Core Binding Factor Acute Myelogenous Leukemia Research Articles

Metabolomic profile of acute myeloid leukaemia parallels of prognosis and response to therapy

The heterogeneity of acute myeloid leukemia (AML), a complex hematological malignancy, is caused by mutations in myeloid cells affecting their differentiation and proliferation. Thus, various cytogenetic alterations in AML cells may be characterized by a unique metabolome and require different treatment approaches. In this study, we performed untargeted metabolomics to assess metabolomics differences between AML patients and healthy controls, AML patients with different treatment outcomes, AML patients in different risk groups based on the 2017 European LeukemiaNet (ELN) recommendations for the diagnosis and management of AML, AML patients with and without FLT3-ITD mutation, and a comparison between patients with FLT3-ITD, CBF-AML (Core binding factor acute myelogenous leukemia), and MLL AML (mixed-lineage leukemia gene) in comparison to control subjects. Analyses were performed in serum samples using liquid chromatography coupled with mass spectrometry (LC–MS). The obtained metabolomics profiles exhibited many alterations in glycerophospholipid and sphingolipid metabolism and allowed us to propose biomarkers based on each of the above assessments as an aid for diagnosis and eventual classification, allowing physicians to choose the best-suited treatment approach. These results highlight the application of LC–MS-based metabolomics of serum samples as an aid in diagnostics and a potential minimally invasive prognostic tool for identifying various cytogenetic and treatment outcomes of AML.

Dr. Elihu H. Estey (1946–2021)

Dr. Elihu H. Estey (1946–2021)

Baseline Mutations Lack Impact on Clinical Outcomes and Molecular Response in Core Binding Factor Leukemia Treated with Highly Effective Regimen

Baseline Mutations Lack Impact on Clinical Outcomes and Molecular Response in Core Binding Factor Leukemia Treated with Highly Effective Regimen

Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin (FLAG-GO) Regimen Results in Better Molecular Response and Relapse-Free Survival in Core Binding Factor Acute Myeloid Leukemia Than FLAG and Idarubicin (FLAG-Ida)

Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin (FLAG-GO) Regimen Results in Better Molecular Response and Relapse-Free Survival in Core Binding Factor Acute Myeloid Leukemia Than FLAG and Idarubicin (FLAG-Ida)

Addition of Gemtuzumab Ozogamicin (GO) to Fludarabine, Cytarabine and G-CSF (FLAG) Based Induction Regimen Results in Better Early Molecular Response and Relapse Free Survival Compared to Idarubicin (FLAG-Ida) in Newly Diagnosed Core Binding Factor Leukemia

Addition of Gemtuzumab Ozogamicin (GO) to Fludarabine, Cytarabine and G-CSF (FLAG) Based Induction Regimen Results in Better Early Molecular Response and Relapse Free Survival Compared to Idarubicin (FLAG-Ida) in Newly Diagnosed Core Binding Factor Leukemia

Wilms Tumor 1 Expression at Diagnosis Correlates With Genetic Abnormalities and Polymorphism But Is Not Independently Prognostic in Acute Myelogenous Leukemia: A Hokkaido Leukemia Net Study

BackgroundThe prognostic effect of Wilms tumor 1 (WT1) expression at the diagnosis of acute myelogenous leukemia (AML) has been controversial. The aim of the present study was to determine the correlations of WT1 expression at the diagnosis of AML with established prognostic alterations. Patients and MethodsWe analyzed diagnostic bone marrow samples from 252 patients. WT1 expression, single nucleotide polymorphism (SNP) in the WT1 gene (rs16754), and Fms-like tyrosine kinase receptor-3 internal tandem duplication (FLT3-ITD) mutation were analyzed for all patients. The nucleophosmin 1 (NPM1) mutation and CCAAT/enhancer-binding protein-α (CEBPA) double mutation were analyzed for cytogenetically normal (CN)-AML. The KIT mutation was analyzed for core-binding factor AML. ResultsWithin the cytogenetically favorable prognosis group, WT1 expression in AML with inv(16) or t(15;17) was significantly greater than that in AML with t(8;21). In cases with CN-AML, FLT3-ITD and NPM1 mutations both correlated with greater expression of WT1, and the CEBPA double mutation was related to lower WT1 expression. The existence of both FLT3-ITD and NPM1 mutations showed synergistically greater expression of WT1 in CN-AML. SNP in the WT1 gene (rs16754) was significantly associated with lower expression of WT1. The WT1 levels were not prognostic factors in the total cohort or any cytogenetic group or stratified by SNP status. ConclusionBecause WT1 expression has correlated with known prognostic factors, the prognostic effect of WT1 levels could be misunderstood depending on the distribution of the collaborative mutations in each cohort. We have concluded that the prognostic significance of WT1 at the diagnosis of AML is weak compared with the other established prognostic factors.

Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia.

Despite being considered "good-risk" acute myelogenous leukemia (AML), long term outcomes in core binding factor (CBF) AML suggest room for improvement. We report on a regimen consisting of fludarabine, cytarabine, granulocyte colony stimulating factor, and low dose gemtuzumab ozogamicin (FLAG-GO) as front-line therapy of patients with CBF AML. Forty-five patients were enrolled (median age 48 years). Remission rate was 95% with 5% induction deaths. The overall survival (OS) and relapse free survival (RFS) probability at 3 years are 78% and 85%, respectively. FLAG-GO regimen results in high rates of RFS and OS in CBF AML. Our data along with recent data from several large groups strongly argues in favor of incorporation of gemtuzumab ozogamicin in frontline regimens for CBF AML.

Replacing Gemtuzumab Ozogamicin With Idarubicin In Frontline Fludarabine, Cytarabine and G-CSF Based Regimen Does Not Compromise Outcome In Core Binding Factor Acute Myelogenous Leukemia

A regimen comprising of fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) has been our frontline treatment regimen for patients with core binding factor acute myelogenous leukemia (CBF-AML) and among 50 patients with median follow up of over 3 years, this regimen resulted in overall survival (OS) and relapse free survival (RFS) of 78% and 85% respectively. This is clearly better than our historical data with idarubicin and cytarabine based regimens (Borthakur et al. JCO. Vol 28, No 15 suppl; 2010:6552). After withdrawal of GO from the market, it has been substituted by low dose idarubicin at 6 mg/m2 on days 3 and 4 in induction and in one post remission cycle during cycles 3-6 (FLAG-Ida). So far 38 patients have been treated with FLAG-Ida (median follow up 1 year) with all patients achieving complete remission. The current report is part of the planned analysis to ensure that patient outcomes have not been compromised by the change in regimen.Univariate and multivariate (MVA) Cox proportional hazards regression was used to identify association of the clinical variables with overall survival (OS), event free survival (EFS) and time to relapse (TTR). Event is defined as death from any cause or relapse. Treatment regimen (FLAG-GO or FLAG-Ida) were included as variables in the analysis. Apart from relevant clinical variables, reduction in fusion transcript ratio (in reference to ABL gene transcript compared to that at diagnosis) at time points 1 month (≥3 log reduction yes/no) and 3 month (≥3 log reduction yes/no) and presence of any mutation (RAS, KIT, FLT3 yes/no) were also added as variables. Stepwise backwards selection method was used to remove variables that did not remain significant in the multivariate model (p ≥ 0.15).T(8;21) is the cytogenetic abnormality in 52% of all 88 patients. Median age of all patients is 51 (range, 19-78 years) and 48% are female. Median time to 3 log reduction in transcript ratio was 1 month (range, 1-22 months). Complete remission rate with or without platelet recovery has been 98% with 2 induction deaths.Kaplan-Meier analysis showed OS (Fig.1), EFS and TTR were not significantly different FLAG-GO and FLAG-Ida regimens. By MVA, OS, EFS and TTR are not different among these regimens (p > 0.5). Three log or more reduction in transcript ration at 1 month was associated with better OS (p=.03) and EFS (p=.008) (not TTR) in MVA. Presence of KIT, RAS or FLT3 gene mutation did not impact outcomes studied.In conclusion, replacing GO with low dose idarubicin in a front-line FLAG regimen does not seem to compromise the excellent outcomes with such a regimen in CBF AML. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Therapy of Core Binding Factor Acute Myeloid Leukemia: Incremental Improvements Toward Better Long-Term Results

Despite being considered as good prognostic acute myelogenous leukemia (AML), the long-term survival rate in core binding factor AML leaves room for substantial improvement. We discuss treatments that have improved outcome in this group of patients with AML and ongoing/future strategies that might contribute toward incremental gains. Despite being considered as good prognostic acute myelogenous leukemia (AML), the long-term survival rate in core binding factor (CBF) AML leaves room for substantial improvement. We reviewed relevant English language literature related to treatment of CBF AML available in PubMed. Review also included meeting abstracts. Multicycle high dose cytarabine in consolidation improves remission duration but larger groups report overall survival in the range of 40% to 50% at 5 years or longer. Concerted effort is needed toward improving outcomes in CBF AML through clinical trials and risk-adapted approach.

Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin (FLAG-GO) on relapse-free survival in patients with newly diagnosed core-binding factor acute myelogenous leukemia.

6528 Background: Prior modulation with fludarabine increases cytarabine-triphosphate (ara-CTP) accumulation and granulocyte-colony-stimulating factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in leukemic blasts. Our front-line regimen of fludarabine, cytarabine and filgrastim (FLAG) based on this rationale showed improved event-free survival compared to anthracycline and cytarabine based regimens in patients (pts) with core-binding factor acute myelogenous leukemia (CBF-AML). Medical Research Council AML 15 trial reported survival benefit from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed CBF-AML, pts received GO on day 1 of induction and of post-remission cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in induction and 3-4 days in post-remission cycles) with filgrastim started on day-1 and continued till neutrophil recovery. Pts who received one non-FLAG-GO induction could enroll irrespective of their remission status. Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5 of 50 (10%) were in remission at enrollment from prior induction]. Median age is 48 years (range, 19-76), median WBC count 12.3 x106/L (range, 1.3-97.2); 12 patients (24%) were >60 years of age and frequency of kit mutation is 8%. Complete remission with or without platelet recovery (CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction. With 6 planned consolidations, the median number of consolidation treatments received is 5 (range, 0-6). Two-thirds of pts needed dose reduction during post-remission cycles. Seven (14%) pts [t(8;21)= 5, Inv 16=2] relapsed and with a median follow-up of 34 months (range, 15-54 months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a highly effective regimen and has resulted in high rate of relapse-free survival in pts with newly diagnosed CBF AML.

Most Patients with Core Binding Factor AML Require Hematopoietic Stem Cell Transplantation for Long-Term Survival: Long Term Follow-up of a Cohort of Unselected Patients.

AbstractAbstract 4560 Introduction:About 15% of acute myelogenous leukemia (AML) patients will have disruption of the core binding factor (CBF) transcription factor as indicated by the detection of t(8;21) or inv(16) on metaphase cytogenetic analysis. In general, patients with CBF-AML are younger and regarded as having a favorable outcome when treated with anthracycline-based induction chemotherapy and multiple cycles of high-dose cytarabine consolidation. Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are usually perceived as unnecessary in the management of CBF-AMLs. However, most data indicating the favorable prognosis of CBF-AML with non-HSCT management originates from young selected patients participating in clinical trials and information on relapse treatments is often lacking. We performed a retrospective analysis of consecutive patients diagnosed with CBF-AML at a regional leukemia center over the last twelve years to assess long term survival of unselected patients and the likelihood of therapeutic success without ever requiring HSCT. Methods:The study cohort was identified through a search of all AML reports issued by the institutional clinical cytogenetics laboratory since the introduction of electronic records (1998-2010). We subsequently reviewed the charts of all patients with CBF-AML (irrespective of other cytogenetic abnormalities) to extract demographic, treatment, and outcome information. Survival status and subsequent treatments in other institutions were determined by contacting the patient, attending physician or review of public death records. Data collection and analysis were approved by the Institutional Review Board. Results:Thirty patients with CBF-AML were identified, 14 with t(8;21) and 16 with inv(16) AML. Median follow up for survivors in this series is 35.3 months (range 6.4–117.4) with all survivors currently in remission. Median age at diagnosis was 43 years (range 18–69) with 10 (33%) patients older than 55. All patients initially received therapy with curative intent with anthracycline-based induction chemotherapy. Only 47% of the patients were treated on clinical trials. There was 1 death during induction therapy and 22/29 patients (73.3%) achieved a complete remission with initial induction therapy. Overall 13 patients (43.3%) have required some modality of HSCT. Six patients received HSCT in CR1 due to perceived high risk of relapse (5 autologous, 1 allogeneic). None of the 6 patients who underwent HSCT in CR1 (5 autologous, 1 allogeneic) have relapsed. Among the 16 patients receiving non-transplant consolidation in CR1, 6 have subsequently relapsed and required a HSCT (3 autologous, 3 allogeneic) and 3 of these patients are alive 20.9–117.4 months from the initial diagnosis. Seven patients received HSCT in CR2 or in relapse (4 autologous, 3 allogeneic) and 6 of these patients are long-term survivors. Estimated 5 year overall survival for the entire cohort is 58.8 +/− 10.8%, comparable to what has been described for younger patients entering clinical trials (Grimwade et al, 2010). However, the likelihood of survival at 5 years without requiring HSCT was only 28.1+/− 8.8% (Figure). Conclusions:The favorable outcome previously reported for CBF-AMLs was reproducible in unselected patients. However, only a minority of patients were long term survivors relying exclusively on conventional chemotherapy. In the near future, strategies for molecular risk stratification of CBF-AML patients need to be coupled with risk-adapted therapy, likely including early use of HSCT for high-risk patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

ASH 2009 meeting report—Top 10 clinically oriented abstracts in acute leukemia

summary Acute myelogenous leukemia (AML) associated with core binding factor (CBF) abnormalities is sensitive to high-dose cytarabine-based chemotherapy leading to complete remission (CR) in over 90% of patients. The efficacy of cytarabine can be enhanced by the addition of fludarabine and GCSF with report of improved event free survival with this regimen [1]. Inclusion of gemtuzumab ozogamicin (GO) to induction chemotherapy produces favorable outcomes without additional toxicity [2]. Thirty-four patients with CBF AML were treated with induction/consolidation chemotherapy consisting of GO-FLAG. Of 29 patients not in CR at the time of initiation of therapy, all but two patients achieved CR or CR with incomplete platelet recovery. A sustainable more than three-log reduction in fusion transcript to ABL ratio from the median pretreatment value remained evident through follow-up at 9 months. Two patients died during induction therapy. The most common grade 3/4 toxicity was liver dysfunction in three patients. Additional toxicity reported included atrial fibrillation, pancreatitis, and respiratory failure. Discussion Despite repeated cycles of cytarabine-based chemotherapy, the relapse free survival of CBF AML decreases over time. Therapy sustaining clinical, as well as molecular remissions is vital to improving overall survival. The addition of GO to AML induction chemotherapy improved outcomes in CBF AML without additional toxicity. 2. Decitabine-Based Salvage Therapy in Adults with Acute Myeloid Leukemia (#2063) Abstract summary Poor response to salvage chemotherapy is common in relapsed AML,summary Poor response to salvage chemotherapy is common in relapsed AML, however the achievement of CR, specifically after second salvage therapy, may not correlate with survival benefits [3]. Low intensity options have been recognized to prolong survival in relapsed or refractory AML without significant toxicity. Medical records of patients aged 24–89 years (median 65.5 years) who received decitabine-based chemotherapy from September 2006 through July 2009 were reviewed. Twenty-nine patients received decitabine 20 mg/m daily for 10 days while 51 patients were treated with decitabine 20 mg/m daily for 5 days in combination with gemtuzumab 3 mg/ m on day 5. Median survival and CR rate reported in first salvage (n 5 25), was 181 days and 13%, second salvage (n 5 32) 207 days and 9%, and third or greater salvage (n 5 22) 209 days and 23%. The difference in survival between those patients receiving single agent decitabine versus decitabine in combination with gemtuzumab was not significant (209 days decitabine versus 177 days decitabine-gemtuzumab). Significant survival benefits were evident for those patients with normal and favorable cytoge-

Survival is poorer in patients with secondary core‐binding factor acute myelogenous leukemia compared with de novo core‐binding factor leukemia

Therapy related secondary acute myelogenous leukemia (AML) was commonly associated with prior exposure to alkylating agents or topoisomerase inhibitor. The long-term outcome of such patients with secondary AML was found to be worse than that of patients with de novo AML. Earlier reports suggested similar outcomes for patients with de novo and secondary AML associated with core-binding factor (CBF) abnormalities. A total of 188 patients with CBF AML were analyzed. The frequency of secondary CBF AML was 9%. Patients with secondary CBF AML were found to have significantly worse overall (OS) and event-free survival (EFS) compared with patients with de novo CBF AML. Secondary CBF AML status appeared to have only marginal significance in multivariate analysis. Matched analysis (by age, Eastern Cooperative Oncology Group performance status, and additional cytogenetic abnormality) indicated worse OS and EFS in patients with secondary CBF AML.

Treatment of core‐binding‐factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony‐stimulating factor results in improved event‐free survival

Acute myelogenous leukemia (AML) associated with core-binding-factor (CBF) abnormalities is the type of leukemia most responsive to cytarabine (ara-C) therapy and is of relative favorable prognosis. In vitro and ex vivo observations suggest that increases in intracellular ara-C levels influenced by administration of fludarabine and granulocyte colony-stimulating factor (GCSF) increase the effect of ara-C, prompting us to clinically evaluate the efficacy of such combinations. We analyzed the event-free survival of patients with newly diagnosed CBF AML treated with fludarabine and ara-C (FA) (N = 45) or with FA and GCSF (FLAG) (N = 22) and compared results to patients treated with regimens consisting of idarubicin and ara-C with or without GCSF (IA/IAG) (N = 47). After accounting for prognostic covariates other than treatment (including year in which treatment was administered), FA, and in particular FLAG, were associated with longer event-free survival than IA/IAG. Thus, our data lends clinical credence to the observed modulation of ara-C by fludarabine and GCSF.

Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate

Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)-dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)-AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT.