Intermediate-dose Ara-C Research Articles

Efficacy and safety of intermediate-dose cytarabine in the treatment of children with refractory high risk Langerhans cell histiocytosis

Objective: To analyze the efficacy, safety, and long-term prognosis of intermediate-dose cytarabine (Ara-c) regimen in the treatment of children with refractory risk organ involvement Langerhans cell histiocytosis (LCH). Methods: Clinical data of 17 children with multisystem and risk organ involvement LCH who failed the first-line therapy and were treated with intermediate-dose Ara-c (250 mg/m2, twice daily) regimen in the Hematology Center, Beijing Children's Hospital from January 2013 to December 2016 were analyzed retrospectively. In addition to the basic treatment of vindesine and dexamethasone, the patients received two regimens: regimen A: the intermediate-dose Ara-c combined with cladribine and regimen B: the intermediate-dose Ara-c alone. The efficacy, safety and prognosis of the two regimens were analyzed. Results: Among all 17 patients, there were 11 males and 6 females, with the diagnosis age of 2.1 (1.6, 2.7) years. Ten children received regimen A, all of them achieved active disease-better (AD-B) after 8 courses of induction therapy. The disease activity scores (DAS) decreased from 5.5 (3.0, 9.0) to 1.0 (0, 2.3). Seven children received regimen B, and 6 of them achieved AD-B after 8 courses of induction therapy. The DAS decreased from 4.0 (2.0, 4.0) to 1.0 (0, 2.0). The follow-up time was 6.2 (4.9,7.2) and 5.2 (3.7,5.8) years in group A and B. The 5-year overall survival rate was 100.0% in both groups, and the 5-year event free survival rate was (88.9±10.5)% and (85.7±13.2)% in group A and B. Grade 3 or 4 myelosuppression was observed in 8 patients in group A and 2 patients in group B. Conclusions: The intermediate-dose Ara-c regimen (with or without cladribine) is effective and safe for patients with refractory high-risk LCH, with a good long-term prognosis.

Venetoclax Combining with Homoharringtonine，Daunorubicin and Cytarabine (HAD) As Induction Treatment in Newly Diagnosed Adult Acute Myeloid Leukemia Patients

INTRODUCTION Venetoclax (Ven), a potent oral inhibitor of BCL-2, has improved clinical outcomes in acute myeloid leukemia. For chemotherapy-fit patients, Ven combined with intensive chemotherapy (IA, CLIA, FLAG-IDA and DA) achieves high complete response (CR) rate and measurable residual disease (MRD)-negative rates in de novo AML after one cycle of induction therapy. Homoharringtonine (HHT, omacetaxine mepesuccinate) is an alkaloid derived from trees of the genus Cephalotaxus. HHT, cytarabine (Ara-C) and daunorubicin (DNR) regimen (HAD) have been used as standard remission induction regimen in China. Here, we reported the data of 25 patients with newly diagnosed AML who were administered with Venetoclax combining with dose-reduced HAD as induction treatment in our hospital. The purpose of this study was to observe the efficacy and safety of the regimen. METHODS Between May 2022 and February 2023, twenty-five newly diagnosed AML who fulfilled the criteria of AML according to the 2016 World Health Organization (WHO) classification were treated with Ven combined with HAD as induction treatment. The induction regimen consisted of oral Ven (100mg Day -1; 200mg Day 0; 400 mg, Days 1-7), intravenous HHT (2mg/m 2/d, Days 2-6), DNR (45 mg/m²/d, Days 4-5), and Ara-c (100 mg/m 2/d, Days 2-6). After achieving CR, allogeneic hematopoietic stem-cell transplantation (allo-HSCT) were recommended according to ELN guidelines. Patients who could not or did not need allo-HSCT received consolidation ± maintenance therapy. The consolidation therapy included two cycles of Ven combining with intermediate-dose Ara-C (Ven 400 mg on Days 1-7, Ara-C 1 g/m 2/q12 h Days 2-4), two cycles dose-reduced DA (DNR 45 mg/m², Days 1-2 and Ara-C 100 mg/m², Days 1-5) chemotherapy and one cycle HA (HHT 2 mg/m², Days 1-5 and Ara-C 100 mg/m², Days 1-5). After completing consolidation treatment, patients (intermediate and adverse risk) entered maintenance therapy with AZA (100 mg/d, Days 1-5) every month for at least four cycles. The primary endpoints were the overall response rate (ORR), included of complete remission (CR), complete remission with incomplete blood cell count recovery (CRi), and partial response (PR). Secondary endpoints were overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and the safety of regimens. RESULTS Between May 2022 and February 2023, 25 patients who were enrolled in this study. Baseline characteristics of the twenty-five patients are shown in Table 1. After one cycle of induction therapy, twenty-one patients achieved CR, CR rate was 84.0% (21/25 95% CI, 68.6-99.4); one patient achieved PR. The ORR (CR+PR) was 88.0% (22/25 patients; 95% CI, 74.3-100). Three NR patients and one PR patient achieved remission after salvage therapy. For patients who achieved CR after one cycle of induction therapy, MRD was evaluated in 21 patients by flow cytometry and 17 patients attained MRD negative (81.0%; 95% CI, 61.6-96.7). None patient died before response evaluation . To June 20, 2023, with a median follow-up of 10.0 (4-13) months, 9 (36.0%) patients underwent allo-HSCT. The median OS, EFS, and DFS were not reached, and the estimated 1-year OS, EFS, and DFS rates were 100%, 94.7% (95% CI, 89.6-99.8%), and 94.7% (95% CI, 89.6-99.8%), respectively (Figure 1). The most frequent hematological adverse events were Grade 3 to 4 anemia, thrombocytopenia, and neutropenia during the induction treatment and occurred in all patients (25/25 100%). The most frequent grades 3-4 non-hematological adverse events were febrile neutropenia (25/25 patients, 100%). None of patients died during the induction therapy. Conclusion: Ven combined with HAD is an effective and safe induction regimen in de novo AML patients. It is worth and necessary to enroll more patients to further verify this regimen. 【Keywords】Venetoclax; HAD; AML; induction treatment

Venetoclax Combined with Homoharringtonine and Cytarabine ( HAV) As Induction Treatment in Elder or Intensive Chemotherapy (IC) Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia

INTRODUCTION In recent years, venetolax (Ven)-based combination therapy has significantly improved the efficacy of patients with newly diagnosed acute myeloid leukemia (AML). In CAVEAT trial (VEN+IA), both 200mg and 400mg Ven combining with IA 2+5 achieved promising results. Homoharringtonine (HHT, omacetaxine mepesuccinate) is an alkaloid derived from trees of the genus Cephalotaxus. HHT combined with Ara-C (HA) based regimens as induction regimen have been used broadly in new diagnosed AML patients in China. Previous reports shown that HHT could inhibit the anti-apoptotic protein MCL-1, BCL-XL and may exert a synergistic effect when combining with Ven. Therefore, we designed the VEN combining HA (HAV) as induction regimen in newly diagnosed AML patients. We retrospectively collected and analyzed the clinical data of HAV as induction treatment in thirty-threeelder or intensive chemotherapy ineligible patients with newly diagnosed AML. The purpose of this study was to evaluate the efficacy and safety of the regimen. METHODS Retrospectively collected and analyzed the clinical data of thirty-three patients treated with Ven+HA as induction therapy between July 2020 and April 2023. The induction regimen consisted of oral Ven (100mg Day 0; 200mg Day 1-14), intravenous HHT (2 mg/m², days 3-9), and cytarabine (50 mg/m 2, days 3-9). After achieving CR or CRi, allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) were recommended according to ELN guideline and Chinese guidelines for the diagnosis and treatment of adult AML. Patients who are ineligible to allo-HSCT received consolidation and maintenance therapy. The consolidation therapy included two cycles of Ven combining with intermediate-dose Ara-C (Ven 400 mg on Days 1-7, Ara-C 1 g/m 2/q12 h Days 2-4, or Ara-C 0.5g/m 2/q12h Days in the patient older than 65 years ), one cycles DA (DNR 45 mg/m², Days 1-2 and Ara-C 100 mg/m², Days 1-5) chemotherapy and two cycle HA (HHT 2 mg/m², Days 1-5 and Ara-C 100 mg/m², Days 1-5). Patient (intermediate and adverse risk) who remained in CR after consolidation therapy received maintenance therapy. The maintenance treatment adopted AZA (100 mg/d, Days 1-5) every month for at least four cycles. The primary purpose was evaluated the efficacy and safety of HAV regimen in elder or intensive chemotherapy ineligible patients with de novo AML. Secondary purpose was overall survival (OS), event-free survival (EFS), disease-free survival (DFS). RESULTS Until April 2023, thirty-three patients with de novo AML were treated with HAV as induction therapy. Baseline characteristics of the 33 patients are shown in table 1. The ORR (CR+PR) after one cycle of induction was 90.9% (95% CI, 80.6-100%)with CR rate of 87.9% (95% CI, 76.1-99.6%). Moreover, 79.3% (23/29) of the CR patients were MRD undetectable (95% CI 63.6-95.0%). Grade 3 or worse adverse effects included neutropenia (100%), thrombocytopenia (100%), febrile neutropenia (100%). None of patients died during the induction therapy. The median neutrophil and platelet recovery times were 10 (range: 5-15) and 10 (range: 3-17) days, respectively. Until June 30, 2023, with a median follow-up of 10 (2-23) months, 5 patients proceed allo-HSCT, the estimated 12-month OS, EFS, and DFS rates were 83.0% (95% CI: 73.4-92.6%), 71.3% (95% CI: 60.0-82.6%), and 75.9% (95% CI: 64.4-87.4%), respectively. (Figure 1) Conclusion: HAV is a highly effective and safe induction therapy for elderly or IC ineligible newly diagnosed AML. 【Keywords】Venetoclax; HAV; AML; induction treatment; elder ; ineligible

Shotgun Sequencing of Multi-Site Oral and Colonic Microbiota in Patients with AML: Site-Specific Patterns and Microbiota Decompartmentalization

Gut microbiota is a source of pathogens in immunocompromised patients. While most microbiota studies in patients with AML receiving induction chemotherapy have focused on the gut microbiota, the few on salivary microbiota suggest less severe dysbiosis. As the saliva does not have its own intrinsic microbiota and takes fractions of the microbiota from the different oral tissues it bathes, the extent to which the salivary microbiota reflects microbial changes in other oral sites is unknown. To fill this knowledge gap, we characterized the microbiota in longitudinal salivary, supragingival plaque, and fecal samples of AML patients receiving inpatient chemotherapy. 31 patients have been enrolled in this prospective single-center study. Baseline stool, saliva, and plaque samples were collected at baseline and repeated weekly until 5 weeks after starting chemotherapy or discharge from the hospital, whichever occurred first. Time was divided into 3 intervals: admission to day 10 of chemotherapy, days 11-20, and day 21 and later. 111 samples (stool: 39, saliva: 36, plaque: 36) from 16 patients have been sequenced to date. Samples underwent shotgun sequencing targeting 10M paired-end reads/sample. MetaPhlAn4 was used for taxonomic assignment. Alpha diversity was quantified by Shannon index and beta diversity by Bray-Curtis dissimilarity. 9 patients were male and 7 were female. Median age was 64 (range 34-82). 15 patients were newly diagnosed and 1 was relapsed/refractory. Chemotherapy regimens included CLAG-M (n=10), ATRA+ATO (n=3), Vyxeos (n=1), Venetoclax+Azacitidine (n=1), and intermediate-dose Ara-C (n=1). The 3 most frequently used antibacterial antibiotics were cefepime (n=14), IV vancomycin (n=12), and levofloxacin (n=11). Median hospitalization length was 19 days (range 6-31). Neutropenic fever occurred in 13 patients. Documented infections included bacteremia (n=8), skin/soft tissue (n=5), intestinal (n=4), urinary tract (n=4), and pneumonia (n=1). Four bacterial species isolated from blood cultures of patients with fever were detected by sequencing 1-2 weeks before bacteremia: Gemella Haemolysans in saliva, plaque, and stool, Streptococcus mitis in saliva and stool, Rothia mucilaginosa in saliva and plaque, and Citrobacter freundii in stool. Microbiota diversity from the 3 sites showed markedly different dynamics ( Fig. 1). Plaque microbiota diversity remained stable throughout, with levels as high as fecal microbiota in intervals 1 and 2, and higher than both fecal and salivary microbiota in interval 3. Salivary microbiota diversity was the lowest among sites in intervals 1 and 2 and experienced only a slight reduction in interval 3. In contrast, fecal microbiota diversity was high compared to the other sites in intervals 1 and 2 but dropped in interval 3 to the lowest among all sites. With all 3 intervals combined, salivary microbiota had lower diversity (median 1.9, range 0.04-3.9) than plaque (median 2.7, 0.2-4.3; P=0.01) and fecal microbiota (median 2.9, 0.3-3.7; P=0.048). The 3 sites largely segregated on hierarchical clustering using species abundances ( Fig. 2). However, microbiota in several low-diversity samples from different sites in the same patient coalesced: Veillonella parvula and R. mucilaginosa were detected in all 3 sites, V. dispar in stool and plaque, and S. parasanguinis in stool and saliva. Each overlap was present in 5 or more patients. This first shotgun sequencing analysis of longitudinal salivary, plaque, and fecal microbiota in AML patients offers several novel findings. First, plaque microbiota diversity is stable despite exposure to antibiotics, whereas fecal microbiota diversity is not. Second, while healthy adults show no overlap between oral and colonic microbiota, low-diversity fecal samples from AML patients contained species of their own oral microbiota, particularly at later time points. These data suggest ectopic colonization of the gut by oral flora. Future mechanistic studies of plaque biofilms may reveal community-protective mechanisms that sustain oral plaque microbial diversity and contribute oral flora to the gut. Mitigating gut dysbiosis in AML patients by manipulating plaque biofilms could be a novel approach to improve patient outcomes.

The prognostic benefit from intermediate-dose cytarabine as consolidation therapy varies by cytogenetic subtype in t(8;21) acute myeloid leukemia: a retrospective cohort study.

BackgroundPatients with different karyotypes had different prognosis in t(8;21) acute myeloid leukemia (AML). Cytarabine (Ara-C) plays an important role as consolidation therapy in t(8;21) AML. T(8;21) AML patients with different karyotypes responded differently to post-remission therapy with Ara-C. However, the optimum dose of Ara-C in patients with different karyotypes remains unclear.MethodsFrom January 2002 to September 2018, a total of 188 younger adult (14–60 years) patients with t(8;21) AML were enrolled in this retrospective study. Cytogenetic analysis and aberration descriptions followed the International System for Human Cytogenetic Nomenclature. All the patients achieved first complete remission (CR1) after induction chemotherapy. Patients received low-dose Ara-C [LDAC (<1 g/m2)], intermediate-dose Ara-C [IDAC (1–1.5 g/m2)], or high-dose Ara-c [HiDAC (2–3 g/m2)] regimens as consolidation therapy after CR1. All patients were followed for survival or relapse until death, or study completion. We analyzed the prognosis of LDAC, IDAC, and HiDAC regimens as consolidation therapy in patients with different karyotypes. The primary endpoint was overall survival (OS) and the secondary endpoint was relapse-free survival (RFS).ResultsThe results showed IDAC significantly improved OS compared with LDAC [hazard rate (HR) =0.55, P=0.0375] when the clinical factors were adjusted. However, no significant difference between HiDAC and IDAC was found. Subgroup analysis further showed that the OS advantage of IDAC was focused on patients with additional cytogenetic abnormalities, including loss of X chromosome (-X), del(9q), or complex karyotype (group B, HR =0.21, P=0.0125), but not on patients with t(8;21)-only or additional loss of Y chromosome (-Y) cytogenetics (group A, HR =0.77, P=0.4804) in multivariate analysis. Similarly, better OS was shown after IDAC than LDAC consolidation in patients in group B, whether they received allogeneic hematopoietic stem cell transplantation (allo-HSCT) or not, but not in group A.ConclusionsIDAC was suitable for patients with additional -X, del(9q), or complex karyotype, while LDAC might be sufficient for patients with t(8;21)-only or additional -Y cytogenetics. It suggested that t(8;21) AML patients with different karyotypes should use different consolidation regimens.

NT-Probnp As Personalized Medicine Tool and New Biomarker Predicting Response to Chemotherapy and Survival in AML

NT-Probnp As Personalized Medicine Tool and New Biomarker Predicting Response to Chemotherapy and Survival in AML

Outcome after Midam Regimen and Impact of Post-Remission Strategy in Patients with Relapsing or Refractory Acute Myeloid Leukemia

Introduction. The immune-conjugate gemtuzumab ozogamicin (GO) represents the main available therapeutic possibility beyond combinations of anthracycilines and cytarabin for patients with refractory or relapsed acute myeloid leukemia (AML). Combining GO, intermediate dose Ara-c and mitoxantrone (MIDAM) has been shown as a valid option as salvage therapy based on a prospective phase II study including 62 patients (Chevallier JCO 2007). Whether this regimen is safe in patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT) as post-remission therapy remained to be determined.Method. This retrospective study included the consecutive patients with relapsed or refractory AML treated by the MIDAM regimen in our center (Clermont-Ferrand University Hospital) between 2008 and 2013. MIDAM consisted of GO 9 mg/m2 on day 4, cytarabine 1g/m2 every 12 hours on days 1 through 5, and mitoxantrone 12 mg/m2/d on days 1 through 3. GO is available according to a compassionate use program in France.Results. A total of 86 consecutive patients with relapsed (n=62) or refractory (n=24) AML were included. Median age was 60 years (range, 17 to 75 years old). The MIDAM regimen was administered as salvage therapy after 1 (n=73) or more (n=13) therapeutic lines. Distribution according to ELN 2008 cytogenetic risk classification was as following: favorable (n=12), intermediate-1 (n=23), intermediate-2 (n=15) and high risk (n=22). Complete response (CR) rate was 63% including 23 patients (27%) CR with delayed platelets recovery (CRp). Treatment failure was observed in 23 (27%) patients. Nine (10%) deaths during induction occurred. Infusion-related reaction was observed in 24 (28%) patients and tumor lysis syndrome were seen in 4 (4.6%) patients. Eight (9.3%) patients had veno-occlusive disease (VOD).CR rate (CR+CRp) was significantly better in patients with low WBC (71% if <10 G/L vs 44% if WBC >10 G/L, P=0.028) and in those with good performance status (70% if ECOG 0 or 1 vs 27% if ECOG >1, P=0.003). No significant influence of percentage of CD33 positive cells was found.Among the 54 patients with CR or CRp, post-remission therapy consisted of chemo-based approaches in 13 patients (chemotherapy only, n=10; chemotherapy + auto-HSCT, n=3) because a lack of allogeneic donor and allo-HSCT in 29 patients (including 7 with consolidation chemotherapy prior to allo-HSCT). Twelve patients did not receive any consolidation therapy. Median follow up was 6 years. Among patients achieving CR or CRp, 2-year RFS was 25%. No influence of neither age, WBC count, percentage of CD33 positive cells nor ELN 2008 risk cytogenetic group was observed on RFS. Allo-HSCT as post-remission therapy confers significant better RFS compared to chemo-based approaches and absence of consolidation therapy (51%, 33% and 9%, respectively, P=0.001). Among the whole population, 2-year OS was 20%. High WBC count (>10 G/L), intermediate and high risk ELN cytogenetic, ECOG performance status more than one were significant adverse prognostic factors on OS. Allo-HSCT as post-remission therapy was associated with better 2-year OS (43%) compared to those without available donor and treated by chemo-based approaches (15%) (P=0.005). Importantly, among patients treated by allogenic stem cell transplantation, no veno-occlusive disease was found.Conclusion. The MIDAM regimen in relapsed or refractory AML is an option therapeutic as a salvage chemotherapy with a relatively acceptable toxicity profile. Allogeneic transplantation is the consolidation of choice and can be performed after this regimen with no increased risk of VOD. DisclosuresTournilhac:GILEAD: Honoraria, Other: Travel Funding, Research Funding; Janssen: Honoraria, Other: travel funding; Abbvie: Honoraria, Other: Travel funding; AMGEN: Other: Travel funding, Research Funding; ROCHE: Honoraria, Other: Travel funding, Research Funding. Guieze:GILEAD: Other: Educational Presentation; JANSSEN: Other: Educational Presentation; ABBVIE: Other: Educational Presentation.

Results of the Full Pediatric, Minimal Residual Disease (MRD)-Oriented Trial LAL-RI/2008 for Adolescents and Young Adults (AYA) with Standard Risk (SR), Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL)

Background and objective. Full pediatric or pediatric-derived trials constitute the treatment of choice for AYA with SR-ALL. In the MRD era, patients (pts) with SR factors at baseline with poor MRD clearance should be considered as HR patients. The objectives of the full pediatric LAL-RI/2008 trial (NCT02036489) from the Spanish PETHEMA group were to assess the proportion of AYA with SR-ALL at baseline who have HR features based on poor early cytological response and/or poor MRD clearance, and to compare their prognosis with that from those pts who achieve good early cytological response and good MRD clearance.Patients and methods. SR ALL was defined in adolescents (age 15 to 18 years) and young adults (age 19 to 29 years) fulfilling all the following criteria: WBC count ≤30 × 109/L, and absence of t(9;22), t(1;19), t(4;11) or any other 11q23 rearrangements. Induction therapy included vincristine (VCR), prednisone (PDN), daunorubicin (DNR) and native E. coli asparaginase (ASP) for 4 weeks. Pts who achieved complete remission (CR) and MRD<0.1% proceeded to consolidation-1 (high-dose methotrexate [MTX], intermediate-dose ARA-C, etoposide and mercaptopurine [MP]), consolidation-2/reinduction (VCR, dexamethasone, DNR, cyclophosphamide and ASP), maintenance-1 (MP and MTX with monthly reinductions with VCR, PDN and ASP until the end of the 1st year) and maintenance-2 (MP and MTX without reinductions until the end of the 2nd year). CNS prophylaxis consisted of triple intrathecal therapy (MTX, ARA-C and hydrocortisone, 16 doses throughout the treatment). Pts with poor early cytological response (BM blast cells >10% on day 14 of induction), MRD level >0.1% (assessed by flow cytometry) at CR or MRD level >0.05% at any time after CR were considered as high risk (HR) pts and received the ALL-HR trial consisting of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) (Ribera JM et al. J Clin Oncol 2014; 32:1595-604).Results. Between 2008 and 2017, 79 eligible pts were treated according to the ALL-RI-08 protocol. Median age (range) was 20 years (15-29), 34 (43%) were adolescents and 45 (57%) YA. The mean (SD) WBC count was 10 (9) x109/L, and 73 patients (94%) had B-cell precursor ALL. Two patients are on treatment and 74 out of the remaining 77 (96%) achieved the CR. From the 77 pts, 15 had poor early cytological response, 3 had MRD >0.1% at the time of CR and 1 pt showed reappearance of MRD level >0.05% during maintenance. In all, 19 patients were considered as HR. Of the 58 patients who remained SR and followed the LAL-RI/2008 protocol, 14 relapsed (7 during treatment and 7 off therapy), whereas in the HR group, 3 were resistant, 4 relapsed and 2 died by toxicity (transplant-related in 1 out of 4 pts submitted to alloHSCT). Table 1 shows the DFS, OS and cumulative incidence of relapse (CIR) at 5-yrs for the whole series, the patients remaining SR and those who turned HR. Of note, OS was lower in the HR pts (Figure 1). On comparison with the results of the ALL-RI-96 trial (same inclusion criteria, same treatment but no follow-up by MRD, Ribera JM et al. J Clin Oncol 2008; 26:1843-9), no differences were observed in DFS, OS and CIR (Table 1).ConclusionsTwenty-five percent of AYA pts with SR ALL at baseline are in fact HR based on slow early cytological response to therapy and/or poor MRD clearance. High-risk pts showed lower OS despite being moved to a HR protocol.Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain. [Display omitted] DisclosuresRibera:Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; ARIAD: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Amgen Inc.: Research Funding, Speakers Bureau. Montesinos:Celgene Corporation: Honoraria, Research Funding.

Italian Observational Study on Real-Life Use of Venetoclax in Acute Myeloid Leukemia (AVALON study): Results of Interim Analysis on Relapsed/Refractory Patients

Italian Observational Study on Real-Life Use of Venetoclax in Acute Myeloid Leukemia (AVALON study): Results of Interim Analysis on Relapsed/Refractory Patients

Clinical heterogeneity under induction with different dosages of cytarabine in core binding factor acute myeloid leukaemia

Repeated cycles of post-remission high-dose cytarabine (Ara-C) have been suggested to improve survival in core binding factor (CBF) acute myeloid leukaemia (AML). High-dose Ara-C used for induction regimens has also been reported to be associated with increased treatment-related mortality (TRM). Few data are available about intermediate-dose Ara-C serving as induction therapy. The aim of our study was to compare the tolerance and outcomes of standard- and intermediate-dose levels of Ara-C as induction in CBF AML and to analyse the clinical heterogeneity of the two AML entities under these induction settings. We retrospectively investigated the outcomes in adults with CBF AML induced with regimens based on standard-dose Ara-C at 100 to 200 mg/m2 or intermediate-dose Ara-C at 1,000 mg/m2. In total, 152 patients with t(8; 21) and 54 patients with inv(16) AML were administered an induction regimen containing anthracyclines plus either standard- or intermediate-dose Ara-C. After a single course of induction, the complete remission (CR) rate in the inv(16) cohort was 52/52 (100%), higher than the 127/147 (86.4%) in the t(8; 21) cohort (P = 0.005). Intermediate-dose Ara-C (HR = 9.931 [2.135–46.188], P = 0.003) and negative KITmut (HR = 0.304 [0.106–0.874], P = 0.027) independently produced an increased CR rate in the t(8; 21) cohort. Positive CD19 expression (HR = 0.133 [0.045–0.387], P = 0.000) and sex (male) (HR = 0.238 [0.085–0.667], P = 0.006) were associated with superior leukaemia-free survival (LFS) in the t(8; 21) cohort independently of KITmut status or the induction regimen. We conclude that intermediate-dose Ara-C is superior to standard-dose Ara-C for induction of remission in t(8; 21) AML, and CD19 status and sex independently confer prognostic significance for LFS. The KITmut status alone does not have an independent effect on survival in t(8; 21) AML. More intensive induction therapy is unnecessary in inv(16) AML.

Efficacy and Safety of DAC Combined with CAG Regimen (decitabine in combined with aclacinomycin, cytarabine and G-CSF) As a Second Induction Regimen Compared with Non-DAC Regimen for Acute Myeloid Leukemia Who Failed the First Course of Standard Induction IA Chemotherapy

BACKGROUND: Acute myeloid leukemia (AML) patients who failed the first course of standard induction chemotherapy remain a challenge owing to poor response to the second induction regimen. We retrospectively compared the efficacy and safety of DAC+CAG regimen with non-DAC regimen in AML patients who failed the first course of standard induction regimen. MATERIALS AND METHODS: The three regimens consisted of (1) DAC combined with CAG regimen (decitabine, cytarabine, aclarubicin and granulocyte colony stimulating factor, n=25) ; (2) the repeated first course (IA 3+7, n=30); (3) Intermediate-dose AraC -based chemotherapy including IA 3+3 (idarubicin, Ara-C n=14) or CLAG (cladribine, aclarubicin and granulocyte colony stimulating factor, n=15). RESULTS: Our data indicate that after the second course, the overall response (OR, complete remission [CR]+partial remission [PR]) rates in DAC+CAG group was higher than the Intermediate-dose AraC -based group (80% vs 48.3%, P= 0.049), whereas the CR rates among 3 groups were not statistically different (P = 0.09). The overall survival (OS) of DAC+CAG group is longer than IA 3+7 group and Intermediate-dose AraC -based group with significance (21 months VS 18.5 months, P=0.038 and 21 months VS 10 months, P=0.023, respectively), the relapse-free survival (RFS) of DAC+CAG group is longer than Intermediate-dose AraC-based group (16 months VS 8.5 months, P=0.016), though there was no significant difference in overall survival (OS) of the transplanted patients among the 3 groups (P = 0.064). The median duration of thrombocytopenia in the DAC+CAG group is shorter than IA 3+7 group and Intermediate-dose AraC-based group (10 days vs 12 days, P&lt;0.001 and 10 days vs 14 days P=0.023, respectively). Fewer incidence of lung infection and febrile neutropenia in the DAC+CAG group than other two groups (P=0.018 and P=0.025, respectively) were observed, no patients died within 4 weeks after initiating the second induction course in the DAC+CAG group whereas 2 patients died in the Intermediate-dose AraC -based group. CONCLUSION: Our data indicate that DAC combined with CAG regimen may represent a better alternative option with good response and safety for AML patients who failed the first course of standard induction chemotherapy. Disclosures No relevant conflicts of interest to declare.

Maintenance Decitabine (DAC) Improves Disease-Free (DFS) and Overall Survival (OS) after Intensive Therapy for Acute Myeloid Leukemia (AML) in Older Adults, Particularly in FLT3-ITD-Negative Patients: ECOG-ACRIN (E-A) E2906 Randomized Study

Maintenance Decitabine (DAC) Improves Disease-Free (DFS) and Overall Survival (OS) after Intensive Therapy for Acute Myeloid Leukemia (AML) in Older Adults, Particularly in FLT3-ITD-Negative Patients: ECOG-ACRIN (E-A) E2906 Randomized Study

Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

BackgroundLimited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease.MethodsWe retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML.ResultsComplete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p = 0.01; p = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III–IV aGVHD (p = 0.02) and cGVHD (p = 0.006), with no influence on relapse.ConclusionsIn conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.

Cytogenetics and FLT3-ITD mutation predict clinical outcomes in non transplant patients with acute myeloid leukemia

BackgroundCytogenetic abnormalities and mutated genes indicate the role of consolidation therapy with hematopoietic stem cell transplantation (HSCT) or chemotherapy in acute myeloid leukemia (AML). In this study, we conducted a retrospective study in adult AML patients with newly diagnosed with de novo AML who did not undergo HSCT, to study long term relapse free survival (RFS) and overall survival (OS) after consolidation chemotherapy.MethodsWe recruited 141 consecutive AML patients during January 2010–June 2017, the patients received induction chemotherapy with standard dose Ara-C and Idarubicin (7 + 3 or 5 + 2 regimen) followed by intermediate (IDAC) or high dose Ara-c (HiDAC) consolidation therapy.ResultsNormal karyotype, complex, favorable, intermediate and adverse chromosomal aberrations were found in 59%, 16%, 5%, 14% and 6%, respectively. Mutated NPM1, FLT3-ITD and CEBPA genes in CN-AML were seen in 33%, 18% and 19%, respectively. A 5 year follow up, 5y-RFS was 16% and 5y-OS was 14% in the whole study population. 5y-RFS and 5y-OS in patients completed 4 cycles of consolidation therapy were 25% and 40%, respectively. Adverse cytogenetic risk and mutated FLT3-ITD were significantly associated with poor RFS (9 and 15 months, respectively) and OS (14 and 16 months, respectively), whereas patients with mutant NPM1 had favorable outcomes (RFS/OS = 51/63 months). Patients receiving 4 cycles of consolidation therapy had significantly impacts on median RFS and OS compared with those treated with 1 or 2 cycles; 15 versus 11 months (p = 0.006) and 31 versus 15 months (p < 0.001), respectively.ConclusionsCytogenetic and mutation tests for FLT3-ITD, NPM1 and CEBPA genes were meaningful for predicting outcomes in adult AML patients. Adverse cytogenetic abnormalities and FLT3-ITD mutation showed dismal RFS and OS.

Minimal Residual Disease (MRD) at Time of Complete Remission Is Commonly Detected in Acute Myeloid Leukemia (AML) Patients Age ≥60 Years and Significantly Impacts Outcome Based on Post-Remission Treatment Strategies: Prospective Analysis of ECOG-ACRIN (E-A) E2906 Phase III Trial

Minimal Residual Disease (MRD) at Time of Complete Remission Is Commonly Detected in Acute Myeloid Leukemia (AML) Patients Age ≥60 Years and Significantly Impacts Outcome Based on Post-Remission Treatment Strategies: Prospective Analysis of ECOG-ACRIN (E-A) E2906 Phase III Trial

Cladribine Combined with Idarubicin and High-Dose AraC (CLIA2) As a Frontline and Salvage Treatment for Young Patients (≤65 yrs) with Acute Myeloid Leukemia

Cladribine Combined with Idarubicin and High-Dose AraC (CLIA2) As a Frontline and Salvage Treatment for Young Patients (≤65 yrs) with Acute Myeloid Leukemia

FLT3-ITD Mutations Are Prevalent and Significantly Impact Outcome after Intensive Therapy in Elderly Adults with Acute Myeloid Leukemia (AML): Analysis of the North American Intergroup E2906 Phase III Trial in Patients Age ≥60 Years

BackgroundActivating mutations in FLT3 - and in particular FLT3-ITD (internal tandem duplication) - are common in younger patients with AML, and are associated with relapse and with inferior overall survival (OS), however their prevalence and impact in older adults remains uncertain. We performed an analysis of FLT3-ITD mutations in patients age ≥60 yrs in the large prospective multicenter ECOG-ACRIN (E-A) E2906 Phase III trial.MethodsEligible patients (pts) age ≥60 yrs (n=727) were randomized to ‘Standard’ therapy with 7&3 (Dauno 60mg/m2) induction, and 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70yrs) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). As previously reported (Foran et al, ASH #217a, 2015), there was superior overall survival (OS) with standard therapy. AML diagnostic samples collected prospectively in the central E-A Leukemia Translational Research Lab (LTL) were used to detect mutations in the FLT3 gene by PCR using cDNA from total RNA. LTL investigators were blinded to treatment assignment. Patients with no RNA available or blast count <10% (threshold of sensitivity for the PCR assay) on the submitted sample were excluded. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine FLT3-ITD effect on OS and disease-free survival [DFS; relapse or death after complete remission (CR)/CRi (CR with incomplete CBC recovery)].ResultsIn the first 231 pts tested, FLT3-ITD mutations were identified in 43 (18.6%) pts, and the remainder were FLT3-ITD-negative (i.e. non-ITD). The proportion with FLT3-ITD was the same for patients age 60-69 yrs (18.8%) vs. ≥70 yrs (18.3%). In comparison to non-ITD, FLT3-ITD+ pts had significantly higher WBC (median 18.1 vs. 6.3, p=0.002) and BM blasts (80% vs. 51.5%, p=0.0004) at AML diagnosis, and were more likely to have intermediate risk (79.1% vs. 59%) vs. unfavorable risk (7.0 % vs. 31.4%) cytogenetics (p=0.002). There was no difference in CR/CRi rate overall (p=0.40), however standard (Arm A) pts with FLT3-ITD had a significantly higher CR/CRi rate (78.9% vs. non-ITD 51.5%, p=0.04). With median follow-up 53.5 months, FLT3-ITD patients tended to have worse OS (HR 1.24, 95%CI 0.85-1.81) but this was not statistically significant (Figure 1, p=0.26), and results were similar for both Arms A/B. DFS similarly tended to be worse overall for FLT3-ITD (HR 1.44, 95%CI 0.65-2.43) (p=0.17), and DFS was significantly worse for FLT3-ITD+ Arm A/Standard pts (Figure 2, p=0.033), while Arm B/CLO pts had a worse DFS regardless of FLT3 mutation status (Arm B, FLT3-ITD vs. non-ITD, p=0.93). More patients with FLT3-ITD underwent allogeneic transplantation (25.6% vs. non-ITD 19.7%), although this was not significant (p=0.41).ConclusionsFLT3-ITD mutations are prevalent in older and elderly (age ≥70 yrs) patients with AML, and while they occur at somewhat lower rates than reported for younger adults, FLT3-ITD+ AML in this population has a leukemia phenotype similar to that reported in younger patients. Despite significantly higher CR/CRi rates with Standard therapy, older pts with FLT3-ITD also have significantly worse DFS following intensified Ara-C consolidation therapy than non-ITD pts. These results support routine assessment of FLT3-ITD status in older AML patients, and the incorporation of novel post-remission treatment strategies to improve outcome in FLT3-ITD+ pts ≥60 yrs. [Display omitted] DisclosuresForan:Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Tallman:BioSight: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding.

Intensive Post-Remission Consolidation with G-CSF-Support: Tolerability, Safety, Reduced Hospitalization, and Efficacy of a New Treatment Protocol for AML Patients ≥60 Years

Treatment of AML in elderly patients (≥60 years) deserves special considerations and has to balance toxicity against efficacy as well as life expectancy against the risk of AML-related death and relapse after intensive treatment. We have previously shown that induction chemotherapy followed by repetitive cycles of intermediate dose ARA-C (IDAC) is a well-tolerated and highly effective approach for elderly patients with AML (Sperr et al, Clin Cancer Res 2004;10:3965-3971). The aim of the current multi-center study (EudraCT number: 2007-005806-29) was to evaluate the efficacy and feasibility of intensified consolidation therapy employing FLAG (cycle 1; fludarabine, 30 mg/m² iv, days 1-5, ARA-C, 2000 mg/m² iv, days 1-5) and IDAC (cycles 2-4; ARA-C, 2x1,000 mg/m2 iv, days 1,3,5) in elderly AML patients and to analyze the effect of pegfilgrastim (6 mg s.c. on day 6) on the duration of neutropenia, overall toxicity, and hospitalization-time during consolidation in these patients. In addition, overall survival (OS) and relapse-free survival were captured. To evaluate the efficacy of pegfilgrastim we compared consolidation cycles where pegfilgrastim was given routinely on day 6 (IDAC-P; consolidation 2 and 4) with cycles where pegfilgrastim was only used in case of infections and/or prolonged neutropenia (consolidation 3). Between Jul/2008 and Nov/2012 (observation period until Sept/2014) 64 patients with de novo AML were included (median age: 69.9 years; range 60.1- 85.2 years; 53 patients < 75 years, 11 patients ≥75 years; f:m ratio 1:1.56). Following induction therapy, 43 patients (68%) entered complete remission (CR), 33 after the 1st (DAV), 9 after a 2nd (MiDAC light: ARA-C 2x1g/m², days 1,3,5; mitoxantron 12 mg/m², days 3,5), and 1 patient after a 3rd (FLAG) induction cycle. In 16 patients no remission (NR) was achieved. Of these, 7 received only one induction cycle, 3 two, and 6 three cycles. Two patients died and 2 patients were withdrawn from the study during the 1st induction. Thirty-nine CR-patients (91%) were eligible for consolidation therapy. All 4 planned consolidation cycles could be administered in 23/39 patients (59.0%), 5/39 (12.8%) received 3 cycles, 3/39 (7.7%) 2 cycles, and 8/39 (20.5%) 1 cycle of consolidation therapy. Relapse (n=8; 20.5%) was the major cause of withdrawal, followed by persistent cytopenia (n=4; 10.2%), severe infections (n=2; 5.1%), and stem cell transplantation (n=1). Four patients died in the consolidation phase (treatment related, n=2; not treatment related, n=2). In 17 patients the efficacy of pegfilgrastim could be evaluated. The median duration of severe neutropenia (ANC<500/µL) was 7 days (range: 3-14 days) in the 2nd (IDAC-P), 12 days (range: 3-21 days) in the 3rd (IDAC), and 7.5 days (range: 5-19 days) in the 4th (IDAC-P) consolidation cycle. Differences in the duration of severe neutropenia between consolidation 2 and 3 and between consolidation 3 and 4, were significant (p<0.05). The duration of hospitalization differed also significantly among these patient-groups, with 21 days (range 13-42) in consolidation 2 (IDAC-P), 28 days (range 7-41) in consolidation 3 (IDAC), and 22 days (range: 9-40) in consolidation 4 (IDAC-P) (p<0.05). The median OS, continuous complete remission and disease-free survival were 1.1, 1.3, and 1.2 years respectively. The probability to be alive after 5 years was 32% (Figure). The median OS differed significantly between patients aged <75 years (1.5 years) and ≥75 years (0.5 years) (p<0.05) (Figure). Together, our data show that intensified consolidation can be safely administered in AML patients aged ≥60 years. Patients aged <75 years seem to benefit from this strategy. Moreover, the administration of pegfilgrastim on day 6 in IDAC consolidation cycles shortened the duration of neutropenia and the duration of hospitalization significantly. [Display omitted] DisclosuresSperr:Novartis: Honoraria; Amgen: Honoraria, Research Funding. Knoebl:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Geissler:Novartis: Honoraria. Valent:Celgene: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Deciphera Pharmaceuticals: Research Funding; Amgen: Honoraria.

The Impact of Allogeneic Hematopoietic Stem-Cell Transplantation on Outcome of the Patients with Intermediate-Risk Acute Myeloid Leukemia

Background:Patients with AML who obtain first complete remission (CR) are subsequently treated with post-remission treatment, including chemotherapy or hematopoietic stem cell transplantation (HSCT). Suitable post-remission treatment in patients with intermediate-risk acute myeloid leukemia (AML) is remaining investigation.Objectives:To retrospectively investigatethe value of allo-HSCT in the patients with intermediate-risk AML.Patients and Methods:From August 2010 to January 2016, newly diagnosed adultpatients (15 to 55 years old) with AML were consecutivelyenrolled in a prospective trial (ChiCTR-TRC-10001202). Patients were assigned HAD containing conventional dose of cytarabine (homoharringtonine, cytarabine (Ara-c), and daunorubicin) induction therapy (Ara-C 100mg/m2, d1-7) or HAD containing intermediate dose Ara-c (Ara-C 100mg/m2, d1-4, 1.0g/m2, q12h, d5-7). All patients who achieved CR received either high dose Ara-c or intermediate dose Ara-c plus anthracyclines. Allo-HSCT was based on therapeutic responseand patients' intention. Patients received 6 courses of consolidation therapy if they did not receive HSCT. Minimal residual disease (MRD) was analyzed by multi-color flow cytometry after induction and consolidation therapy.Results:181 enrolled patients were intermediate-risk AML (median age 36 years old). The median follow-up was 15.5 (0.5-67.9) months. One patient was lost to follow-up after induction, 180 patients were evaluated. 128 patients (71.1%) achieved CR after one induction cycle, 7 patients (3.9%) were early death, and 45 patients (25.0%) did not achieve CR. Forty patients received allo-HSCT, 33 of them were in CR1. The median time from diagnosis to transplantation was 6.5(3.9-16.0) months. Three years overall survival (OS) of transplantation group was higher than that of chemotherapy group (78.0% vs 48.0%, P = 0.000). Three years relapse-free survival (RFS) was 42.0% and 45.0% for patients in transplantation group and chemotherapy group, respectively (P = 0.196).However, taking transplantation time into account, the outcome was different. If the median transplantation time (6.5 months) was defined as cut-off value, there is no statistically difference of 3 years OS (77.0% vs 69.0%, P=0.182) and 3 years RFS (42.0% vs 53.0%, P=0.320) between transplantation and chemotherapy groups in the patients without relapse within 6.5 months. Twenty-one patients relapsed within 6.5 months, only one of them proceeded to allo-HSCT, and 1 year OS was 29.0%. For 45 patients who did not achieve CR after one induction cycle, 3 years OS was much better by allo-HSCT as compared with chemotherapy (85.0% vs22.0%, P = 0.008).In order to evaluate prognosis earlier, we analyzed MRD by flow cytometry after induction, first and second consolidation cycles in those achieving CR after one induction cycle. The patients with once or more MRD positive of three time points had significantly inferior 6 months RFS than those with continuous MRD negative (61.0% vs 92.0%,P = 0.005). Similar trend was observed on 1 year RFS (46.0% vs 76.0%, P = 0.005).Conclusion:According to the actual treatment, the OS of the patients with intermediate-risk AML was improved by allo-HSCT. When transplantation time was considered in the analysis, there was no difference between allo-HSCT and chemotherapy in survival. The patients with poor early response to chemotherapy (those did not achieve CR after one induction cycle) really benefited from allo-HSCT. The patients without continuous MRD negative after induction, first and second consolidation cycles trended to be early relapse, they might be another subgroup benefiting from allo-HSCT.Acknowledgments: This study was supported, in part, by State Key Program of National Natural Science of China (81430004), Foundation for Innovative Research Groups of the NaturalScience Foundation of China (81421002). DisclosuresNo relevant conflicts of interest to declare.

MRD Is an Independent Prognostic Factor in Acute Myeloid Leukemia Carrying t(8;21) Chromosomal Abnormalities

Background:Minimal residual disease (MRD) based on quantitativeRT-PCR has become an important prognostic factor for leukemia. There are few cohort based studies to investigate prognostic factors for t(8;21) AML, especially after MRD is integrated.Objectives:To retrospectively investigatethe prognostic factors in t(8;21) AML when MRD is integrated.Patients and Methods:From August 2010 to January 2016, newly diagnosed adultpatients (15 to 55 years old) with AML were consecutively enrolled in a prospective trial(ChiCTR-TRC-10001202). Patients were assigned standard dose HAD (homoharringtonine,cytosine arabinosine(Ara-c), and daunorubicin) induction therapy or HAD containing intermediate dose Ara-c. All patients who achieved CR received either high dose or intermediate dose Ara-c. Allogeneic SCT was based on c-Kit mutation and patients' intention. Patients received 6 courses of consolidation therapy if they did not receive transplantation. MRD based on quantitative RT-PCR was performed after induction therapy and each consolidation therapy.Results:113 enrolled patients were t(8;21) AML (median age 33 years old).108 patients (95.6%) achieved CR. Six of them receivedallogeneicstem-cell transplantation in CR1.The median follow-up is 14.6(0.6-59.2) months. Three years relapse-free survival (RFS) and overall survival (OS) is 57.2% and 71.8%, respectively.Analyses of prognostic factors were performed. In univariate analysis, high WBC count (cut-off value at 25X109/L) (P=0.007), c-Kit mutation (P=0.017), and MRD positive during therapy (P=0.001)were adverse prognostic factors for RFS. But Age (cut-off value at 45 years old) (P=0.957), gender (P=0.418), induction regimen (P=0.055), and consolidation regimen (P=0.311) were not prognostic factors for RFS. MRDpositive during therapy (P=0.004) was the only adverse prognostic factors for OS. High WBCcount (P=0.824), c-Kit mutation (P=0.052), Age (P=0.596), gender (P=0.714), induction regimen (P=0.222), and consolidation regimen (P=0.299) were not prognostic factors for OS. In multivariate analysis, WBC count and MRD were independent prognostic factors for RFS. And MRD was the only prognostic factors for OS.MRD tests were performed in 83 patients after induction and during consolidation therapy. All of tests were positive in 37 (44.6%) patients. 46 (55.4%) patients achieved negative at least one of tests. The cumulative MRD negative was 3.6%, 15.7%, 34.9%, 39.8%, 47.0%, 50.6%, 55.4% after induction therapy, the first, the second, the third, the forth, the fifth, and the sixth consolidation therapy, respectively. Patients with negative MRD had better 3 years RFS (78.6% vs. 32.1%, P=0.001) and OS (85.3% vs. 55.2%, P=0.004) than patients with positive MRD.C-Kit mutation analysis was performed in 105 patients. 27(25.7%) patients had c-Kit mutation and 78(74.3%) patients had wild type c-Kit. 3 years RFS in patients with wild type c-Kit is superior to that in patients with c-Kit mutation (57.5% vs. 35.8%, P=0.017). There was no statistically difference between wild type and mutated c-Kit in 3 years OS (73.6% vs. 42.4%, P=0.052). MRD became negative during consolidation therapy in 66.1% (39/59) patients with wild type c-Kit, which is significantly higher than patients with mutated c-Kit (27.8%, 5/18, P=0.004). But there was no significant difference in RFS or OS between MRD negative and positive in c-Kit mutated patients (P=0.847 for RFS, P=0.11 for OS).To evaluate prognosis earlier, we analyzed MRD after induction therapy. MRD after induction therapy was performed in 76 patients. MRD decreased to ≤0.1%, >0.1% to≤1%, and >1% in 15 (19.7%), 45 (59.2%), and 31(40.8%) patients, respectively.Patients with MRD ≤1% after induction therapy had favorable 3 years RFS (75.4% vs. 29.7%, P=0.004) and OS (77.9% vs. 53.3%, P=0.013) compared with patients with MRD >1% after induction therapy.In multivariate analysis, in addition to c-Kit mutation and WBC count, MRD after induction therapy was still an independent prognostic factor for RFS. And MRD was the only prognostic factors for OS.Conclusion:MRD is an independentprognostic factor for OS and RFS for patients with t(8;21).Acknowledgments:This study was supported, in part, by State Key Program of National Natural Science of China (81430004), Foundation for Innovative Research Groups of the Natural Science Foundation of China (81421002) DisclosuresNo relevant conflicts of interest to declare.