scholarly journals The Platelet Isoform of Phosphofructokinase in Acute Myeloid Leukemia: Clinical Relevance and Prognostic Implication

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5251-5251
Author(s):  
Xiaodan Luo ◽  
Dantian Zheng ◽  
Runhui Zheng ◽  
Chunyan Wang ◽  
Lihua Xu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Survival Rate ◽  
Mrna Expression ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Risk Groups ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Background: Phosphofructokinase (PFK), a key enzyme of the glycolytic pathway, has L (liver), M (muscle), and P (platelet) isoforms with different tissue distributions. The Platelet Isoform of PFK (PFKP) plays an important role in regulating aerobic glycolysis and macromolecular biosynthesis to support cell growth. Up-regulation of PFKP is associated with progression and metastasis of varied kinds of solid organ tumor. However, less is known about the association between PFKP and hematology malignancy. Here, we investigated the role of PFKP in acute myeloid leukemia (AML). Methods: To characterize PFKP mRNA expression in AML, we performed qRT-PCR on bone marrow cells (BMCs) from 55 newly diagnosed AML patients with the median age of 47 years (range 16-82 years). The FAB type is M0 (2/55), M1 (3/55), M2 (15/55), M3 (11/55), M4 (11/55) and M5 (11/55). Two patients were diagnosed with myelodysplastic syndromes related AML. We screened for mutations in a selected panel of genes (NPM1, CEPBA, FLT3, KIT, WT1 and TP53), based on which patients were further categorized into standard (19/55), intermediate (21/55) and poor (15/55) cytogenetic risk groups. Patients were categorized into PFKPhigh and PFKPlow groups according to the median mRNA expression of PFKP. Complete remission (CR) rate was compared between two groups after 1 cycle and 4 cycles of chemotherapy. One year-relapse rate, overall survival rate (OS) and disease free survival rate (DFS) was also compared between PFKPhigh and PFKPlow groups. Results: PFKP mRNA expression of AML patients was significantly higher than that of the normal control (P<0.05). PFKP expression in different cytogenetic risk groups were evaluated and the result showed that the mRNA expression in poor risk group was much higher than that in standard or intermediate group (P<0.05). According to the median mRNA expression of PFKP, patients were categorized into PFKPhigh (28/55) and PFKPlow (27/55) groups. The CR rate after the first cycle of treatment was higher in PFKPlow group, but did not differ significantly after another 3 cycles of chemotherapy were finished. PFKP mRNA expression was decreased after patients received CR (P<0.05). In 32 out of 55 patients, autologous hematopoietic stem cell transplantation (HSCT) (N=20) or allogeneic HSCT (N=12) was performed after 4 cycles of chemotherapy. In 20 patients post auto-HSCT, 1 year-relapse rate was higher and OS and DFS was decreased significantly in PFKPhighgroup compared to PFKPlow group. However, results showed no difference between two groups for patients post allo-HSCT. Conclusions: PFKP expressions were increased in AML especially patients in poor cytogenetic risk group. PFKP might be a prognostic factor of poor clinical outcome of AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acute myeloid leukemia–induced remodeling of the human bone marrow niche predicts clinical outcome

2020 ◽  
Vol 4 (20) ◽  
pp. 5257-5268
Author(s):  
Yiyang Chen ◽  
Lina Marie Hoffmeister ◽  
Yasmin Zaun ◽  
Lucas Arnold ◽  
Kurt Werner Schmid ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Survival Rate ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Bone Marrow Niche ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Acute Myeloid ◽  
First Diagnosis

Abstract Murine models of myeloid neoplasia show how leukemia infiltration alters the hematopoietic stem cell (HSC) niche to reinforce malignancy at the expense of healthy hematopoiesis. However, little is known about the bone marrow architecture in humans and its impact on clinical outcome. Here, we dissect the bone marrow niche in patients with acute myeloid leukemia (AML) at first diagnosis. We combined immunohistochemical stainings with global gene expression analyses from these AML patients and correlated them with clinical features. Mesenchymal stem and progenitor cells (MSPCs) lost quiescence and significantly expanded in the bone marrow of AML patients. Strikingly, their HSC- and niche-regulating capacities were impaired with significant inhibition of osteogenesis and bone formation in a cell contact–dependent manner through inhibition of cytoplasmic β-catenin. Assessment of bone metabolism by quantifying peripheral blood osteocalcin levels revealed 30% lower expression in AML patients at first diagnosis than in non-leukemic donors. Furthermore, patients with osteocalcin levels ≤11 ng/mL showed inferior overall survival with a 1-year survival rate of 38.7% whereas patients with higher osteocalcin levels reached a survival rate of 66.8%. These novel insights into the human AML bone marrow microenvironment help translate findings from preclinical models and detect new targets which might pave the way for niche-targeted therapies in AML patients.

Childhood acute myeloid leukemia: outcome in a single center using chemotherapy and consolidation with busulfan/cyclophosphamide for bone marrow transplantation.

1994 ◽  
Vol 12 (10) ◽  
pp. 2138-2145 ◽  
Author(s):  
P J Shaw ◽  
M E Bergin ◽  
M A Burgess ◽  
L Dalla Pozza ◽  
S J Kellie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Survival Rate ◽  
Complete Remission ◽  
Relapse Rate ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Free Survival ◽  
Acute Myeloid

PURPOSE To report the impact of bone marrow transplantation (BMT) with busulfan/cyclophosphamide (BuCy) as end consolidation in a cohort of consecutively diagnosed children with acute myeloid leukemia (AML). PATIENTS AND METHODS Between May 1987 and November 1992, 43 patients were diagnosed with AML. Tissue typing at diagnosis determined whether patients would proceed to autologous or allogeneic BMT as end consolidation after six cycles of chemotherapy. Conditioning for BMT was with BuCy, followed by allogeneic or unpurged autologous marrow infusion. RESULTS Of 37 patients who received chemotherapy, 35 achieved remission (95%) after one to six courses of treatment and 34 (92%) were transplanted. Five relapsed before BMT, four were subsequently transplanted in second complete remission (CR2) (n = 3) or untreated first relapse (n = 1), and one failed to respond to further therapy. All other patients proceeded to BMT in first complete remission (CR1). Eleven patients received allografts: one relapsed and one died of graft-versus-host disease (GvHD), for a leukemia-free survival rate of 90% at a median of 41 months after BMT (range, 3 to 60). For 23 autografts, there were two toxic deaths and eight relapses, with a leukemia-free survival rate of 61% at a median of 11 months after BMT (range, 0 to 66). The high relapse rate following autologous BMT led us to escalate the dose of Bu from 16 mg/kg to 600 mg/m2 using a single daily dose of Bu. CONCLUSION With modern supportive therapy, most newly diagnosed children with AML will enter remission and are eligible for intensification therapy. BuCy is well tolerated in children, which allowed us to escalate the dose of Bu in recent patients. Further follow-up is needed to determine whether this has an impact on the relapse rate following autologous BMT.

Impact of allogeneic hematopoietic stem cell transplantation on pediatric acute myeloid leukemia of FAB subtypes M4 and M5

2020 ◽  
Author(s):  
Yu-juan Xue ◽  
Pan Suo ◽  
Yi-fei Cheng ◽  
Ai-dong Lu ◽  
Yu Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Low Risk ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Pediatric Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Background: FAB-M4 and M5 are unique subgroups of pediatric acute myeloid leukemia. However, for these patients, few studies have demonstrated the clinical and biological characteristics and efficacy of hematopoietic stem cell transplantation (HSCT), and especially haplo-HSCT. Procedure: We retrospectively evaluated the outcomes of 70 children with FAB-M4/M5 enrolled in our center from January 2013 to December 2017. Results: Of the patients, 32, 23, and 15 were in low-risk, intermediate-risk, and high-risk groups, respectively. T(16;16), inv16/CBFB-MYH11 was the most frequent cytogenetic abnormality. Among detected genetic alterations, WT1 was mutated at the highest frequency, followed by FLT3-ITD, NPM1, and CEBPA. Thirty-three patients received HSCT (haplo-HSCT = 30), of which four, 18, and 11 were in low-risk, intermediate-risk, and high-risk groups, respectively. For all patients, the 3-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 85.3 ± 4.3%, 69.0 ± 5.7%, and 27.9 ± 5.2%, respectively. By multivariate analysis, low-risk stratification predicted superior OS, EFS, and PLT ≤ 50 × 109/L at diagnosis, with FLT3-ITD mutations predicting higher CIR and poorer EFS. In intermediate- and high-risk groups, HSCT was independently associated with higher EFS and lower CIR. With a median post-transplant observation time of 30.0 months, the 3-year OS, EFS, CIR, and non-relapse mortality in the haplo-HSCT group were 74.2 ± 8.6%, 68.3 ± 8.9, 24.6 ± 7.6%, and 6.6 ± 4.1%, respectively. Conclusions: Risk-oriented treatment is important for pediatric FAB-M4/M5. For intermediate- and high-risk groups, HSCT significantly improved survival and haplo-HSCT might be a viable alternative approach.

Heterogeneity in Infants with Acute Myeloid Leukemia: Retrospective Analysis of a Japanese Nationwide Survey

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1477-1477
Author(s):  
Akira Shimada ◽  
Daisuke Tomizawa ◽  
Akitoshi Kinoshita ◽  
Kazuko Hamamoto ◽  
Ichiro Tsukimoto ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Survival Rate ◽  
Retrospective Analysis ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1477 Introduction: When compared to older patients, infants with acute leukemia exhibit distinct cytogenetic features, such as higher prevalence of MLL gene rearrangement (MLL-R), and are known to have higher vulnerability to intensive cytotoxic therapy, such as hematopoietic stem cell transplantation. In contrast to acute lymphoblastic leukemia (ALL), there have been few reports on acute myeloid leukemia (AML) in infants. To develop more appropriate therapeutic strategies for infants with AML, it is necessary to elucidate the distinct clinical features of this subgroup. We therefore performed a retrospective analysis on infant AML in Japan. Patients: Infants with AML, aged less than 1 year at diagnosis, registered in any of the 6 Japanese AML clinical trials between 1991 and 2010 (TCCSG M91-13, TCCSG M96-14, AML99, CCLSG9805, CCLSG9805RE, and JPLSG AML-05) were included in this study. Patients with Down syndrome were excluded. Results: A total of 122 infant AML patients were included in the present analysis, which comprised approximately 10% of all pediatric AML patients. The most frequent FAB classification type was M5 (28.7%), followed by M7 (22.9%) and M4 (10.8%). About 30% of patients had 11q23 abnormalities/MLL -R, but there was no impact on prognosis. Several cases with normal karyotype were revealed to be MLL -R on FISH analysis or on MLL -fusion chimeric transcript analysis by RT-PCR. t(8;21), inv(16) and t(15;17) cases were very rare among the infant cohorts. Furthermore, 7.8% had t(1;22)(p13;q13), and 2.5% had t(7;12)(q36;p13). Genetic mutation results could be obtained in 11 cases in the AML99 study; only one case each was confirmed to have NRAS, KRAS or KIT gene mutation. No cases with FLT3-ITD were detected among the 11 cases in the AML99 or the 44 cases in the AML-05 study. Survival rate varied based on treatment received; 5-year OS rate was 58.3% to 71.4%, and 5-year EFS rate was 49.4% to 64.2%. Discussion: Survival rate in infant AML was identical to that in older pediatric AML. However, there was a possible underestimation of MLL -R patients based on sole chromosome analysis; the prevalence of MLL -R was less than 50% in infant AML patients, without any prognostic impact. Other well-known genetic alterations in pediatric AML also had no effect on outcome of infant AML. Infant AML is a heterogeneous subgroup of pediatric AML, and further studies, as well as novel biomarkers, will be necessary to fully understand its biology. Disclosures: No relevant conflicts of interest to declare.

Clinicopathologic Characterization of Acute Myeloid Leukemia and Myelodysplastic Syndrome with Inv(3)(q21q26.2)/t(3;3)(q21;q26.2) Reveals That Complex Karyotype but Not Blast Percentage Is Associated with Poor Survival; A Bone Marrow Pathology Group Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3847-3847
Author(s):  
Heesun J. Rogers ◽  
James W. Vardiman ◽  
John Anastasi ◽  
Gordana Raca ◽  
Natasha M Savage ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Risk Group ◽  
Risk Groups ◽  
Complex Karyotype ◽  
Genetic Abnormalities ◽  
Very High ◽  
Acute Myeloid

Abstract Abstract 3847 Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2); RPN1-EVI1 [inv3/t3] is a distinct type of AML with recurrent genetic abnormalities (RGA) in the 2008 WHO classification, with poor response to therapy and poor prognosis. The resulting dysregulation of EVI1 plays an important role in stem cell self-renewal and leukemogenesis. Although myelodysplastic syndrome (MDS) with inv3/t3 has a high risk of progression to AML, inv3/t3 is not among the genetic abnormalities sufficient for diagnosis of AML, irrespective of blast percentage (%) in the WHO classification. The revised International Prognostic Scoring System (IPSS-R) includes comprehensive cytogenetic subgrouping to better define prognosis in MDS patients. In this system, inv3/t3 is included in a poor risk karyotype group. The objective of this multicenter study was to evaluate a series of patients with MDS/AML and inv3/t3 in order to characterize their clinicopathologic features and outcome, and to apply the IPSS-R to inv3/t3 MDS patients. 111 patients (40 MDS and 71 AML with inv3/t3) were gathered from 8 medical centers. The median age at diagnosis was 56.5 years and was significantly older in MDS than AML with inv3/t3 patients (65 vs 54.5, p=0.03). Patients typically presented with normocytic anemia, thrombocytopenia and mild leukopenia (median Hb 9.1 g/dL, platelet 91 x109/L, WBC 3.6 x109/L). MDS with inv3/t3 patients had lower WBC than AML with inv3/t3 (median 3.1 vs 5.5, p<0.001). 19% of patients had hepatosplenomegaly. The median bone marrow (BM) blast% was 4% in MDS and 50% in AML with inv3/t3 and BM cellularity was higher in AML (70%) than MDS (40%) with inv3/t3 (both p<0.001). 88% of patients showed dysmegakaryopoiesis with characteristic small uni/bilobated forms. Dysgranulopoiesis (46%) and dyserythropoiesis (56%) were common and 59% of patients displayed multilineage dysplasia. The cytogenetics showed isolated inv3/t3 in 41% of patients, one additional abnormality in 33% and complex karyotype in 26%. −7/del7q (37%) was a frequent additional abnormality. Philadelphia chromosome (Ph) was noted in 10% of AML with inv3/t3. Overall 83% of patients (75% of MDS and 87% of AML with inv3/t3) expired (median follow up of 7.9 months (mo)). Most patients received therapy including 54% with chemotherapy (CTX; topoisomerase II inhibitors and/or antimetabolites) alone, 27% with CTX and allogeneic stem cell transplant (SCT) and 19% with supportive care. 16% of patients (10 MDS and 8 AML with inv3/t3) were associated with prior therapy for solid tumors and lymphomas. 57% of MDS with inv3/t3 patients subsequently evolved to AML. There was no significant difference in overall survival (OS) between MDS and AML with inv3/t3 (12.9 vs 8.0 mo, Cox PH p=0.11, Figure 1). There was no OS difference between MDS and AML after excluding Ph+ cases (Cox PH p=0.17) nor between de novo and therapy related MDS/AML with inv3/t3 (Cox PH p=0.89). Patients with isolated inv3/t3, one additional cytogenetic abnormality, and a complex karyotype showed progressively shorter OS (12.9, 10.0 and 4.3 mo, Cox PH p<0.001, Figure 2). The patients who received CTX and SCT showed superior OS to patients receiving CTX alone or supportive care only (15, 7 and 5 mo, respectively, Cox PH p=0.02). In multivariate analysis, choice of therapy and complex karyotype retained independent prognostic significance (Cox PH p= 0.02 and p<0.001, respectively). MDS with inv3/t3 patients were classified into IPSS Intermediate (Int)-1 (21), Int-2 (13), and high (6) risk groups. IPSS-R categorized MDS patients into low (3), Int (6), high (14) and very high (17) risk groups. 57% of IPSS Int-1 risk group patients (expected OS 3.5 year) were reclassified to high or very high risk group in IPSS-R (expected OS <1.6 year). Thus, the IPSS-R scores were higher relative to IPSS score (signed rank test, P<0.001). However, 72.5% and 77.5% of MDS with inv3/t3 patients had shorter OS than expected OS by IPSS-R and IPSS scores. The IPSS-R better reflects the OS of inv3/t3 than IPSS but may not fully reflect the generally dismal prognosis. Patients with MDS and AML with inv3/t3 follow a similarly aggressive clinical course, supporting classification of MDS with inv3/t3 as an AML with RGA irrespective of blast%. Additional cytogenetic abnormalities are associated with shorter OS in AML/MDS with inv3/t3 and our data suggest that aggressive therapy with SCT should be considered in these patients. Disclosures: Vardiman: Celgene Corporation: review of slides for clinical trials not relevant to this abstract Other. Foucar:e. Honoraria–Scientific Symposium Pathology Education: ASCP Press; ARP, Amirsys, ASCP Press; ARP, Amirsys Patents & Royalties, Honoraria, Not relevant to this abstract Other.

Integrative prognostic risk score in acute myeloid leukemia with normal karyotype

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4561-4568 ◽  
Author(s):  
Frederik Damm ◽  
Michael Heuser ◽  
Michael Morgan ◽  
Katharina Wagner ◽  
Kerstin Görlich ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Normal Karyotype ◽  
Risk Groups ◽  
Risk Of Death ◽  
Risk Patients ◽  
Acute Myeloid

Abstract To integrate available clinical and molecular information for cytogenetically normal acute myeloid leukemia (CN-AML) patients into one risk score, 275 CN-AML patients from multicenter treatment trials AML SHG Hannover 0199 and 0295 and 131 patients from HOVON/SAKK protocols as external controls were evaluated for mutations/polymorphisms in NPM1, FLT3, CEBPA, MLL, NRAS, IDH1/2, and WT1. Transcript levels were quantified for BAALC, ERG, EVI1, ID1, MN1, PRAME, and WT1. Integrative prognostic risk score (IPRS) was modeled in 181 patients based on age, white blood cell count, mutation status of NPM1, FLT3-ITD, CEBPA, single nucleotide polymorphism rs16754, and expression levels of BAALC, ERG, MN1, and WT1 to represent low, intermediate, and high risk of death. Complete remission (P = .005), relapse-free survival (RFS, P < .001), and overall survival (OS, P < .001) were significantly different for the 3 risk groups. In 2 independent validation cohorts of 94 and 131 patients, the IPRS predicted different OS (P < .001) and RFS (P < .001). High-risk patients with related donors had longer OS (P = .016) and RFS (P = .026) compared with patients without related donors. In contrast, intermediate-risk group patients with related donors had shorter OS (P = .003) and RFS (P = .05). Donor availability had no impact on outcome of patients in the low-risk group. Thus, the IPRS may improve consolidation treatment stratification in CN-AML patients. Study registered at www.clinicaltrials.gov as #NCT00209833.

scholarly journals ARPP19 promotes MYC expression and associates with patient relapse in acute myeloid leukemia

2019 ◽  
Author(s):  
Eleonora Mäkelä ◽  
Eliisa Löyttyniemi ◽  
Urpu Salmenniemi ◽  
Otto Kauko ◽  
Taru Varila ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Standard Chemotherapy ◽  
Group Status ◽  
Phosphatase 2A ◽  
Multivariable Analyses ◽  
Pp2a Inhibitor ◽  
Acute Myeloid

AbstractDespite of extensive genetic analysis of acute myeloid leukemia (AML), we still do not understand comprehensively mechanism that promote disease relapse from standard chemotherapy. Based on recent indications for non-genomic inhibition of tumor suppressor protein phosphatase 2A (PP2A) in AML, we examined mRNA expression of PP2A inhibitor proteins in AML patient samples. Notably, out of examined PP2A inhibitor proteins, overexpression of ARPP19 mRNA was found independent of current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and another PP2A inhibitor CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p=0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p=0.007) and in multivariable analyses (p=0.0001); and gave additive information to EVI1 expression and risk group status (additive effect, p=0.005). Low ARPP19 expression also associated with better patient outcome in TCGA LAML cohort (p=0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression associated with disease activity (p=0.034).Together, these data identify ARPP19 as a novel oncogenic PP2A inhibitor protein in AML, and demonstrate its risk group independent role in predicting AML patient relapse tendency.

Study AML-BFM 2004: Improved Survival In Childhood Acute Myeloid Leukemia without Increased Toxicity

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 181-181 ◽  
Author(s):  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
Michael Dworzak ◽  
Jean-Pierre Bourquin ◽  
Christine Neuhoff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Therapeutic Window ◽  
Liposomal Daunorubicin ◽  
Off Label ◽  
Acute Myeloid

Abstract Abstract 181 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy Study AML-BFM 2004 was designed to improve outcome of children and adolescents with AML without increasing toxicity. Patients were stratified into a standard- (SR)* or high-risk (HR)** group according to morphology, cyto-/molecular genetics including FLT3-ITD, and therapy response on day 15. Notably, reclassification of SR patients to the HR group in case of FLT3-ITD positivity was newly established in this study. Improvement of prognosis was attempted by intensification of chemotherapy: (1) Randomized introduction of liposomal daunorubicin (L-DNR) in a higher equivalent dose than idarubicin during induction in both risk groups (L-DNR 80mg/m2/day/3x) in comparison to standard induction using idarubicin 12mg/m2/day/3x, each combined with cytarabine and etoposide (L-DNR may offer an increased therapeutic window due to lower cardiotoxicity) and (2) randomised introduction of 2-chloro-2-deoxyadenosine (2-CDA, 2×6mg/m2) as intensification during the cytarabine/idarubicin (AI) consolidation in HR patients only. Overall results improved compared to the previous study AML-BFM 98: Survival estimates at 5 year (pOS) in patients (excluding Myeloid leukemia in Down syndrome) were 72% + 3% vs. 64% + 2% (AML-BFM 04 n=566 vs. AML-BFM 98 n=472), plogrank=0.02; the 5-year event-free survival (pEFS): was 54% + 3% vs. 50% + 2%, plogrank=.40. Results in the 197 SR patients were excellent: pOS 88% + 3% vs. 78% + 3% (n=182), plogrank=.01, EFS 69%, + 4% vs. 64% + 4%, plogrank=.40. Results in the 368 HR patients also improved: pOS 63% + 4% vs. 56% + 3% (n=290), plogrank=.07, EFS 46%, + 3% vs. 41% + 3%, plogrank=.43. OS improvement was partly due to better results after treatment of relapse or nonresponse (3-year pOS after nonresponse/relapse in 171 patients of study 2004 40% + 5% vs. 32% + 4% in 198 patients in AML-BFM 98, plogrank=.017). Results for the 1st randomization L-DNR vs. idarubicin during induction were similar (pOS 78% + 4% vs. 70% + 4%, plogrank=.15, pEFS 60% + 4% vs. 54% + 4%, plogrank=.17). There were less early deaths (4 vs. 8 patients) and less treatment related deaths in remission in the L-DNR group (2 vs. 5 patients). The rate of severe infection was slightly lower with L-DNR (pFisher 0.15). Two L-DNR vs. 6 idarubicin patients showed grade III/IV cardiotoxicity after induction. Results of the 2nd randomization in HR patients (AI/2-CDA vs. AI) were also similar: p=OS 75% + 5% vs. 65% + 5%, plogrank=.18, pEFS 51% + 5% vs. 51% + 5%, plogrank=.98. Toxicity rates of the intensification with 2-CDA were tolerable. In conclusion, compared to the previous study AML-BFM 98, results of study AML-BFM 2004 show significant improvement in both risk groups. This appears attributable to a combination of factors including therapy intensification, better supportive care and improved treatment of patients with relapse or nonresponse. Given the reduced toxicity of L-DNR and a trend towards better survival rates by adding L-DNR during induction and 2-CDA during HR consolidation, these agents will be further used in the forthcoming AML-BFM study. *Standard risk group definition: FAB M1/M2 with Auer rods, FAB M4eo or favorable cytogenetics [t(8;21) or inv(16)] and blasts in the bone marrow on day 15 <5%, and FAB M3 (all patients) **High-risk group definition: all others. Disclosures: Off Label Use: liposomal daunorubicin is used, which is off label for pediatric AML. It was used because it offers a possibility to increase cumulative dosages of anthracyclines with lower cardiotoxicity.

Treatment of Acute Myeloid Leukemia with the NOPHO-AML 2004 Study in Chinese Children: A Single Center Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5270-5270
Author(s):  
Xiaoqin Feng ◽  
Chunfu Li
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Chinese Children ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Objectives: The objective of the present study was to investigate the therapeutic efficacy and feasibility of NOPHO-AML 2004 study in the treatment of acute myeloid leukemia (AML; excluding acute promyelocytic leukemia) in Chinese children. Methods: Thirty-one children with novo AML treated with the NOPHO-AML 2004 study were recruited from Jan. 2010 to Dec. 2013, and the clinical data were retrospectively analyzed. Among 31 AML children, their age were from 2-14 years old (median age 8 years old). There were 12,15 and 4 children classified in low risk group, intermediate risk group and high risk group by cytogenetic risk classification respectively. Eight children received concomitant hematopoietic stem cell transplantation. Kaplan Meier method with Log-Rank testing was employed for survival analysis. Results: Follow-up was for a median 24 months (range: 5–50 months). The complete remission rate was 83.8%. The predicted 3-year leukemia free survival (LFS) rate was 53.8%. The LFS rate of low, intermediate and high risk group were 55.6%, 52.5% and 50.0% respectively. There was no significance in risk groups. The LFS rate of chemotherapy and chemotherapy concomitant HSCT were 42.7% and 87.5%, P<0.05. There were 2 cases of treatment related mortality including one case of sepsis and one case of ARDS. Conclusions: NOPHO-AML 2004 study is clinically efficacious for the treatment of AML in Chinese children. HSCT treatment had better outcome than only chemotherapy in childhood with non low risk AML in CR1 phase. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (5) ◽  
pp. 371-380 ◽  
Author(s):  
Konstanze Döhner ◽  
Christian Thiede ◽  
Nikolaus Jahn ◽  
Ekaterina Panina ◽  
Agnes Gambietz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Risk Group ◽  
Cox Model ◽  
Risk Groups ◽  
Mutational Status ◽  
Genetic Features ◽  
Poor Outcomes ◽  
Acute Myeloid

Abstract Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P &lt; .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

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