Expression of CD56 Is an Independent Prognostic Factor to Predict Relapse in Acute Myeloid Leukemia with t(8;21): Results of Japan Adult Leukemia Study Group (JALSG) AML97 Protocol.

Abstract Abstract 2511 Background: Although prognosis of acute myeloid leukemia (AML) with t(8;21) is better than other types of AML, outcome of the patients has not been satisfied. Previously, aberrant antigen expression has been reported as risk factor for AML with t(8;21). However, in the reported series, number of cases was not large enough and chemotherapy regimens were variable. We investigated the association of prognosis and several biomarkers including immunophenotype, WBC count, age, and performance status for large number of AML patients with t(8;21) uniformly treated in JALSG AML97 regimen. Patients and Methods: Seven hundred eighty-nine eligible AML patients were evaluated for the multicenter JALSG AML97 study. Adult patients with de novo AML except for APL, ages 15–64 years, were registered consecutively from 103 institutions that participated in JALSG from December 1997 to July 2001. One hundred forty-four patients with AML with t(8;21) were analyzed in this study with a median 1205 days of observation term from diagnosis. Complete remission (CR), relapse-free survival (RFS), and overall survival (OS) rates were analyzed by Fisher's exact test and log-rank test. Factors that would affect clinical outcome were analyzed by multivariate Cox proportional hazard regression model. Results: AML with t(8;21) frequently expressed CD19, CD34, and CD56 compared to other subtypes of AML. CD11b was rarely expressed. Expression of CD19 favorably affected on CR rate (96% in CD19 positive and 87% in negative patients, p<0.05). Univariate analysis showed WBC>20×109/L, CD19 negativity, and CD56 positivity were adverse factors for RFS. CD56 expression was the only independent adverse factor for RFS by multivariate analysis (73.7% in CD56 negative and 48.2% in CD56 positive patients at 3 yrs) although its expression did not affect on OS. There was no difference of age, sex, WBC count, presence or absence of Auer rod, performance status, or CD15 expression between CD56 positive and negative cases. Expression of CD19 was more common in CD56 negative patients (50% in CD56 negative and 30.6% in CD56 positive patients, p<0.05). Conclusions: We demonstrated that the expression of CD56 was a distinctive adverse factor in a large number of AML patients with t(8;21) treated with JALSG AML97 regimen. CD56 positive AML patients with t(8;21) are possible candidates for hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

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Chemotherapy Cannot Replace Transplantation in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.5186.5186 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5186-5186

Author(s):

Xiaoyu Li ◽

Baoan Chen ◽

Jian Cheng ◽

Min Lin ◽

Xiaoping Zhang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Performance Status ◽

Univariate Analysis ◽

Individual Therapy ◽

Rank Test ◽

Kaplan Meier ◽

One Year ◽

Acute Myeloid

Abstract Abstract Text: Objective: The mortality rate of refractory/relapsed acute myeloid leukemia (AML) is very high with poor prognostic. Three are still no standard treatments for these patients nowadays. Our research compared the treatment effect between patients with chemotherapy and transplantation. Method: A retrospective research of 45 patients with refractory/relapsed AML was performed in our center. We analyzed the clinical features including gender, age, classification of AML, performance status (PS), complete remission (CR) duration, cytogenetic and molecular abnormities. Survival analyses were made by using the Kaplan Meier method and took the Log - rank test. Results: The mean survival time of the 45 patients with refractory/relapsed AML was (36.25¡À8.40) months and the median follow up was (9¡À2.58) months. The one year and two years overall survival rate was (40.6¡À7.5)% and (23.7¡À7.0)%. Univariate analysis results demonstrated that age¡Ý60 years and failing to undergo HSCT after relapse had poor influence on OS. Conclusion: Performance of HSCT after relapse can improve the prognosis through the single center study. HSCT is still the effective salvage therapy for patients with refractory/relapsed AML. Our research is benefit for individual therapy and can be applied to improve the survival. Disclosures No relevant conflicts of interest to declare.

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A Scoring System for Prediction of FLT3-ITD Positivity in Patients with Newly Diagnosed Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v120.21.2590.2590 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2590-2590

Author(s):

Fabiana Ostronoff ◽

Megan Othus ◽

Hagop M. Kantarjian ◽

Soheil Meshinchi ◽

Farhad Ravandi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Scoring System ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Cancer Center ◽

Newly Diagnosed ◽

Wbc Count ◽

Acute Myeloid

Abstract Abstract 2590 Background FLT3-internal tandem duplication (ITD) is found in about 30% of patients with acute myeloid leukemia (AML) at diagnosis and confers a high risk of relapse. Thus allogeneic hematopoietic transplant (HCT) is recommended for these patients in first complete remission (CR) and after HCT they become candidates for trials of FLT3-ITD inhibitors (such as quizartinib) to prevent relapse. However at referral to tertiary centers after reaching CR, FLT3-ITD status at diagnosis is often unknown, complicating decisions about HCT. FLT3-ITDs are known to be associated with a normal karyotype (NK), translocation 6;9 and a high white blood cell (WBC) count, and we hypothesized that assessment of likely FLT3-ITD status at diagnosis in patients presenting in CR not tested at diagnosis would be improved by examining these covariates simultaneously. Methods Our initial analysis included 434 adult patients with newly diagnosed AML (excluding APL) treated on three SWOG trials (S9031, S9333, and S0106) in whom FLT3-ITD status (positive/negative) was established at diagnosis. Univariate and then multivariate analyses were used to identify covariates independently associated with FLT3-ITD positivity. The relative abilities of these to predict FLT3-ITD positivity were quantified using the area under the receiver operator characteristic curve (AUC); an AUC of 1.0 denotes perfect prediction, whereas an AUC of 0.5 is analogous to a coin flip. The log odds ratios (ORs) from the multivariate models were used to assign a score to each covariate and scores were summed; such that the higher the score, the greater is the likelihood of the FLT3-ITD positivity at diagnosis. We tested the performance of the scoring system in 2 newly-diagnosed populations that had not contributed to the system's development and in whom FLT3-ITD status at diagnosis was known: (a) 210 patients treated at FHCRC (Fred Hutchinson Cancer Research Center) and (b) 1,401 patients treated at MDACC (M.D. Anderson Cancer Center). Covariates examined were: age, sex, performance status (PS), WBC count, platelet count, bone marrow blast percentage, secondary AML, and cytogenetic risk (using SWOG/Eastern Cooperative Oncology Group criteria). Results FLT3- ITD was present in 101 of the 434 SWOG patients (23%) in the scoring system development population. The log OR were rounded to the nearest half point to create the scoring system. Only WBC > 20,000 (reference, WBC < 20,000) and cytogenetics (reference, normal) had non-zero scores, which are summarized below: Scores less than −0.5 were called low, ≥−0.5 and <0.5 intermediate, ≥ 0.5 high. The AUC was 0.75 and contrasted with 0.66 and 0.69 when only WBC or cytogenetics were considered. However when this system was tested in the FHCRC population (16% FLT3-ITD positive) its AUC was only 0.58, not better than when each covariate was examined separately (AUC 0.54 and 0.6 for WBC and cytogenetics, respectively). Similarly at MDACC (17% FLT3-ITD positive) the system's AUC was 0.68 vs. 0.59 and 0.68 for WBC and cytogenetics, respectively. Conclusion Although this scoring system seemed useful tool within the population it was developed (SWOG), such was not the case in two independent cohorts of AML patients with known FLT3-ITD status (FHCRC and MDACC). This indicates that there is no obvious substitute for actual data on FLT3-ITD status. Disclosures: No relevant conflicts of interest to declare.

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Clinical Significance of Free Circulating CD34 in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v108.11.4495.4495 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4495-4495

Author(s):

Menna Hodge ◽

Francis Giles ◽

Adam Abdool ◽

Susan O’Brien ◽

Michael Keating ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Performance Status ◽

Signal Transduction Pathway ◽

Leukemic Cells ◽

Neural Cells ◽

And Performance ◽

Wbc Count ◽

Acute Myeloid

Abstract CD34 is an approximately 116-kd glycophosphoprotein expressed in hematopoietic progenitor cells, endothelial cells, and some mesenchymal and neural cells. CD34 is a typical adhesion molecule capable of inducing the cell signal transduction pathway leading to adhesion and differentiation. We used a newly developed bead-based assay to measure cell-free circulating CD34 (cCD34) in the plasma of patients with acute myeloid leukemia (AML; n = 98) and myelodysplastic syndrome (MDS; n = 50). Levels of cCD34 were significantly higher in AML (median 10983, range: 844–100,4191 U/10 μl than in MDS (median: 8749, range:102–791,350 U/10 μl) patients (P<0.01). cCD34 levels were higher among patients with high-risk cytogenetic abnormalities in AML (P = 0.01) but not MDS (P = 0.92). When grouped together, AML and MDS patients with cCD34 levels higher than the median (10,845 U/μl) had significantly shorter survival than those with lower levels (P = 0.01). This association was independent of cytogenetic grouping, age, and performance status. cCD34 levels did not correlate with percent of blasts or CD34+ cells but did correlate with WBC count (R = 0.36) in patients with AML, suggesting that cCD34 reflects the overall leukemia load. Although further study is needed for confirmation, cCD34 appears to result from turnover of leukemic cells and may affect the activation of certain pathways, therefore influencing survival and clinical outcome. Figure Figure

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Fludarabine, Cytarabine, and Attenuated-Dose Idarubicin (m-FLAI) Induction for Elderly Patients with Acute Myeloid Leukemia: Results of a Multicenter Phase II Study,

Blood ◽

10.1182/blood.v118.21.3626.3626 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3626-3626

Author(s):

Yoojoo Lim ◽

Youngil Koh ◽

Sung-Soo Yoon ◽

Seonyang Park ◽

Byoung Kook Kim ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Phase Ii ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Performance Status ◽

Free Survival ◽

Induction Regimen ◽

Acute Myeloid

Abstract Abstract 3626 Introduction: Although there have been remarkable improvements in treatment of acute myeloid leukemia (AML), the prognosis of AML in elderly patients remains poor, and the best induction chemotherapy for these patients remains yet unknown. To devise an effective induction regimen for elderly patients with AML, we conducted a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) regimen in these patients. Patients and Methods: Elderly (60 years or older) AML patients who did not receive previous chemotherapy were enrolled. Patients received two consecutive cycles of m-FLAI chemotherapy as an induction. The m-FLAI regimen was comprised of fludarabine (25mg/m2, days 1–4), cytarabine (1000mg/m2, days 1–4), and attenuated-dose idarubicin (5mg/m2, days 1–3). The primary end point was complete remission (CR) rate. Results: A total of 108 patients (median age 68.4 years, M:F=64:44) were enrolled. CR was achieved in 62.9% of patients, and treatment-related mortality rate (TRM) was 25.8%. Median overall survival (OS) was 9.3 months, and median event-free survival (EFS) was 6.6 months. The mortality at 30 and 60 days was 18% and 24%, respectively. Performance status and comorbidity did not have prognostic value in these patients. Bone marrow expression of CD117 was related to long EFS and OS. Conclusion: In conclusion, m-FLAI is a safe and effective induction regimen for previously untreated AML in elderly patients. Bone marrow CD117 expression is an independent good prognostic factor in these patients. (ClinicalTrials.gov number, NCT01247493) Disclosures: No relevant conflicts of interest to declare.

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Combination of Mitoxantrone,Ara-C and Homoharringtonine In Treatment of Refractory and Relapsed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v118.21.4294.4294 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4294-4294

Author(s):

Jianda Hu ◽

Tingbo Liu ◽

Chunxia Cai ◽

Xinji Chen ◽

Buyuan Chen

Keyword(s):

Drug Resistance ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Median Time ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Abstract 4294 Advances in effective chemotherapy have improved clinical outcomes in acute leukemia in recent years. 5-year survival rate approaches 50–60% for acute myeloid leukemia (AML). However, the prognosis remains poor for patients who are relapsed or refractory to first-line therapy. Drug resistance and early disease recurrence are major contributing factors in the limited survival of patients with AML. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation. New combinations of different agents were employed in refractory patients to overcome drug resistance. The current study is to evaluate the efficacy of a MAH regimen comprising Mitoxantrone,Ara-C and Homoharringtonine in refractory or relapsed AML. 37 patients aged 14–65 years with refractory or relapsed AML (15 refractory AML patients, 22 relapsed AML patients) were treated with the MAH regimen(Mitoxantrone 10mg qd, iv.gtt, for 2□‘3 days;Ara-C 100mg bid, iv.gtt, for 5□‘7 days; Homoharringtonine 4mg qd iv.gtt, for 5□‘7 days). Chemotherapy duration lasted for 5 or 7days depended on bone marrow cellurarity. 15 (40.5%)and 1 (2.7%) patients achieved complete remission (CR) and partial remission (PR) respectively. The overall response rate was 43.2%. There was no relation between remission duration and previous chemotherapy. All patients who achieved CR received a consolidation and intensification therapy. The median overall survival (OS) for all patients was 97 days (range 18–487 d). For the patients who were in CR or PR,the median relapse-free survival(RFS) was 147 days(range 4 to 341 d). All patients experienced profound myelosuppression. The most common observed side effect of the regimen was infection because of grade ‡W neutropenia, which could be observed in 33 patients(89.1%). 4 patients died in aplasia due to severe infection and brain hemorrhage. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×109/l was (16.0±6.4)d. Platelet levels of more than 20×109/l were achieved in a median time of (12.7±6.2)d. Nonhematological side effects, consisting mainly of gastrointestinal toxicity(21/37,56.8%) and transient liver ALT and AST increase (4/37), were generally mild to moderate and tolerated. To a conclusion, MAH regimen can be employed in treatment of the refractory or relapsed AML patients who were not responded to other regimen. It is effective and is good tolerant.It could provide some refractory patients the chance to receive hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

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EZH2 Mutations Are Associated with Low Blast Percentage in Bone Marrow and −7/Del(7q) Karyotype in De Novo Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v120.21.2544.2544 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2544-2544

Author(s):

Xiuli Wang ◽

Haiping Dai ◽

Qian WANG ◽

Qinrong Wang ◽

Yang Xu ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Myelogenous Leukemia ◽

Prognostic Impact ◽

Coding Region ◽

Acute Myeloid

Abstract Abstract 2544 Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

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CXCR4 Invalidation Limits the MLL-ENL Induced Leucemogenesis in Vivo

Blood ◽

10.1182/blood.v120.21.4089.4089 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4089-4089

Author(s):

Yanyan Zhang ◽

Hadjer Abdelouahab ◽

Aline Betems ◽

Monika Wittner ◽

William Vainchenker ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Abstract 4089 The receptor CXCR4 and its ligand SDF-1 play major physiological roles especially on hematopoietic stem cells homing and retention. Many studies have implicated CXCR4 in the invasion by tumor cells of organs that produce SDF-1. In acute myeloid leukemia, the physiological role of CXCR4 is not fully understood. We used retrovirus to express MLL-ENL oncogene in CXCR4+/+ and CXCR4−/− hematopoietic primitive cells (Lin- isolated from fetal liver) and showed that CXCR4 is dispensable for generation of immortalized colonies in vitro. To determine CXCR4 function in vivo, CXCR4+/+ and CXCR4−/− transformed cells were transplanted into lethally irradiated mice. Whatever their phenotype, the recipient developed a myelo-monocytique leukemia characterized by their expression of Gr-1 and Mac-1. As expected, all recipients of MLL-ENL transduced CXCR4+/+ cells were moribund within 35 to 80 days post transplant (median survival time: 50 days). Strikingly, recipients of MLL-ENL transduced CXCR4−/− cells showed significantly increased lifespan, with a median survival time of 90 days. The cellularity of the peripheral blood of recipients of MLL-ENL transduced cells displayed considerable increases over time although this increase was much lower in CXCR4−/− than in CXCR4+/+ chimera. Bone marrow of MLL-ENL transduced CXCR4−/− chimera had moderately decreased numbers of mononuclear cells. There were important numbers of leukemic CD45.2+/Gr1+/Mac1+/c-kit+ cells in spleen from MLL-ENL CXCR4+/+ chimera which suggested that CXCR4 is important for leukemic progenitors cells retention in the bone marrow and especially in the spleen. The homing capacity of transduced CXCR4+/+ cells is comparable to the CXCR4−/− cells. Finally, more DNA damages were found in the BM cells of MLL-ENL CXCR4−/− chimera. All these results were confirmed by treating of MLL-ENL CXCR4+/+ chimera with CXCR4 inhibitor (TN140). These results demonstrated that in absence of CXCR4, the cells transduced by oncogene MLL-ENL are capable of generating leukemia in the recipients. However, mice transplanted with MLL-ENL transduced CXCR4−/− FL cells developed acute myeloid leukemia with reduced aggressiveness and organ infiltration, which is associated with induced differentiation and DNA instability. These results indicated that the MLL-ENL progenitors are dependent on CXCR4 for their maintenance in the BM and spleen suggesting that CXCR4 inhibitors might have potential therapeutic applications. Disclosures: No relevant conflicts of interest to declare.

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Poor Prognosis With Different Induction Rate Was Observed In Children With Acute Myeloid Leukemia and FLT3-ITD According To The ITD/WT Allelic Ratio: A Result From The Japanese Pediatric Leukemia/Lymphoma Study Group

Blood ◽

10.1182/blood.v122.21.3891.3891 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3891-3891

Author(s):

Akira Shimada ◽

Yuka Yamashita ◽

Daisuke Tomizawa ◽

Akio Tawa ◽

Tomoyuki Watanabe ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Pediatric Leukemia ◽

Hematopoietic Stem ◽

Allelic Ratio ◽

Induction Rate ◽

Wbc Count ◽

Acute Myeloid

Abstract Background Acute myeloid leukemia harboring internal tandem duplication of fms-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis, but the previous studies have reported that the inferior outcome is only confined to those with high allelic ratio (AR) of ITD/wild type (WT). In our previous AML99 study (2000-2002), AMLFLT3-ITD showed a poor outcome compared to the WT cases (5-year OS; 35% vs. 84%, P<0.0001). We, therefore, assigned all the patients with AMLFLT3-ITD to receive hematopoietic stem cell transplantation (HSCT) in first remission (1CR) in the JPLSG AML-05 study. Patients & Methods AML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a Japanese nation-wide multi-institutional study for children (age<18 years) with de novo AML and enrolled 443 eligible patients from Nov. 2006 to Dec. 2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. FLT3-ITD was examined centrally for all the patients. After the 2 consecutive induction chemotherapies [(ECM: etoposide, Ara-C, and mitoxantrone) and (HCEI: HD Ara-C, etoposide, and idarubicin)], all the AMLFLT3-ITD patients were allocated to the high risk group and further received intensification therapy including HD Ara-C followed by HSCT in 1CR. All DNA samples were extracted from the first diagnostic bone marrow or peripheral blood and subjected to PCR and direct sequencing. AR of FLT3-ITD/WT was examined by GeneScan, and defined AR >0.4 as high and AR ≤ 0.4 as low as previously reported (Meshinchi S. Blood2006). Results We found 47 patients (10.6%) with AMLFLT3-ITD in this study (30 males, 17 females, and median age of 11 years at diagnosis). The median WBC count was 65,300/ml (3,690 - 522,050/mL). FAB classification included M1 (n=10), M2 (n=9), M4 (n=9), and M5 (n=11), and AML with normal karyotype was dominant (19/47, 40.4%). Of the 29 patients (61.7%) who achieved CR, twenty-seven received HSCT in 1CR and 19 patients survived (19/27, 70.4%). On the other hand, 14/16 non-CR patients received HSCT, but only 4 survived. The only demographic difference between the 29 CR and 16 non-CR cases was the median WBC count at diagnosis (19,000 vs. 124,000/μL, P<0.001), and rapid clearance of bone marrow blasts after single induction course was observed in the CR group (median blast percentage dropped from 73% to 1.1% in the CR group, while that was 85% to 30.6% in the non-CR group). Finally, five-year OS, DFS and EFS for all 47 AMLFLT3-ITD patients were 41.3%, 58.4% and 36.1%, respectively. AR was analyzed in 44 patients with median ratio of 0.68 (range, 0.11 to 4.47). Median AR was not different between CR vs. non-CR cases (0.53 vs. 0.72). There were no difference in 5-year OS (52.8% vs. 42.5%, P=0.302), DFS (54.5% vs. 64.5%, P=0.524), and EFS (50.0% vs. 34.4%, P=0.283) between patients with low (n=12) and high AR (n=32), however, induction rate was significantly higher in the low AR patients (91.7% vs. 53.1%, P=0.018). It was rather surprising that all FLT3-ITDs were found only in JM domain and not in TKI domain in the current trial. In addition, six of 47 (12.8%) AMLFLT3-ITD patients had NPM1mutation simultaneously, and all received HSCT at 1CR and survived. Discussion and Conclusion We observed a different induction rate between AMLFLT3-ITD patients with low and high AR, but poor final outcomes in both. Regardless of the level of AR, patients with AMLFLT3-ITD, especially who fail to achieve remission, have dismal outcome and effective therapy combined with novel FLT3 inhibitor is urgently needed to overcome the disease. Disclosures: No relevant conflicts of interest to declare.

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TIM-3 Is Highly Expressed On Blast Cells In Patients With Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.4931.4931 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4931-4931

Author(s):

Caixia Li ◽

Xiao Yu ◽

Yibei Zhu ◽

Xiaojin Wu ◽

Xiao Ma ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Negative Regulator ◽

Clinical Implications ◽

Potential Marker ◽

Blast Cells ◽

Acute Myeloid

Abstract T cell immunoglobulin-3(TIM-3) is known as a negative regulator in anti-tumor immunity through its reaction with TIM-3 ligand, galectin-9. It has been confirmed that TIM-3 is expressed on Th1 cells, dendritic cells, monocytes, macrophages, malignant stem cells and so on. But the expression of TIM-3 and its clinical implications in patients with acute myeloid leukemia(AML) remains unknown. In this study, we sought to determine the expression and clinical implications of TIM-3 in AML. From August 2012 to June 2013, in total of 32 AML patients with sixteen male and sixteen female were enrolled in this study. We collected their peripheral blood before they received any treatment and then obtained their peripheral blood mononuclear cells(PBMC). Monoclonal antibody was added into PBMC and cell population was analyzed by flow cytometry. Blast cells were identified with SSC CD45±and mature lymphocytes with SSC CD45+. The average expression of TIM-3 on blast cells was 43.46%, while on mature lymphocytes was 13.78% (P<0.001). In univariate analysis, the level of expression was not correlated to the percentage of blast cells and there was no difference between each type of AML. Complete remission was similar between different levels of TIM-3 expression(P>0.05). These results demonstrated that TIM-3 was highly expressed on blast cells than on mature cells in AML, which indicated that TIM-3 could be associated with the differentiation of blast cells and a potential marker to detect the tendency of relapse. TIM-3-targeted antitumor therapy presents a perspective possibility. Disclosures: No relevant conflicts of interest to declare.

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Inhibition of HDAC8 Reactivates p53 and Abrogates Leukemia Stem Cell Activity in CBFβ-SMMHC Associated Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.363.363 ◽

2014 ◽

Vol 124 (21) ◽

pp. 363-363

Author(s):

Jing Qi ◽

Qi Cai ◽

Sandeep Singh ◽

Ling Li ◽

Hongjun Liu ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Bone Marrow Cells ◽

Conflicts Of Interest ◽

Cell Activity ◽

Disease Free Survival ◽

Hematopoietic Stem ◽

The Impact ◽

Acute Myeloid

Abstract The inv(16)-created CBFβ-SMMHC fusion protein inhibits differentiation of hematopoietic stem and progenitor cells (HSPCs) and creates pre-leukemic populations predisposed to acute myeloid leukemia (AML) transformation. However, the molecular mechanism underlying the leukemogenic function of CBFβ-SMMHC has been elusive. Given the low TP53 mutation rate in AML, alternative mechanisms disrupting p53 function are expected. We showed thatCBFβ-SMMHC impairs p53 acetylation and p53 target gene activation through formation of an aberrant protein complex with p53 and HDAC8 (Blood, 120: A772; 122(21): 224). We now show that CBFβ-SMMHC binds to p53 and HDAC8 independently through distinct regions and that HDAC8 mediates the deacetylation of p53 associated with CBFβ-SMMHC. In addition, we generated mice carrying a floxed Hdac8 (Hdac8f) allele and crossed with Cbfb56M/+/Mx1-Cre (Kuo YH et al, Cancer Cell 2006). Deletion of Hdac8 signifiacntly (p<0.0001) reduced the incidence of AML and prolonged disease-free survival. Pharmacologic inhibition of HDAC8 activity with HDAC8-selective inhibitors (HDAC8i) reactivates p53 and selectively induces apoptosis of inv(16)+ AML CD34+ cells while sparing normal HSPCs. To test the effect of HDAC8i on LSC engraftment and leukemia-initiating capacity, we generated Cbfb56M/+/Mx1-Cre mice with a Cre-reporter line expressing tdTomato fluorescence protein following Cre-mediated recombination. AML cells (dTomato+/cKit+) treated with HDAC8i (22d) ex vivo showed reduced engraftment (p=0.025) and enhanced survival (p=0.025) in transplanted mice. To examine whether HDAC8i 22d treatment affects the engraftment capacity on surviving cells, we transplanted equal number (2 x 106) of AML cells treated with either 22d or vehicle in another cohort of mice (n=4). We show that HDAC8i 22d treatment reduced the engraftment of dTomato+/cKit+ AML cells and enhanced survival, suggesting that the engraftment capacity is altered in addition to reducing AML cell survival. We next performed preclinical studies to determine the efficacy of in vivo administration of HDAC8i 22d. AML transplanted mice were randomized into two groups, one group treated with vehicle and the other treated with HDAC8i 22d for 2 weeks. Flow cytometry analysis revealed significantly reduced frequency (p=0.0097) and number (p=0.0101) of dTomato+/cKit+ AML cells in the bone marrow and spleen of 22d treated mice compared to vehicle treated group. To further assess the impact on LSC activity, we transplanted bone marrow cells from these treated mice into secondary recipients and analyzed for AML engraftment. Significant reduction in the frequency (p<0.0001) and the number (p=0.0006) of dTomato+/cKit+ AML cells was observed in the bone marrow and spleen. Furthermore, HDAC8i 22d treated transplants showed no signs of leukemia while vehicle treated transplants are moribund with aggressive AML. These results indicate that HDAC8 inhibition by 22d treatment effectively eliminates engraftment and leukemia-initiating capacity of AML LSCs. In conclusion, our studies identify a novel post-translational p53-inactivating mechanism and demonstrate selective HDAC8 inhibition as a promising approach to target inv(16)+ AML LSCs. Disclosures No relevant conflicts of interest to declare.

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