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.

Allogeneic Hematopoietic Stem Cell Transplantation Improved Survival for Adult Core Binding Factor Acute Myelogenous Leukemia Patients with Intermediate- and Adverse-Risk Genetics in the 2017 European LeukemiaNet

The use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for consolidation therapy in patients with core binding factor (CBF) acute myelogenous leukemia (AML) with intermediate- and adverse-risk genetics remains controversial. We retrospectively analyzed the clinical outcomes of 286 CBF-AML patients with intermediate- and adverse-risk genetics in first complete remission following consolidation with chemotherapy (n=122), auto-HSCT (n=27), or allo-HSCT (n=137) between January 2009 and December 2018 at our center. Patients with allo-HSCT showed superior 5-year overall survival (OS; 74% versus 38% or 49%; P < .001) and progression-free survival (PFS; 74% versus 26% or 49%; P < .001) and lower cumulative incidence of relapse (CIR; 9% versus 69% or 31%; P < .001) compared with chemotherapy alone or auto-HSCT. In the allo-HSCT group, minimal residual disease (MRD) at the second and third months after allo-HSCT could predict relapse in t(8;21) patients (2 months: PCIR=.002; 3 months: PCIR < .001) but not in inv(16) patients. Moreover, positive MRD after 2 courses of consolidation chemotherapy before allo-HSCT was an independent risk factor for survival in CBF-AML patients with intermediate- and adverse-risk genetics, whereas haploidentical donor (haplo-) HSCT could overcome the adverse prognosis (5-year OS, 87%; 5-year PFS, 81%; 5-year CIR, 7%). Allo-HSCT could be the optimal first-line consolidation therapy for patients with intermediate- and adverse-risk genetics, and haplo-HSCT could improve survival for patients with positive MRD after 2 courses of consolidation chemotherapy.

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

Core-binding factor acute myeloid leukemia: Heterogeneity, monitoring, and therapy.

Core binding factor acute myelogenous leukemia (CBF AML) constitutes 15% of adult AML and carries an overall good prognosis. CBF AML encodes two recurrent cytogentic abnormalities referred to as t(8;21) and inv (16). The two CBF AML entities are usually grouped together but there is a considerable clinical, pathologic and molecular heterogeneity within this group of diseases. Recent and ongoing studies are addressing the molecular heterogeneity, minimal residual disease and targeted therapies to improve the outcome of CBF AML. In this article, we present a comprehensive review about CBF AML with emphasis on molecular heterogeneity and new therapeutic options.

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.

Characteristics and Outcome of Patients with Core Binding Factor Acute Myelogenous Leukemia Treated with Timed Sequential Chemotherapy.

AbstractAbstract 1045 Background:Core-binding factor (CBF) leukemias represent 13% of adults with acute myeloid leukemia (AML). Favorable cytogenetic abnormalities encompassing t(8;21) and inv (16) achieve a complete remission (CR) rate of over 80% of the time with therapy. In general, CBF patients (pts) are reported to have a better disease free survival (DFS) than those without CBF alterations. Conventionally, postinduction outcome is improved with repetitive high dose cytarabine (HiDAC). The 5-year overall survival (OS) is reported at 45 to 76%. Timed sequential chemotherapy (TST) exploits augmented leukemic cell-cycle dependent killing by recruitment and synchronization of residual malignant clones and results in improved induction and postremission outcomes in poor-risk AML subtypes. We performed a retrospective study evaluating our single institutional experience on the outcome(s) of patients with CBF-AML treated with TST from 1984 to 2004. Methods:We identified 66 previously untreated pts who underwent a single cycle of induction TST (AcD-VP16) consisting of daunorubicin 45 mg/m2/d (days 1–3) and cytarabine 667 mg/m2/d IV continuous infusion (days 1–3) followed by etoposide 400mg/m2/d (days 8–10). Patients in remission received a single cycle of consolidation TST (Ac-D-Ac) consisting of one of two regimens: (1) daunorubicin 45mg/m2/d (days 1–3) and cytarabine 2g/m2/d IV continuous infusion (days 1–3) followed by cytarabine 0.667g/m2/d IV continuous infusion (days 10–12) or (2) daunorubicin 45mg/m2/d (days 1–3) plus cytarabine 0.667g/m2/d IV continuous infusion (days 1–3) followed by cytarabine 0.667g/m2/d (days 10–12). CR rates per pre-treatment cytogenetics were examined as well as overall survival (OS) after post-remission treatment. Results:Among 66 patients (median age, 42 years; range 12–72 years) with CBF-AML treated with TST, 25(37.8%) and 41(62.1%) were t (8;21) and inv (16), respectively. CR was achieved with induction TST in 24/25(96%) of patients with t(8;21) and in 38/41(93%) of patients with inv(16). Refractory disease was seen in 1/66 pts (1.5%). CR rates of 94%, 95% and 89% were observed in pts treated with TST at (a) all ages, (b) age <60 years and (c) 60–75 years, respectively. The most common additional cytogenetic abnormality was loss of sex chromosome in the t(8;21) group in 10/29(34%) pts. For the inv (16) group, trisomy 8 was the most frequent associated additional abnormality and was present in 10/47(21%) of pts. The 5 year overall survival (OS) for the CBF cohort was 50%. Cox proportional hazards regression models for survival were performed using cytogenetic grouping as the main effect. OS was superior for pts with complex t(8;21) compared to simple t(8;21) (P=0.02); however, a trend for improved outcome was observed in pts with complex inv (16). Conclusions:TST resulted in excellent CR rates for pts with CBF AML, and this is associated with a low incidence of refractory disease. Secondly, TST is associated with acceptable 5-year OS of about 50% and is comparable to historical data. Disclosures:Gore:Celgene: Research Funding, Stock options.

Clinical and Molecular Response in Core Binding Factor Acute Myelogenous Leukemia with Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin.

Abstract 2056Poster Board II-33 Background:Core binding factor associated acute myelogenous leukemias (CBF AML) are characterized by sensitivity to high dose cytarabine (ara-C). Attempts to modulate intra-cellular ara-C tri phosphate (ara-CTP) by induction/consolidation therapy with fludarabine, cytarabine and granulocyte colony stimulating factor (GCSF) (FLAG) has resulted in improved event free survival (EFS) (median EFS not reached after median follow-up of 118 weeks) in patients with CBF AML (Borthakur et al. 2008, Cancer 113:3181). Addition of gemtuzumab ozogamicin (GO) to induction and consolidation has resulted in improved disease free survival (DFS) in patients with AML and “favorable cytogenetics” (Burnett,A. et al. ASH 2006#13). Method:In an attempt to improve upon these results we have initiated a study incorporating GO with FLAG (GO-FLAG) in induction/consolidation for treating patients with newly diagnosed CBF AML. Patients with CBF AML, untreated or who received one cytarabine based induction regimen are eligible. Induction regimen comprises of fludarabine 30 mg/m2 IV days 1- 5, cytarabine 2 g/m2 IV days 1- 5 (3.5 h after completion of that day's fludarabine infusion, Gemtuzumab ozogamicin 3 mg/m2 IV on Day 1, filgrastim (G-CSF) 5 mcg/kg body weight starting day-1 till recovery of absolute neutrophil count (ANC) to 1.0 × 109/L or above (filgrastim is started on day 2 for patients with presenting WBC count > 10 × 109/L). We report on clinical and molecular responses in patients enrolled in this study. Extracted RNA is reverse transcribed and analyzed by real-time quantitative PCR for the fusion transcript associated with CBF leukemias. Values are expressed as a percentage of fusion transcript to normalizing ABL transcripts. The sensitivity of detection is approximately 1 in 100,000 for AML1-ETO and 1 in 10,000 for CBFb-MYH11. Results:Thirty-four (Inv 16=10/t 8;21=24) patients (male=20)[median age 48 years (range, 29-73)]have been treated to date with a median follow-up of 11 months (range,1-24). Patient characteristics at presentation include median WBC 12.3 (range, 1.3-97.2) x 109/L, hemoglobin 9.1 (range, 7.8-11.9) gm/dL, platelet count 22 (range, 6-365) x 109/L. Additional cytogenetic abnormalities were present in 18 patients; +8 and –Y being most frequent. Three patients had kit mutations. Five patients were in complete remission at start (from other ara-C based induction) and except two deaths in induction all others achieved CR or CR with incomplete platelet recovery (CRp). Two patients died in CR from infectious complications. One patient has relapsed (initially resistant to “3=7” regimen). Median pre-treatment value for fusion transcript to Abl ratio by Q-PCR is 100 (range, 100-857). More than 3 log reduction in this median value has sustained post induction/consolidation in follow up evaluations extending up to 9 months at the time of this report. Grade≥3/4 induction toxicities included liver dysfunction (N=3, 9%), atrial fibrillation, pancreatitis, respiratory failure 1 patient each and 2 deaths in induction (one from pulmonary hemorrhage and other from intra-cranial bleed). Conclusion:Induction/consolidation therapy with GO-FLAG regimen in CBF AML results in excellent clinical and molecular response. Accrual and multi-variate comparison with historical regimens used to treat patients with CBF AML at MDACC are ongoing. Disclosures:Off Label Use: Use of Gemtuzumab Ozogamicin in frontline therapy of AML.

Molecular Response in Core Binding Factor Acute Myelogenous Leukemia with Fludarbine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin.

Background: Core binding factor associated acute myelogenous leukemias (CBF AML) are characterized by unique fusion transcripts that are amenable to molecular monitoring. Multiple log reduction in the fusion transcript level has been reported to be associated with lower relapse rates in CBF AML (Liu-Yin JA et al. ASH 2007# 543). Addition of gemtuzumab ozogamicin (GO) to induction and consolidation has resulted in improved disease free survival (DFS) in patients with AML and “standardrisk” or “favorable cytogenetics” (Burnett,A. et al. ASH 2006#13). Historical data from M.D. Anderson Cancer Center indicates that induction/consolidation therapy with fludarabine, cytarabine and granulocyte colony stimulating factor (GCSF) (FLAG) results in improved event free survival (EFS) (median EFS not reached after median followup of 118 weeks) in patients with CBF AML (Borthakur et al. 2008, Cancer in press).Method: In an attempt to improve upon these results we have initiated a study incorporating GO with FLAG (GO-FLAG) in induction/consolidation for treating patients with newly diagnosed CBF AML. We report on molecular responses in patients enrolled in this study. Extracted RNA is reverse transcribed and analyzed by real-time quantitative PCR for the fusion transcript associated with CBF leukemias. Values are expressed as a percentage of fusion transcript to normalizing ABL transcripts. The sensitivity of detection is approximately 1 in 100,000 for AML1-ETO and 1 in 10,000 for CBFb-MYH11.Results: Seventeen (Inv 16=6/t 8;21=11) patients (male=15)[median age 49 years (range, 29–73)]have been treated to date with a median follow-up of 10 months (range,1–16). Patient characteristics at presentation include median WBC 10.4 (range, 1.5–41.5) x 106/ml, hemoglobin 9.3 (range, 7.8–11.9) gm/dL, platelet count 22 (range, 6–365) x 109/ml. Additional cytogenetic abnormalities were present in 10 patients; +8 and –Y being most frequent. Two patients had kit mutations. All patients achieved complete remission (CR) except one (partial remission). Two patients died in CR from infectious complications. There has been no relapse. Median pre-treatment value for fusion transcript to Abl ratio by Q-PCR is 100 (range, 100–857). After induction the median Q-OCR value dropped to 0.04 (range, 0–9.17) and after three cycles of therapy the median value is 0.01 (range, 0–0.12).Conclusion: Induction/consolidation therapy with GO-FLAG regimen in CBF AML results in excellent molecular response. Further patient accrual and follow-up will generate information about impact on overall and disease/event free survival.

Survival Is Poorer in Patients with Secondary Core Binding Factor Acute Myelogenous Leukemia Compared with De Novo Core Binding Factor Leukemia.

Translocation (8;21)(q22;q22) and inversion of chromosome 16 [inv(16) (p13q22)] are considered good-risk cytogenetic abnormalities in acute myeloid leukemia (AML) accounting for 15% of primary AML cases (Blood. 2002 Dec 15;100(13):4325–36) and are characterized at the molecular level by disruption of genes encoding subunits of core binding factor (CBF). Increasing age, increasing peripheral blast percentage and complex cytogenetics are associated with poor overall survival in these patients (Br J Haematol. 2006 Oct;135(2):165–73). Here we assess differences in patient characteristics and outcomes between the primary and secondary core binding factor AML. One hundred eighty nine CBF AML patients treated at our institution were studied; 18 (9.5%) had secondary AML. Patients with secondary CBF AML were older (p= 0.02, median ages 57 vs. 44 years) and had lower WBC counts (p=0.03) (Table1). Overall survival (OS) was worse in the secondary AML patients (94 weeks versus 621 weeks, p=0.0016) (Figure 1). Age, hemoglobin, platelet count, and bilirubin were significantly associated with OS in the univariate analysis. In the multivariate analysis, after adjusting for age, hemoglobin, WBC, and bilirubin, secondary CBF AML was marginally significantly associated with worse OS (hazard ratio 1.884, CI95% 0.979–3.625, p=0.058) but not worse PFS (p= 0.15) (Table 2). These data suggest that the secondary CBF AML has much poorer prognosis than the primary CBF AML, further indicating that “CBF AML” is not a homogeneous entity with a uniformly good prognosis.Table 1:Summary statistics of patients' continuous characteristics by abnormality statusPatient characteristicsTotal patientsPrimary AML (n=171, male=96)Secondary AML (n=18, male=8)p-value (primary vs secondary AML)Median (range)Median (range)Median (range)Age (years)44 (16–88)44 (16–88)57 (31–75)0.02WBC (103/mm3)14.7 (0.6–387)16.4 (0.6–387)6.6 (0.8–103.8)0.03Hemoglobin (g/dl)8.1 (2.5–14.3)8.2 (2.5–14.3)7.8 (4.8–10.8)0.33Platelet count (103/mm3)38 (5–350)38 (5–350)39 (9–139)0.88Bilirubin (mg/dl)0.6 (0.0–15.3)0.6 (0.0–5.0)0.6 (0.1–15.3)0.94Creatinine (mg/dl)0.9 (0.5–2.9)0.9 (0.5–2.9)0.9 (0.5–1.8)0.66Table 2:Multivariate Cox proportional hazards model in estimating the association between covariates and patients' survivalVariableHazard ratio (95% CI)p-valueAbnormality (secondary vs primary)1.884 (0.979–3.625)0.058Age (1 year increase)1.028 (1.012–1.044)0.0004Hemoglobin (1gm/dl increase)0.864 (0.769–0.970)0.014WBC (103/mm3 increase)1.003 (1.000–1.007)0.061Bilirubin (1 mg/dl increase)1.179 (1.044–1.332)0.008 [Display omitted]