare each parameter between groups. Results: In 700 patients from 10 hospitals retrospectively studied, 52 patients had E. coli- asparaginase treatment discontinued due to the development of severe pancreatitis in 17 patients, severe thrombosis in 2, and severe allergic reactions in 33. In Taiwan, Erwinase has been available since 2012, and could be purchased from foreign countries before. PEG-asparaginase is not available in Taiwan. In the 33 patients had E. coli- asparaginase discontinued due to severe allergic reactions, 17 continued Erwinase and 16 did not. The parameters between these two groups were similar. They were of more HR group reflecting that HR patients received more E. coli- asparaginase than other patients. The 5-year OS did not differ significantly among the 648 patients without discontinuation (81±1.6%, mean±S.E.), the 17 with allergic reactions and continued with Erwinase (88±7.8%) and the 16 with allergic reactions not treated with Erwinase (87±8.6%). The P value for the difference between the latter two groups was 0.96. In the 16 patients who did not receive Erwinase, all the 10 patients, who had received 〉= 50% scheduled dose of E.coli- asparaginase before discontinuation, survived without events. Conclusions: We suggest that patients who had received 50% or more of the scheduled doses of E. coli- asparaginase before the development of severe allergic reactions do not need to continue treatment with Erwinase. This may be helpful in those who cannot afford Erwinase or in the vast majority of the world where Erwinase is not available. It also raises a question on that how much asparaginase is enough for the treatment of childhood ALL. Disclosures No relevant conflicts of interest to declare.

Description: Background: Calreticulin (CALR) mutations are one of the major driver mutations in BCL-ABL1-negative myeloproliferative neoplasm (MPN) and are frequently detected in JAK2/MPL-unmutated essential thrombocythemia and primary myelofibrosis. Mutant CALR activates JAK-STAT signaling through an MPL-dependent mechanism to mediate pathogenic thrombopoiesis in MPNs. Although JAK inhibitors such as ruxolitinib can provide important clinical benefits to MPN patients including those harboring CALR mutations, JAK inhibition does not preferentially target the MPN clone and acquired resistance develops over time. We aimed to characterize the mechanisms of acquired resistance to JAK inhibitors in CALR-mutated hematopoietic cells and to screen for novel therapeutic approaches specifically target CALR-mutant cells in this study. Methods: UT-7/TPO-derived cell lines expressing wild-type and type 1 and type 2 mutant CALR (CALRdel52 and CALRins5) were kindly provided by Drs. Komatsu and Araki. JAK2-inhibitor-resistant cells were generated by co-cultured with ruxolitinib and fedratinib (TG101348, a JAK2-selective inhibitor). JAK-STAT signaling was evaluated by Western blot on CALR-wild-type and mutated cells exposed to JAK2 inhibitor compared to untreated cells. For the detection of acquired secondary mutations in CALR-mutated cells exposed to JAK2 inhibitor, whole exome sequencing (WES) was performed using the BGISEQ-500 Sequencing platform (BGI, Shenzhen, China) with the 2 x 100 bp paired-end protocol. Genome Analysis Toolkit was used for variation detection. Reads were aligned to human reference genome hg19 using BWA version 0.7.15. Targeted resequencing was performed on leukocytes from patients with MPN who had been treated with ruxolitinib. Screening with chemical libraries/novel compounds will be conducted on UT7/TPO-CALR cell lines. Results: Compared to the parental cells, ruxolitinib-resistant UT7/TPO-CALR mutant cell lines have developed significant cross resistance to other JAK inhibitor as shown in the cell viability study. Signalling downstream of JAK2 in all 3 inhibitor-naïve UT-7/TPO/CALR parental cell lines was inhibited by acute treatment of ruxolitinib as shown on Western blot. Whereas, constitutive JAK2 activation was observed in all 3 inhibitor-resistant UT-7/TPO/CALR cell lines. No change in the expression of Epo and MPL receptors in these cell lines was found. Interestingly, constitutive JAK3 activation was also seen in inhibitor-resistant UT-7/TPO/CALR cells in comparison with parental cells. These findings indicated the presence of transphosphorylation by JAK3 in inhibitor-resistant UT-7/TPO/CALR cell lines. In addition, the results of WES identified several acquired secondary mutations in 3 inhibitor-resistant UT-7/TPO/CALR cell lines including SH2B1, ABCC1, HOXB3 and KRTAP4-5. No acquired secondary mutation was identified in CALR and other genes involved in JAK-STAT signaling. Acquired secondary mutation will be screened in primary MPN patients' samples treated with JAK inhibitor. Type II JAK inhibitor such as BBT-594 has been shown to inhibit JAK activation and signaling in JAK-persistent/resistant cells. Conclusions: Our results confirmed that the in vitro efficacy of JAK2 inhibition on CALR-mutant cells. Our data also suggested that JAK2 transphosphorylation and acquired secondary mutations could be underlying mechanisms for acquired resistance to JAK inhibitors in CALR-mutated cells. Novel therapeutics approaches should be developed to overcome acquired resistance in CALR-mutated cells. Disclosures No relevant conflicts of interest to declare.

Description: Key Points L5 is elevated in ischemic stroke patients, and its receptor, LOX-1, plays a critical role in increasing stroke size. L5 induces platelet secretion of Aβ to potentiate platelet activation and aggregation via LOX-1 and IKK2.

Description: Mutations in the additional sex comb-like 1 (ASXL1) gene were recently shown in various myeloid malignancies, but they have not been comprehensively investigated in acute myeloid leukemia (AML). In this study, we analyzed ASXL1 mutations in exon 12 in 501 adults with de novo AML. ASXL1 mutations were detected in 54 patients (10.8%), 8.9% among those with normal karyotype and 12.9% among those with abnormal cytogenetics. The mutation was closely associated with older age, male sex, isolated trisomy 8, RUNX1 mutation, and expression of human leukocyte antigen–DR and CD34, but inversely associated with t(15;17), complex cytogenetics, FLT3–internal tandem duplication, NPM1 mutations, WT1 mutations, and expression of CD33 and CD15. Patients with ASXL1 mutations had a shorter overall survival than patients without, but the mutation was not an independent adverse prognostic factor in multivariate analysis. Sequential analyses showed that the original ASXL1 mutations were lost at relapse and/or refractory status in 2 of the 6 relapsed ASXL1-mutated patients studied, whereas 2 of the 109 ASXL1-wild patients acquired a novel ASXL1 mutation at relapse. In conclusion, AML bearing ASXL1 mutations showed distinct clinical and biological features. The ASXL1 mutation status can change during disease evolution in a few patients.

Description: Background Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is the preferred treatment for patients with severe acquired aplastic anemia (SAA) ineligible for hematopoietic stem cell transplantation. In 2007, horse ATG (hATG) was removed from most markets outside the US limiting patients to the use of rabbit ATG (rATG). Response rates for hATG range from 60-70%, with overall survival (OS) rates of 60-90% (Korean J Intern Med. 2014;29:713-726). Although, many studies have shown no differences in efficacy between ATG types, others have shown rATG to be inferior to hATG. A prospective study by the US National Institutes of Health (NIH) showed a 6-month RR of 37% for rATG compared to 68% for hATG (N Engl J Med. 2011;365:430-438). The discrepancies in efficacy could be due to many factors including dose and ethnicity. We aimed to analyze hematologic response, survival, and safety of rATG (Thymoglobulin®) as first-line therapy of SAA and very SAA (vSAA) in Asian patients of all ages. Methods We retrospectively reviewed the medical records of 97 consecutive patients who received rATG in combination with cyclosporine and/or a corticosteroid as first-line treatment of SAA or vSAA at participating centers in Malaysia, Taiwan, Hong Kong, and Thailand between 2006 and 2012. The primary endpoint was overall RR (ORR) (complete response [CR] plus partial response [PR]) at 6 and 12 months for patients receiving rATG within the recommended dose range (2.5-3.75 mg/kg/day). Response was evaluated using British Guidelines (Br J Haematol. 2009;147:43-70). Secondary endpoints included ORR in patients receiving any dose of rATG, 2-year OS, OS in responders vs non-responders, relapse rate, and safety. Response and survival with 95% confidence intervals (CI) were estimated using the Kaplan-Meier method. Results Patient median age was 31 years (range 2-81 years); 51% (n= 49) were male and 49% (n=48) female. Eighty-seven percent (n=84) were diagnosed with SAA and 13% (n=13) with vSAA. Twelve patients were excluded from the response evaluation due to the following: lack of post-baseline response data, n=6; second-line rATG within 3 months of first-line treatment, n=3; did not meet criteria for SAA, n=3. Of the 85 patients evaluable for response, only 73% (n=62) received rATG within the recommended dose range; 20% (n=17) received 〈 2.5 mg/kg/day and 7% (n=6) received 〉 3.5 mg/kg/day. For patients who received rATG within the recommended dose range, 6- and 12-month ORR were 17.4% (95% CI, 9.8-30.0) and 63.6% (95% CI, 49.4-77.7), respectively. For patients who received any dose of rATG, 6- and 12-month ORR were 24.3% (95% CI, 16.2-35.4) and 68.6% (95% CI, 56.9-80.1), respectively. The 2-year OS rate was 86.3% (95% CI, 77.0-92.0). For patients with a response to treatment (n=46), the 2-year OS was 97.7% (95% CI, 84.6-99.7) compared to 78.9% (95% CI, 59.9-89.6) for patients with no response (n=39), P =.006. The 2-year rate of relapse rate was 6.3% (95% CI 2.1-18.2). The most common serious adverse events (≥ 5%) that occurred within 30 days of last treatment were febrile neutropenia (28%), sepsis (12%), pyrexia (5%), and pneumonia (5%). Grade 4 infusion-related reactions occurred in only 1 (1%) patient. Conclusions Although the 6-month ORR for rATG was low compared to hATG in the NIH study, the 12-month ORR and 2-year OS were comparable to historical results obtained with hATG, suggesting that more time may be needed to achieve maximal response with rATG. Our results show that rATG is an effective form of IST in the Asian population with over 60% of patients achieving a CR or PR at 12 months and an overall survival rate of 86.3% at 2 years. Disclosures Wong: GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Rojnuckarin:Sanofi: Research Funding. Chang:Novartis: Honoraria.

Description: Introduction: Essential thrombocythemia (ET) is a classic BCL-ABL1-negative chronic myeloproliferative neoplasm (MPN), and is associated with an increased risk of hemorrhagic and thrombotic complications and leukemic transformation. Recently, two research groups discovered a high frequency of somatic calreticulin (CALR) mutations in patients with JAK2 V617F/MPL-unmutated ET and primary myelofibrosis. The pattern of most CALR mutations in MPNs is indels in exon 9 causing one base pair reading frameshift. CALR mutations have been found to have important diagnostic and prognostic significances in patients with ET. High-resolution melting analysis (HRMA) is a well-established method for the detection of or screening for mutations. The aims of this study were to screen for CALR mutations and to determine its clinical correlation in a cohort of adult Taiwanese patients with ET, and to test for the feasibility of HRMA as a screening method for the detection of CALR exon 9 mutations. Methods: The screening for mutations in patients with hematologic neoplasms was approved by the Institutional Review Board of Mackay Memorial Hospital. 92 adult Taiwanese patients with ET were enrolled. Diagnosis of ET was established based on the 2008 WHO criteria. The clinical and laboratory characteristics of all patients at the time of diagnosis or referral were determined retrospectively by chart review. Genomic DNA derived from bone marrow, peripheral whole blood, and peripheral blood granulocytes or peripheral blood mononuclear cells were used for the screening. JAK2 V617F mutational status was screened by allele-specific polymerase chain reaction. CALR exon 9 mutations and MPL exon 10 mutations were screened by nucleotide sequencing on an ABI 3730 sequencer. The correlation between CALR mutational status and clinical characteristics was determined by using SPSS Statistics software (IBM, New York, USA). HRMA was performed with a CFX96 real-time PCR detection system (Bio-Rad Laboratories, Hercules, CA). Results: In this cohort of ET patients, 59 (64%) patients harbored the JAK2 V617F mutation and one (1%) patient harbored the MPL W515K mutation. By Sanger sequencing, 17 (18% overall and 50% in JAK2/MPL-unmutated cases) patients harbored 6 types of CALR exon 9 mutations: 5 type 1 (p.L367fs*46), 6 type 2 (p.K385fs*47), 2 type 3 (p.L367fs*48), 2 type 34 (p.K385fs*47), and 2 novel types (p.L367fs*43 and p.E369fs*50). One patient with JAK2 V617F mutation was found to harbor a single nucleotide polymorphism in CALR exon 9 (c.1142 A〉C, rs143880510). One patient with JAK2 V617F mutation also harbored a CALR type 3 mutation (p.L367fs*48), and was excluded from the correlation study. When compared with JAK2 V617F mutated ET patients, the presence of CALR mutations correlated with higher platelet count (median 1379 x10^9/L vs. 880 x10^9/L; P

Description: Background: Essential thrombocythemia (ET) is a BCL-ABL1-negative myeloproliferative neoplasm characterized by increased number of mature megakaryocytes in the bone marrow and sustained thrombocytosis in the peripheral blood. ET is associated with an increased risk of hemorrhagic and thrombotic complications and leukemic transformation. In addition to somatic mutations, microRNA (miRNA) deregulation has been proposed to play roles in the molecular pathogenesis and disease phenotype in ET patients. The aims of this study were to investigate the plasma miRNA profiles in ET patients with those obtained from healthy adults (HA) and its correlation with clinical and prognostic features. Methods: ET patients seen at the MacKay Memorial Hospital were enrolled into this study. The clinical and laboratory characteristics at the time of diagnosis or referral were determined retrospectively by chart review. Total plasma miRNA was derived from bone marrow or peripheral blood in patients or HA. Mutational status of JAK2V617F,CALR and MPL were detected by Sanger sequencing and/or allele-specific PCR. Plasma miRNA profiling was carried out on PanelChip™ Analysis System (Quark Biosciences, Taiwan) using a customized miRNA panel including 165 miRNAs called mirSCAN™ PanCancer Chips 1 & 2. KEGG pathways that miRNAs were associated with were analyzed using DIANA TOOLS - mirPath v.3. Differentially expressed miRNAs were identified by student t-test (P 〈 0.05) and significantly affected miRNAs in ET were identified by a change in expression of two-fold or more compared to the expression in HA. Statistical analysis was performed using SPSS. Results: A total of 53 ET patients (median age at diagnosis 59 years; 60.4% females) were enrolled. Frequency of the 3 driver mutations was 64% for JAK2V617F, 15% CALR, 4% JAK2V617F and CALR co-mutations, and none for MPL. 17% of patients were classified as triple-negative. A total of 40 differentially expressed miRNAs were identified (Figure left axis) including 4 miRNAs (hsa-miR-940, hsa-miR-411-5p, hsa-miR-596 and hsa-miR-376c-3p) with higher expression levels. The putative target genes of these 40 differentially expressed miRNAs were enriched in signaling pathway including TGF-beta signaling pathway (p-value = 1.86E-12), Hippo signaling pathway (p-value = 1.84E-07), MAPK signaling pathway (p-value = 0.03), and FoxO signaling pathway (p-value 〈 0.001). According to the expression levels of these 40 miRNAs, samples were grouped into two clusters, i.e. low expression group and high expression group. ET patients with JAK2V617F were significantly associated with high expression of 40 miRNAs (n = 31 of 34, 91%) when compared with triple-negative ET patients (n = 5 of 9, 56%) (p = 0.03). ET patients with low expression of 40 miRNAs were significantly associated with acute leukemia transformation (n = 2 of 11, 18%) when compared with high expression group (n = 0 of 42, 0%) (p = 0.04). However, the expression levels of 40 miRNAs were not statistically correlated with other clinical features including hemogram, secondary solid cancer, myelofibrosis transformation, or thrombotic/hemorrhagic events. Conclusions: In this cohort of ET patients, distinct plasma miRNA profiles correlated with JAK2V617F mutation and leukemic transformation. Larger cohort is warranted to validate our findings. Figure Figure. Disclosures Chen: Quark Biosciences, Inc.: Employment. Kang:Quark Biosciences, Inc.: Employment. Huang:Quark Biosciences, Inc.: Employment. Lin:Quark Biosciences, Inc.: Employment. Wang:Quark Biosciences, Inc.: Employment.

Description: Background Iron overloading is a common problem for adult with myelodysplastic syndrome (MDS), aplastic anemia (AA) or other chronic anemia. Deferasirox (DFX) has been proven as an effective therapy to chelating iron in these patients. Anyway, the safety of DFX is still a concern, and the information of safety profiles and efficacy are less understood in Taiwan. This study is planned primarily to collect long-term safety data of DFX treatment in iron-overloaded MDS, AA and other chronic anemia patients in Taiwan. Study Design This is an observational, single-arm, and multi-center study. Low-risk MDS or AA patients with transfusion-related iron overload, or patients with other anemia and serum ferritin more than 2000 ug/ml, were enrolled within the 18-month enrolling period if DFX is planned to be prescribed. Exposure of iron chelating agents other than DFX before trial initiation was allowed. The initial dose and subsequent adjustment of DFX were up to investigator¡¦s preference. All patients were followed for 3 years for adverse events (AEs) and disease outcomes. Results From 2009 to 2011, 79 patients were enrolled in this study, including 38 MDS, 23 AA and 18 other chronic anemias. Forty-seven cases (59.5%) were male, with mean age 64.3¡Ó17.8 y/o. Fifty-six (70.9%) subjects failed to complete the 3-year study period, but only 8 (10.1%) of the subjects withdrew DFX due to drug-related AEs. The mean DFX exposure dose during study was 17.7¡Ó4.02 mg/Kg/day. In contrast with those reported in literature, the most frequently reported drug-related AEs were rash (16, 20.3%), diarrhea (11, 14.0%), hypercreatinemia (8, 10.1%), pruritus (7, 8.9%), and so on (as in Table 1). When classified by organ systems, skin disorders were the frequently reported one (26, 32.9%), and followed by GI disorders (n=24, 30.4%). Grade 3-4 drug-related adverse events were rare (n=4, 5.1%). For all subjects, DFX could effectively decrease serum ferritin level from baseline (-985+/-2090 ng/ml (p=0.0154 vs. baseline) and -1710+/-2290 ng/ml (p=0.0424 vs. baseline) at 1 yr and 3 yr, respectively) (as in Figure 1). Notably, after DFX usage, 23 patients (32.4%) developed erythroid response according to IWG 2006 criteria; the mean hemoglobin could increase from 7.77+/-1.63 gm/dl (baseline) to 8.25+/-2.60 gm/dl (at 36 month, p=0.6172 vs. baseline), when the average transfusion amount was decreased from 2.3+/-1.4 units (baseline) to 1.6¡Ó0.5 units (at 36 months, p=0.0406 vs. baseline). (as in Figure 2). Ten patients (10/46, 21.7%) had platelet response. For the 38 MDS patients, DFX also could significantly lower serum ferritin level (-590+/-2490 ng/ml (p=0.4095 vs. baseline) and -1310+/-362 ng/ml (p=0.0013 vs. baseline) at 1 yr and 3 yr, respectively) but seemed to have a less extent than that in overall population. Similarly, 10 patients (21.7%) developed erythroid response after DFX use. The mean hemoglobin increment (from 7.67+/-1.67 gm/dl (baseline) to 8.55+/-3.45 gm/dl (at 36 month, p=0.6012 vs. baseline)) and the decrease of average transfusion amount (from 2.1+/-1.2 units (baseline) to 1.6+/-0.6 units (at 36 months, p=0.2943 vs. baseline) were not significant, probably due to low case number (as in Figure 2). Four (4/19, 21.1%) patients experienced platelet response. Conclusion This study showed that the profiles of AEs regarding DFX use for adult anemic patients with transfusion-related iron overload in Taiwan were significantly different from those reported in Western countries. The AE-related discontinuation rate was also relatively low. An expected efficacy to lowering serum ferritin by DFX, and a significantly degree of hematological improvement was noted, too. Table 1. Drug-related adverse events, for all events with incidences 〉 5% and all grade 3-4 events: Table 1. Drug-related adverse events, for all events with incidences 〉 5% and all grade 3-4 events: Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Chang: Novartis: Honoraria.

Description: Mutations 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.