CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group

2021 ◽  
Author(s):  
Adam J. Lamble ◽  
Lisa Eidenschink Brodersen ◽  
Todd A. Alonzo ◽  
Jim Wang ◽  
Laura Pardo ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Molecular Alterations ◽  
Disease Characteristics ◽  
High Risk Disease ◽  
Childhood Aml ◽  
Acute Myeloid

PURPOSE Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial ( NCT01371981 ). MATERIALS AND METHODS AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels. RESULTS The study population was divided into CD123 expression–based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations ( P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations ( P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis. CONCLUSION CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.

scholarly journals Correlation of CD123 Expression Level with Disease Characteristics and Outcomes in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 459-459 ◽  
Author(s):  
Adam J. Lamble ◽  
Lisa Eidenschink Brodersen ◽  
Todd A. Alonzo ◽  
Jim Wang ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Oncology Group ◽  
Standard Chemotherapy ◽  
Molecular Alterations ◽  
Disease Characteristics ◽  
Study Population ◽  
Childhood Aml ◽  
Children And Young Adults ◽  
Acute Myeloid

Introduction: Despite maximally intensified chemotherapy, cure rates remain suboptimal for children and young adults with acute myeloid leukemia (AML). As CD123 (IL3RA) is expressed on the majority of AML cells, it is a promising immunotherapeutic target. Increased CD123 expression has been linked to high-risk disease characteristics in adult AML, but clinical implications for childhood AML are less well-defined. Methods: The Children's Oncology Group AAML1031 phase 3 trial (NCT01371981) tested the efficacy of the addition of bortezomib to standard chemotherapy in a randomized fashion. A total of 1400 children and young adults were enrolled on study. All diagnostic specimens were centrally and prospectively evaluated for the expression of CD123 by multi-dimensional flow cytometry (MDF) at Hematologics, Inc. Patients were stratified to either a low-risk (LR) or high-risk (HR) arm of the therapy based on cytogenetic and molecular alterations and end-of-induction (EOI) minimal residual disease (MRD) measured by MDF. LR patients received four cycles of chemotherapy, while HR patients received 3 courses of chemotherapy followed by best allogeneic hematopoietic stem cell transplantation (HSCT). Patients with high allelic ratio FLT3-ITD enrolled on arm C received sorafenib in combination with standard chemotherapy followed by HSCT. Here we provide data on expression of CD123 across all patients and correlate this expression with disease characteristics and clinical outcomes. Results: Surface CD123 expression on AML cells was available for 1040 patients, and expression level varied significantly across the study population with a median CD123 molecules per cell of 1300 (range 120-13,100 molecules per cell). For analysis, the study population was divided into quartiles (n=260 each) based on CD123 expression levels. Significant variation in cytogenetic/molecular characteristics was observed across the four quartiles, where those with highest CD123 expression had a lower prevalence of t(8;21), inv(16), and CEBPA mutations (p&lt;0.001 for all) and higher prevalence of KMT2A rearrangements and FLT3-ITD mutations (p&lt;0.001 for both) (Figure 1A). CD123 expression quartile was not significantly different among those in morphological complete remission (CR) (p=0.278) or MRD negative (bone marrow &lt; 0.1%) (p=0.182) at EOI. Evaluation of outcome parameters across the four quartiles demonstrated that those in lower CD123 expression quartiles 1, 2 and 3 (Q1-3) had similar relapse risk (RR), event-free and overall survival (EFS and OS). However, those with the highest CD123 expression (Q4) had a significantly higher RR (53% vs. 39%, p&lt;0.001), lower EFS (49% vs. 69%, p&lt;0.001), and lower OS (32% vs 50%, p&lt;0.001) (Figure 1B) in comparison to Q1-3. These differences were maintained within the protocol-defined LR cohort, as those with LR disease but high CD123 expression (Q4) had worse RR, EFS, and OS versus those in Q1-3 (p&lt;0.001 for all) (Figure 1C). Given the observed association of CD123 expression with known risk groups, we performed a multivariable Cox regression analysis of all prognostic factors, including cytogenetic/molecular risk group, age, MRD status, and FLT3-ITD status, which demonstrated that high CD123 expression was independently associated with worse OS (HR 1.54, 95% CI 1.21-1.96, p&lt;0.001) (Figure 1D). Conclusions: CD123 expression is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. Patients with highest CD123 surface expression are more likely to have HR genetic alterations and a paucity of LR features. Further, despite similar induction remission rates, those with high CD123 expression had inferior clinical outcomes compared to patients with lower CD123 expression. However, despite an association with HR features, expression of CD123 appears to be independently associated with therapeutic response given that outcome differences were maintained in multivariate regression analysis. This suggests that CD123 expression may provide additional prognostic information, as highlighted by the inferior outcomes in LR patients that had high CD123 expression. In pediatric and young adult patients with the highest risk disease, the higher CD123 expression represents a valuable therapeutic target in the development of immunotherapies for childhood AML. Disclosures Eidenschink Brodersen: Hematologics, Inc: Employment. Pardo:Hematologics, Inc: Employment. Tasian:Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte Corportation: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership.

scholarly journals Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531

2014 ◽  
Vol 32 (27) ◽  
pp. 3021-3032 ◽  
Author(s):  
Alan S. Gamis ◽  
Todd A. Alonzo ◽  
Soheil Meshinchi ◽  
Lillian Sung ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Group Trial ◽  
Acute Myeloid

Purpose To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. Patients and Methods Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three). Results There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P = .04) but not OS (3 years: 69.4% v 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07). Conclusion GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

The Addition of Bortezomib to Standard Chemotherapy for Pediatric Acute Myeloid Leukemia Has Increased Toxicity without Therapeutic Benefit: A Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 899-899 ◽  
Author(s):  
Richard Aplenc ◽  
Soheil Meshinchi ◽  
Lillian Sung ◽  
Todd A. Alonzo ◽  
Jessica Pollard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Oncology Group ◽  
Standard Chemotherapy ◽  
Free Survival ◽  
Risk Patients ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction: Despite the very high intensity of current chemotherapy regimens for children with acute myeloid leukemia (AML), approximately 50% of patients will experience disease relapse. New therapeutic strategies to improve clinical outcomes have centered on improving the efficacy of standard chemotherapy with novel agents such as gemtuzumab and other agents designed to augment standard chemotherapy. Bortezomib, a proteasome inhibitor, is one such agent. The Children's Oncology Group (COG) Phase III clinical trial AAML1031 tested the hypothesis that the addition of bortezomib to standard chemotherapy would improve treatment outcomes in pediatric patients with newly diagnosed AML. Methods: The COG AAML1031 trial randomized patients younger than 30 years of age with de novo AML to either standard chemotherapy (Arm A) or standard chemotherapy with bortezomib (Arm B). Patients with high allelic ratio FLT3 ITD were offered enrollment on a standard chemotherapy plus sorafenib (Arm C, n = 102) and are excluded from this efficacy analysis. All patients received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE). Risk stratification occurred at the end of ADE induction and was based on the presence of high risk cytogenetic/molecular markers and/or minimal residual disease (MRD) >0.1% determined by multidimensional flow cytometry. Low risk patients received three additional courses of chemotherapy consisting of a second course of ADE, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. High risk patients received a second course of cytarabine/mitoxantrone, a third course of cytarabine/etoposide, and then allogeneic stem cell transplant (SCT) from the best available donor. Bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each cycle with one dose de-escalation to 1 mg/m2 allowed for dose limiting toxicity. Results: A total of 1097 patients were randomized to either standard therapy (Arm A, n = 542) or standard chemotherapy with bortezomib (Arm B, n = 555). No statistically significant differences in sex, age, race, ethnicity, WHO classification, initial blast count, or initial CNS status was observed between arms. Remission induction rate did not differ between treatment arms 89% vs 91%, p = 0.457. MRD was negative in 75% of patients on both treatment arms at the end of Induction I and mean MRD measures did not differ significantly: 2.8% vs 1.9%, p = 0.247. For all patients, event free survival (EFS) and overall survival (OS) at 3 years were 44.4% ± 3.8% and 60.6% ± 4.4%. EFS was not significantly different between Arms A and B (44.0% ± 5.2% vs 44.6% ± 5.6%, p = 0.285) (Figure 1). Likewise, OS was similar between arms (59.0 ± 6.7 vs 62.2 ± 6.0, p = 0.732) (Figure 1). One year cumulative treatment related mortality (TRM) was 14.6 ± 9.3 and 10.8 ± 7.5, p = 0.49 for Arms A and B, respectively. No significant differences were seen in OS, disease-free survival, and TRM from the end of Induction I in low and high risk groups. Cox proportional hazards analysis demonstrated that initial WBC count at diagnosis was the only consistently identified risk factor for OS, DFS, and TRM. Targeted toxicity monitoring identified increased toxicity risks in Arm B for peripheral neuropathy (Induction I/II), dose reductions (all chemotherapy courses), and PICU admissions (Induction I/II) and Intensification I). Serial monitoring of cardiac ejection fraction/shortening fraction in all patients did not demonstrate a clinically meaningful difference in drop in ejection fraction/shortening fraction by treatment arm. No other consistent differences in targeted toxicity rates were identified. Conclusions: The addition of bortezomib to standard chemotherapy increased toxicity but did not improve EFS or OS in children with newly diagnosedAML Consequently, bortezomib should not be used in children with de novo AML in combination with standard chemotherapy. Future work will evaluate the role of intensifying Induction II therapy for patients with high risk AML, further refine risk stratification, and define a more optimal role for allogeneic donor SCT in pediatric AML. Figure 1 Figure 1. Disclosures Loken: Hematologics: Employment, Equity Ownership.

Prevalence & Prognosis Value of TET2 Gene Polymorphisms in Childhood Acute Myeloid Leukemia in Taiwan

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1551-1551 ◽  
Author(s):  
Meng-Ju LI ◽  
Yung-Li Yang ◽  
Shiann-Tarng Jou ◽  
Meng-Yao Lu ◽  
Hsiu-Hao Chang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
Event Free Survival ◽  
Free Survival ◽  
Kaplan Meier ◽  
Childhood Aml ◽  
Pediatric Aml ◽  
Gene Alterations ◽  
Acute Myeloid

Abstract Abstract 1551 Introduction: Acute myeloid leukemia (AML) is a phenotypically and genetically heterogeneous disease, accounts for 10% of childhood leukemia. The prognosis of children with AML has improved greatly over the past 30 years, and the Taiwan Pediatric Oncology group (TPOG) AML 97A and B protocols had been designed and explored in 1997 for the treatment of AML in Taiwan with complete remission (CR) and overall survival (OS) rates as high as 80–90% and 50–60%. In recent years, molecular research identified an increasing panel of genetic markers in AML, enhancing better risk stratification, modify treatment strategy and improving prognosis. The tet oncogene family member 2 (TET2) gene, a candidate tumor suppressor gene, and the mutations are found in adult AML with prevalence of around 10–20% and is associated to prognosis. However, the report in childhood AML is limited. Here, we assess the prevalence of TET2 gene alterations in childhood AML and to identify its association with prognosis. Method: We enrolled children who were diagnosed AML and visited national Taiwan university hospital between Jan, 1997 to June, 2010. The patients with APL (acute promyeloid leukemia) were excluded due to different treatment protocol. All the children were treated by TPOG AML 97 protocol. The induction therapy consist two courses of cytarabine (Ara-C) and idarubicin (IDR). Patients who achieved CR subsequently received four courses of consolidation therapy consisted of high-dose Ara-C and mitoxantrone or etoposide. The clinical characteristics, such as age, sex, laboratory data, cytogenetics information, relapse, survival time were all collected from TPOG database. DNA was isolated from bone marrow cells at diagnosis and sequence analysis was carried out for TET2 gene. The all data of eligible cases will be collected and analyzed for estimating EFS (event free survival), and OS (overall survival). Survival curves will be estimated by the Kaplan-Meier method. Comparisons were made by Chi-square test for binary variables and t test for continuous variables. For all analyses, the P-values were two-tailed, and a P < 0.05 was considered statistically significant. Results: Total of 56 pediatric AML patients were enrolled. The mean age is 9.07 ± 5.4 (0.01∼17.54) years. There are 34 (60.7%) males. Twenty-four (42.9%) patients had relapse and the overall survival rate is 44.6% (25/56). In this study, there was no nonsense or frameshift mutation, which is frequently identified in adult AML. Total 44 patients (78.6%) present TET2 SNP (single nucleotide polymorphism) and the details are listed in Table 1. There are 18 SNP, and 3 of them (rs72224084, rs58201766, rs59046770) are located in intron. Other 15 SNP are all located in exon. Most of them are located in exon 3 (27 events) and exon 11 (32 events). Only SNP rs3733609 is located in exon 9, and this is synonymous mutation. There are 9 SNP located in exon are not reported in reference yet. Among these, 4 SNP is synonymous mutation. All SNPs are heterozygous, except 4 SNP are homozygous, which are all SNP rs2454206 (I1762V). The clinical characteristics between patients with or without TET2 SNP, including sex, age, white count while diagnosis, chromosome abnormalities, death and relapse are not different between this 2 groups. Kaplan–Meier survival analysis is used to test the correlation between TET2 gene polymorphism to prognosis, including overall survival and event free survival. There was no difference. Conclusion: As we know, we are the first group to publish TET2 gene alterations in childhood AML in Asian. We conclude the prevalence of TET2 mutations in pediatric AML patients is far lower than in adults and the TET2 polymorphisms are not associated with prognosis. Disclosures: No relevant conflicts of interest to declare.

Outcome of Pediatric Patients with Acute Myeloid Leukemia and -5/5q-Abnormalities Enrolled On Five Children's Oncology Group Acute Myeloid Leukemia Treatment Protocols

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1414-1414
Author(s):  
Donna L Johnston ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Betsy A. Hirsch ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Abstract 1414 Introduction: Studies of acute myeloid leukemia (AML) in adults have documented that abnormalities of chromosome 5q (-5/5q-), primarily deletions, confer a poor prognosis. However, there are no large studies that specifically focus on -5/5q- in pediatric AML. Methods: To elucidate the disease correlates of this group, we retrospectively analyzed cytogenetic data from 5 studies of childhood AML: Children's Oncology Group (COG-AAML03P1), Children's Cancer Group (CCG-2961 and 2891) and Pediatric Oncology Group (POG-8821 and 9421). Data from all patients whose cytogenetic clones included -5/5q-, with the exception of those with acute promyelocytic leukemia (M3) or Down syndrome, were included. A total of 2035 patients from these 5 studies had cytogenetic data available for review. Results: Twenty-two (1.1%) of the 2035 patients had −5 or 5q-. The majority of these patients were male (63.6%). The median age was 12.9 years (range 0.3–20.7 years) with a significant number of patients in the 11–21 year age range (63.6%, p=0.032). The median white blood cell count was 17.4 ×103/μL (range 1.4–98 ×103/μL) and the median bone marrow blast percentage was 77% (range 15–99%). Patients with -5/5q- had a significantly higher median platelet count at diagnosis than those without this abnormality (88×103/μL versus 53×103/μL, p=0.015). Of the 22 patients with -5/5q-, their FAB classification showed that a significant number of patients had M0 morphology (28.6%, p<0.001) versus patients without -5/5q- (2.6%). The remaining patients had M1 morphology (23.8%), M2 (19%), M4 (9.5%), M5 (9.5%), M6 (4.8%) and M7 (4.8%) morphology. Eighteen of the 22 patients (81.8%) had a complete response (CR) to induction chemotherapy. The 5-year event free survival (EFS) from the time of diagnosis for these 22 patients was 27% (±19%) and the 5-year overall survival (OS) was 32% (±20%). The 5-year EFS and OS for the patients on these studies without -5/5q- were 41% (±2%) and 51% (±2%) respectively. The 5-year EFS and OS rates were not significantly different between the two groups (p=0.182 and 0.120 respectively). For the 18 patients who achieved a CR with induction chemotherapy, from time of CR the 5-year disease free survival (DFS) was 33% (±22%), the 5-year OS was 39% (±25%), the 5-year relapse risk (RR) was 61% (±23%) and the 5-year treatment related mortality (TRM) was 6% (±11%). For the 1674 patients without -5/5q- who obtained a CR after induction, from the time of CR the 5-year DFS was 47% (±2%), OS was 57% (±2%), RR was 44% (±3%) and TRM was 9% (±5%). None of these values were significantly different between the groups (p>0.1). Conclusions: In this, the largest retrospective study of pediatric patients with AML and -5/5q- to date, this cytogenetic subgroup was found to have a poor outcome. The median 5-year overall survival across studies was 32%, and the median 5-year event free survival was 27%. These findings support the use of more aggressive therapy for the treatment of children with -5/5q- AML, as has been previously supported based on data from adults with -5/5q- AML. This subset of patients may also benefit from treatment with innovative agents. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

2005 ◽  
Vol 23 (24) ◽  
pp. 5728-5738 ◽  
Author(s):  
Koen van Besien ◽  
A. Artz ◽  
S. Smith ◽  
D. Cao ◽  
S. Rich ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Progression Free Survival ◽  
Free Survival ◽  
High Risk Disease ◽  
Standard Risk ◽  
Acute Myeloid

Purpose This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Patients and Methods Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. Results After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. Conclusion Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5486-5496 ◽  
Author(s):  
Susanne Schnittger ◽  
Claudia Haferlach ◽  
Madlen Ulke ◽  
Tamara Alpermann ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Cumulative Risk ◽  
Intermediate Risk ◽  
Age Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Idh1 Mutations ◽  
French American British ◽  
Acute Myeloid

Abstract Mutations in the IDH1 gene at position R132 coding for the enzyme cytosolic isocitrate dehydrogenase are known in glioma and have recently been detected also in acute myeloid leukemia (AML). These mutations result in an accumulation of α-ketoglutarate to R (2)-2-hydroxyglutarate (2HG). To further clarify the role of this mutation in AML, we have analyzed IDH1R132 in 1414 AML patients. We detected IDH1R132 mutations in 93 of 1414 patients (6.6%) with a clear prevalence in intermediate risk karyotype group (10.4%, P < .001). Although IDH1R132 mutations can incidentally occur together with all other molecular markers, there were strong associations with NPM1 mutations (14.2% vs 5.4% in NPM1wt, P < .001) and MLL-PTD (18.2% vs 7.0% in MLLwt, P = .020). IDH1-mutated cases more often had AML without maturation/French-American-British M1 (P < .001), an immature immunophenotype, and female sex (8.7% vs 4.7% in male, P = .003) compared with IDH1wt cases. Prognosis was adversely affected by IDH1 mutations with trend for shorter overall survival (P = .110), a shorter event-free survival (P < .003) and a higher cumulative risk for relapse (P = .001). IDH1 mutations were of independent prognostic relevance for event-free survival (P = .039) especially in the age group < 60 years (P = .028). In conclusion, these data show that IDH1R132 may significantly add information regarding characterization and prognostication in AML.

scholarly journals Effect of Diagnosis (Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, or Acute Myeloid Leukemia [AML]) on Outcome of AML-Type Chemotherapy

Blood ◽  
1997 ◽  
Vol 90 (8) ◽  
pp. 2969-2977 ◽  
Author(s):  
Elihu Estey ◽  
Peter Thall ◽  
Miloslav Beran ◽  
Hagop Kantarjian ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Multivariate Analyses ◽  
Patient Characteristics ◽  
Refractory Anemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Current Medical Practice ◽  
Acute Myeloid

Abstract In current medical practice, patients with refractory anemia with excess blasts in transformation (RAEB-t), and especially patients with RAEB, receive chemotherapy regimens (AML Rx) administered to patients with acute myeloid leukemia (AML) less often than do patients with AML. These entities are distinguished primarily by marrow blast percentage (5% to 19% RAEB, 20% to 29% RAEB-t, and ≥30% AML). The poor prognosis of many RAEB or RAEB-t patients, if untreated, led us to give them AML Rx using the same plan as for AML. The purpose of this analysis was to see if diagnosis (RAEB, RAEB-t, or AML) affected outcome. We treated 372 patients with AML (acute promyelocytic leukemia [APL] excluded), 106 with RAEB-t, and 52 with RAEB. AML Rx produced a 62% complete remission (CR) rate in RAEB, essentially identical to the rates in RAEB-t and AML, but event-free survival (EFS) from CR and from start of treatment (start of Rx), as well as overall survival, were poorer in RAEB than in AML or RAEB-t, with AML and RAEB-t being identical. However, patients with RAEB or RAEB-t were more likely to have poor prognostic characteristics, in particular complex abnormalities involving chromosomes 5 and/or 7. Multivariate analyses indicated that, when considered together with cytogenetics and other patient characteristics, a diagnosis of RAEB rather than AML or RAEB-t had no effect on EFS from start of Rx, EFS from CR, survival, or achievement of CR. These analyses suggested a trend for patients with RAEB-t to have better EFS from start of Rx than patients with AML or RAEB (P = .08; relative risk, 0.80; 95% confidence interval, 0.62 to 1.03), but there were no differences with respect to the other outcomes. Our data suggest that the propriety of administering AML Rx to patients with RAEB or RAEB-t who have poor prognosis without treatment is identical to the propriety of treating AML in this fashion. Deterrents to standard AML Rx in these patients could justifiably include cytogenetics, age, etc, but not a diagnosis of RAEB or RAEB-t per se.

scholarly journals Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India

2017 ◽  
Vol 3 (6) ◽  
pp. 773-781 ◽  
Author(s):  
Abhijeet Ganapule ◽  
Sandeep Nemani ◽  
Anu Korula ◽  
Kavitha M. Lakshmi ◽  
Aby Abraham ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Cost Effectiveness ◽  
Myeloid Leukemia ◽  
Cost Effective ◽  
Effective Strategy ◽  
Event Free Survival ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Acute Myeloid

Purpose There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML). Patients and Methods We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%). The 5-year overall survival (OS) and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1), second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively ( P < .001). From 2007, reduced intensity conditioning (RIC) with fludarabine and melphalan (Flu/Mel) was used in a majority of patients in CR1 (n = 67). Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38). Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% ( P = .003) and 63.8 ± 6.4% versus 32.3 ± 7.9% ( P = .002), respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients.

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