Expression of 4-1BB and its ligand on blasts correlates with prognosis of patients with AML

2016 ◽  
Vol 64 (8) ◽  
pp. 1252-1260 ◽  
Author(s):  
Joerg U Schmohl ◽  
Tina Nuebling ◽  
Julia Wild ◽  
Tanja Kroell ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Initial Diagnosis ◽  
Lower Probability ◽  
Fluorescence Index ◽  
Related Protein ◽  
Free Survival ◽  
Cellular Survival ◽  
Probability Of Death ◽  
Disease Free

Costimulatory ligands (COLs) and their receptors (COR) regulate immune reactions and cellular survival and might be relevant in acute myeloid leukemia (AML). This study evaluated the clinical relevance of 4-1BBL, glucocorticoid-induced TNFR-related protein (GITR) and ligand (GITRL), CD80, and CD86 in case of expression on AML blasts. 98 patients were evaluated at initial diagnosis. Immunophenotypically evaluated specific fluorescence index (SFI) levels of COR and COL on blasts were correlated with morphological, cytogenetic, and several prognostic parameters. Significantly higher COR expression was seen in monocytic versus non-monocytic AML subtypes; GITR, p=0.05; GITRL, p=0.005; CD86, p=0.001). Cut-off values for two COR and their ligands were evaluated: cases presenting with 4-1BB values above cut-off 1.2 SFI levels correlated (tendentially) significantly with a higher probability for disease-free survival (DFS, p=0.06) and a favorable HR of 0.2; p=0.04 for relapse. HR for death was also significantly lower in this group (0.12; p=0.04). In contrast, a lower probability for DFS and overall survival was seen in cases with 4-1BBL expression above 2.2 SFI levels (p=0.08 and p=0.09). In addition, multivariate analysis showed a significantly higher probability of death in this group (HR 10.3, p=0.04). Expression of CD80 and CD86 did not show significant prognostic relevance. On initial diagnosis, 4-1BB and 4-1BBL qualify as markers for prediction of patients’ course and represent a valuable screening target for patients with AML at initial diagnosis.

Allogeneic Stem-Cell Transplantation Using a Reduced-Intensity Conditioning Regimen Has the Capacity to Produce Durable Remissions and Long-Term Disease-Free Survival in Patients With High-Risk Acute Myeloid Leukemia and Myelodysplasia

2005 ◽  
Vol 23 (36) ◽  
pp. 9387-9393 ◽  
Author(s):  
Sudhir Tauro ◽  
Charles Craddock ◽  
Karl Peggs ◽  
Gulnaz Begum ◽  
Premini Mahendra ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Purpose The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural. Patients and Methods Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years). Results The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation. Conclusion The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.

Autologous Bone Marrow Transplantation as an Intensive Consolidation Therapy for Adult Patients in Remission from Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5121-5121
Author(s):  
Andre S. Jung ◽  
Asad Bashey ◽  
Peter R. Holman ◽  
Eva Carrier ◽  
Januario Castro ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Consolidation Therapy ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Acute Myeloid

Abstract Introduction: Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myeloid leukemia. The optimal consolidation therapy for adults in remission without a histo-compatible donor has yet to be clearly established. Patients and Methods: This was a retrospective analysis of forty patients (23 females and 17 males) diagnosed with de novo acute myeloid leukemia, who were without a histo-compatible donor, that underwent APBSCT between the year 2000 and 2006 at a single institution. The patients’ age ranged from 18 to 73 with a median age of 50. Cytogenetic analysis was available on 37 of the patients. Complete remission (CR) was confirmed by bone marrow morphology and immunophenotype analysis by flow cytometry. Patients in remission were further consolidated with variable cycles of chemotherapy prior to stem cell transplantation. For stem cell mobilization, patients received high-dose cytarabine (2000mg/m2) and etoposide (5mg/kg) for three days followed by G-CSF at 10μg/kg, starting 10 days after the chemotherapy, before the peripheral stem cell collection. The preparative regimen prior to transplantation with unpurged stem/progenitor cells consisted of a combination of intravenous busulfan (0.8 mg/kg for 16 doses) and cyclophosphamide (60 mg/kg for two doses) (37 patients) or busulfan and melphalan (3 patients). Patients were then followed for treatment-related mortality, disease free survival, and overall survival. The analysis was stratified according to age, cytogenetic risk, and remission state. Results: There was no treatment-related mortality. Nineteen out of forty patients had relapse of their disease. The relapse rate was lowest in the low risk cytogenetic group who were under the age of 60 and highest in the high risk cytogenetic group who were over the age of 60. The overall 5 year survival for all patients was 47%. When stratified for cytogenetic risk and age, the overall survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 67%, 59%, and 75% respectively. The overall survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0% respectively. The projected rate of disease free survival at 5 years was 40%. When stratified for cytogenetic risk and age, the disease free survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 33%, 52%, and 50% respectively. Disease free survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0%. Comparing patients in CR1 versus patients in CR2, the overall survival was 47% in CR1 and 50% in CR2. The disease free survival, when grouped as above, were 41% for those in CR1 and 33% for those in CR2. Conclusion: APBSCT is a reasonable and safe intensive consolidation therapy for those patients without a compatible HLA matched donor in first or second complete remissions, notably for those under the age of 60 regardless of their cytogenetic risk. The number of standard consolidations prior to APBSCT may be an important variable predicting outcome.

Impact of Molecular Markers and Cytogenetic Abnormalities on Long-Term Overall Survival and Disease-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Acute Myeloid Leukemia (AML) patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4476-4476
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Xavier Thomas ◽  
Carole Charlot ◽  
Fiorenza Barraco ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Allogeneic Hsct ◽  
Disease Free

Abstract We performed a retrospective analysis from our transplant registry on first allogeneic hematopoietic stem cell transplantations (HSCT) for acute myeloid leukemia (AML) patients (pts) between 1996 and 2007. Our principal objective was to analyze the impact of molecular markers on the long-term overall and disease-free survival (OS and DFS) after first allogeneic HSCT. We found 364 pts, only 63 pts had retrospectively available conserved cells at diagnosis. The expression levels of WT1, Evi1, Flt3 and Hoxa9 were performed by quantitative RT-RQPCR. The mutational status of MLL duplication, FLT3 (internal tandem duplication or nucleotide substitutions) (ITD), NPM1 and CEBPα were determined by PCR, RFLP and/or sequencing analysis. All pts except 1 had a karyotype analysis at diagnosis. Among these 63 pts, there were 27 (43%) males and 36 (57%) females, with a median age of 41 years (18-64). The FAB classification was M0: 6, M1: 10, M2: 13, M4: 6, M5: 21, M6: 3, M7: 1 and 3 unclassified. Concerning the karyotype analysis, 25 (40%) pts had a normal karyotype, 37 (60%) pts presented cytogenetic abnormalities classified as favourable prognosis in 5 cases (8%), intermediate in 13 cases (21%) and poor in 19 cases (31%). Regarding the molecular markers evaluated in all pts: 4(6%) pts had Flt3over-expressed (ov-ex), 19 (30%) FLT3 ITD+, 3 (5%) MLLdup, 10 (16%) Hoxa9 ov-ex, 7 (11%) Evi1 ov-ex, 15 (24%) NPM1mut+, 25 (40%) WT1 ov-ex and 1 CEBPαmut+ (this marker was evaluated only in 12 pts). Associations between these markers and the karyotype prognosis groups are shown in Figure1. Twenty three (36%) pts had no abnormal molecular markers and 40 (54%) pts had at least one abnormal marker: 10 (16%) 1 marker, 10 (16%) 2 markers, 12 (19%) 3 markers, 4 (6%) 4 markers and 4 (6%) 5 markers. Concerning the karyotype, among the 23 negative molecular pts, 22 have been evaluated and there were 9 (41%) normal, 11 (50%) poor and 2 (9%) favourable; and among the 40 positive pts, 16 (40%) were normal, 8 (20%) poor, 13 (32.5%) intermediate and 3 (7.5%) favourable. Concerning transplantation, 50% of HSCT were done after 2004 and the median interval between diagnosis and transplantation was 6 months (2.6–68.5). Before conditioning, 41 pts were in CR (26 CR1, 14 CR2 and 1 CR3), 8 in PR and 14 in relapse. Twenty five (40%) pts received a non-myelo-ablative conditioning and 38 (60%) a myelo-ablative one. There were 34 sex-mismatched (21 M→F and 13 F→M), 21 ABO incompatibility (6 minor and 15 major), 55 were HLA matched and 8 mismatched. Twenty three (36.5%) pts received PBSC, 37 (59%) bone marrow and 4 (6.5%) cord blood cells from 47 (75%) HLA siblings and 16 (25%) unrelated donors. After transplantation, 59 (94%) pts engrafted, 42 developed AGVHD (21gr1, 13 gr2 and 8 gr4), and among 51 evaluable pts, 13 developed cGVHD (7 limited and 6 extensive). At the last follow-up, 20 pts have relapsed, 29 pts are alive (28 CR and 1PR) and 34 died [18 (53%) from TRM and 16 (47%) from relapse]. At the median follow-up of 48 months, the OS and DFS for the whole population were 40% (33–47) and 40% (34–46) respectively with a maximum follow-up of 130 months and for the different subgroups according to karyotype and molecular markers the results are shown in Table 1. The univariate analysis showed a significant impact of FLT3 ITD and over-expression of FLT3RQ on long-term DFS, (p=0.03 and p=0.02 respectively), and a trend on long-term OS (p=0.08). Concerning the karyotype and some other markers (MLL, EVI1, NPM1 and Hoxa9), we did not observe any significant difference because of small number of pts in some subgroups. The known benefic impact of NPM1mut+, was erased because the majority of this group presented an associated FLT3 ITD+. In addition, we are performing a multivariate analysis that will be presented. In conclusion, allogeneic HSCT in this high risk population of AML pts, allowed a good probability of long-term OS and DFS, despite the presence of high number of bad molecular markers and cytogenetic abnormalities. Finally, AML pts with FLT3 ITD+ seem not benefit from allogeneic HSCT as well as patients with NPM1mut+ associated with FLT3ITD+. Figure 1. Frequencies and distribution of different molecular markers and karyotype subgroups Figure 1. Frequencies and distribution of different molecular markers and karyotype subgroups Table 1. OS and DFS according to different molecular markers and karyotype subgroups

Obesity Is An Adverse Prognostic Factor For Overall and Disease-Free Survival In Adult Acute Promyelocytic Leukemia But Not In Acute Myeloid Leukemia: A Pooled Analysis From Four Alliance Prospective Studies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 832-832 ◽  
Author(s):  
Jorge J. Castillo ◽  
Flora Mulkey ◽  
Susan Geyer ◽  
Jonathan E. Kolitz ◽  
William Blum ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Obese Patients ◽  
Free Survival ◽  
Race Ethnicity ◽  
Disease Free ◽  
Acute Myeloid

Abstract Introduction There are mounting data associating obesity with an increased risk of developing acute myeloid leukemia (AML) and acute promyelocytic leukemia (APML). However, the role of obesity in the outcome of patients with AML and APML has not been extensively evaluated. In this study, we assess the effect of obesity in relapse and survival rates of clinical trial patients with AML and APML. Methods Data on patients ≥18 years from 4 prospective clinical trials from the Cancer and Leukemia Group B (Alliance) were pooled for this analysis (n=2,093). This reflects exclusion of 72 patients deemed ineligible or non-evaluable, and 8 patients without height or weight data. Three studies were in de novo AML: 9621 (n=393), 10503 (n=541) and 19808 (n=714), and one study was in de novo APML: 9710 (n=445). BMI was calculated following the formula (BMI=weight/height2) and categorized according to WHO criteria as underweight/normal (BMI <25 kg/m2), overweight (BMI 25-29.9 kg/m2) and obese (BMI 30+ kg/m2). AML and APML cohorts were analyzed separately. Baseline BMI was evaluated in relation to clinical characteristics, including age, gender, ECOG performance status (PS), and race/ethnicity. Univariate and multivariable logistic regression models were used to assess relationships of these factors with obesity. Analysis of clinical outcomes included overall survival (OS) in all patients, and disease-free survival (DFS) in those patients who achieved a complete response. The impact of obesity was evaluated using Kaplan-Meier methods and log-rank tests. Multivariate Cox regression analyses were used to assess prognostic impact of obesity while adjusting for other factors such as age, gender, PS, race and ethnicity on OS and DFS. P-values <0.05 were considered statistically significant. Results In the AML cohort (n=1,648), median age was 46 years (range: 18-66 years), 53% were men, 87% had PS 0-1, 17% were non-white and 7% Hispanic. For the APML cohort (n=445), median age was 43 years (range: 18-80 years), 52% were male, 82% had PS 0-1, 18% were non-white and 11% Hispanic. The proportion of obesity at study entry for AML and APML was 38% and 50%, respectively. APML patients experienced a superior OS than AML patients (5-year OS: 81% vs. 37%). In AML, age, gender and race were all significantly related to whether or not patients were obese in univariate and multivariate settings. In APML, only age and race were significantly associated with obesity. Median follow-up time was 6.8 years for AML and 8.5 years for APML patients. In the AML cohort, 1058 of 1648 patients have died, and 813 of 1246 patients evaluable for DFS had an event. For APML, 102 of 445 patients died and 106 of 401 patients evaluable for DFS had an event. DFS and OS distributions were not significantly different in obese vs. non-obese AML patients (p=0.8 and p=0.6, respectively). However, obese APML patients had a significantly shorter OS than non-obese patients (HR=1.61, p=0.02; 5-year OS rates: 76% vs. 85%, respectively). Similarly, obese APML patients tended to have shorter DFS than non-obese patients (HR=1.49, p=0.05; 5-year DFS rates: 74% vs. 82%, respectively). Only focusing on those APML patients between 18-60 years of age, differential OS and DFS in obese patients was more pronounced with corresponding worse survival (OS: HR=2.13, p=0.003; DFS: HR=1.75, p=0.015). Conclusion Obesity did not influence OS and DFS in AML. However, in a multivariate analysis, obese APML patients had significantly inferior OS and DFS than non-obese patients. Multivariate analysis suggests that the adverse impact of obesity in APML is independent of age, sex, performance and race/ethnicity. Previous studies have suggested that obesity is a risk factor for developing APML; we now show that obesity at diagnosis also confers a worse prognosis. Reasons for our findings could include potential pharmacological issues, such as relative dose intensity, which needs further research. Moreover, it will be necessary to determine if our findings will be replicated in patients with APML treated without chemotherapy as is now becoming the standard of care for those who present with white blood cell counts <10,000/uL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502

2015 ◽  
Vol 33 (35) ◽  
pp. 4167-4175 ◽  
Author(s):  
Steven M. Devine ◽  
Kouros Owzar ◽  
William Blum ◽  
Flora Mulkey ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Complete Remission ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Phase Ii Study ◽  
Disease Free Survival ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
First Complete Remission ◽  
Reduced Intensity

Purpose Long-term survival rates for older patients with newly diagnosed acute myeloid leukemia (AML) are extremely low. Previous observational studies suggest that allogeneic hematopoietic stem-cell transplantation (HSCT) may improve overall survival (OS) because of lower rates of relapse. We sought to prospectively determine the value of HSCT for older patients with AML in first complete remission. Patients and Methods We conducted a prospective multicenter phase II study to assess the efficacy of reduced-intensity conditioning HSCT for patients between the ages of 60 and 74 years with AML in first complete remission. The primary end point was disease-free survival at 2 years after HSCT. Secondary end points included nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, and OS. Results In all, 114 patients with a median age of 65 years received transplantations. The majority (52%) received transplantations from unrelated donors and were given antithymocyte globulin for GVHD prophylaxis. Disease-free survival and OS at 2 years after transplantation were 42% (95% CI, 33% to 52%) and 48% (95% CI, 39% to 58%), respectively, for the entire group and 40% (95% CI, 29% to 55%) and 50% (95% CI, 38% to 64%) for the unrelated donor group. NRM at 2 years was 15% (95% CI, 8% to 21%). Grade 2 to 4 acute GVHD occurred in 9.6% (95% CI, 4% to 15%) of patients, and chronic GVHD occurred in 28% (95% CI, 19% to 36%) of patients. The cumulative incidence of relapse at 2 years was 44% (95% CI, 35% to 53%). Conclusion Reduced-intensity conditioning HSCT to maintain remission in selected older patients with AML is relatively well tolerated and appears to provide superior outcomes when compared with historical patients treated without HSCT. GVHD and NRM rates were lower than expected. Future transplantation studies in these patients should focus on further reducing the risk of relapse.

High Id1 expression is associated with poor prognosis in 237 patients with acute myeloid leukemia

Blood ◽  
2009 ◽  
Vol 114 (14) ◽  
pp. 2993-3000 ◽  
Author(s):  
Ruoping Tang ◽  
Pierre Hirsch ◽  
Fanny Fava ◽  
Simona Lapusan ◽  
Christophe Marzac ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Young Patients ◽  
Disease Free Survival ◽  
Internal Tandem Duplication ◽  
Free Survival ◽  
Downstream Target ◽  
Disease Free ◽  
Flt3 Internal Tandem Duplication ◽  
Acute Myeloid

Inhibitors of differentiation (Id) are a group of dominant inhibitors of basic helix-loop-helix transcriptional factors, which promote excessive proliferation, and also protect cells against drug-induced apoptosis in mammalians. Recently, Id1 has been identified as a common downstream target of several constitutively activated oncogenic tyrosine kinase, such as FLT3 internal tandem duplication, in leukemia cells. We analyzed Id1 expression as possible prognostic factor in 237 acute myeloid leukemia (AML) patients. High Id1 expression was associated with older age (P = .009) and with FLT3 internal tandem duplication (P = .003). However, 61% of the patients in the group of FLT3− AML were Id1+, suggesting that other tyrosine kinases are involved. In whole population, high Id1 expression independently predicted shorter disease-free survival (P = .05) and overall survival (P = .003). In young patients (age ≤ 60 years) with normal cytogenetics, Id1+ was, in multivariate analysis, associated with lower complete remission rates (P = .02), shorter disease-free survival (P = .02), and overall survival (P = .006). In conclusion, our data provide a new molecular marker for refining the risk classification of AML, especially in young patients with normal cytogenetic. Id1− patients with normal cytogenetic should be classified as favorable-risk leukemia. Id1, as a downstream target of constitutively activated tyrosine kinase, could be a suitable candidate for targeted therapy.

scholarly journals Prognostic significance of serum ferritin levels on initial diagnosis in patients with acute myeloid leukemia

2021 ◽  
Vol 2 (4) ◽  
pp. 362-370
Author(s):  
Dejan Dudok ◽  
Marijana Virijević
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Serum Ferritin ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Early Death ◽  
Induction Phase ◽  
Free Survival ◽  
Disease Free ◽  
Acute Myeloid

Introduction/Aim: Acute myeloid leukemia (AML) is a heterogenous malignant disease whose course and outcome are influenced by a number of prognostic factors. Serum ferritin (SF) is often elevated in oncology patients, and it has been shown that it strongly influences an unfavorable outcome in various malignancies. The aim of this study is to assess the effect of high SF values on overall survival and disease-free survival, as well as to assess the correlation of SF values with other prognostic markers, such as clinical and laboratory parameters. Methods: Retrospective analysis included 108 patients diagnosed with AML at the Clinic for Hematology of the Clinical Center of Serbia (CCS), in Belgrade, in the period 2017 - 2019. Patients with acute promyelocytic leukemia, acute mixed lineage leukemia, secondary AML and patients treated with palliative therapy were excluded from the study. Patients were grouped based on the SF cutoff value of 800 µg/L. Results: Patients with higher SF values had a significantly higher incidence of early death (p = 0.020), sepsis in the induction phase of therapy (p < 0.010), and significantly lower initial hemoglobin levels (p = 0.040), as compared to patients with lower SF values. SF at diagnosis appeared to be a significant independent predictive factor of overall survival (p = 0.019) and of disease-free survival (p = 0.040). Conclusion: Our study showed a significant association of high SF values with sepsis in induction, early death, mean hemoglobin, overall survival, and disease-free survival. Identification of SF as an independent prognostic factor and a potential target site of the action of new drugs could contribute to a better prognosis of AML patients.

CBFA2T3-GLIS2 Fusion Is Prevalent in Younger Patients with Acute Myeloid Leukemia and Associated with High-Risk of Relapse and Poor Outcome: A Children’s Oncology Group Report

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 13-13 ◽  
Author(s):  
Heather L Schuback ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Kristen L. Miller ◽  
Samir Kahwash ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Clinical Implications ◽  
Free Survival ◽  
Younger Patients ◽  
De Novo Aml ◽  
Disease Free ◽  
Acute Myeloid

Abstract The cryptic CBA2T3-GLIS2 fusion generated by the inv(16)(p13.3q24.3) was initially identified in megakaryocytic leukemia and later implicated in other acute myeloid leukemia (AML) subtypes. Presence of this fusion may lead to altered expression of the potentially targetable sonic hedgehog and bone morphogenic protein pathways. We determined the prevalence of CBA2T3-GLIS2 in children treated on COG AAML03P1 and AAML0531 protocols, which collectively enrolled 1361 eligible children, adolescents, and young adults with de novo AML, and correlated the presence of this fusion with patient demographics, laboratory features, and clinical outcomes. We also determined the prevalence and clinical implications of CBA2T3-GLIS2 in 71 children with FAB M7 AML treated on 4 consecutive COG AML trials. Of the 1042 diagnostic samples available and tested for CBFA2T3-GLIS2, 45 (4.3%) were positive for the fusion. Fusion-positive patients were significantly younger than fusion-negative patients (2.1 vs. 10.3 years; P<0.001). CBFA2T3-GLIS2 was most prevalent in the youngest patients (10.6% for 0 to <2 year olds and 8.6% for 2 to <5 year olds) [Figure A]. In contrast, no fusion transcripts were identified in 299 unselected adult patients. All FAB subtypes were represented in fusion-positive patients. Overall, FAB M5 and M7 were equally prevalent in fusion-positive patients, and each subtype accounted for 20% of cases [Figure B]. There was a preponderance of MLL rearrangements (N=7) in fusion-positive patients, and 3 more patients had either t(8;21) or inv(16), and 25.6% (N=11) without karyotypic alterations (CN-AML). None of the fusion-positive patients had the t(7;12) or 12p abnormality. There were few common AML-associated mutations: 1 patient had FLT3ITD and 1 had the WT1 mutation (no NPM1 or biallelic CEBPA mutations were identified). Figure 1 Figure 1. Rates of morphologic complete remission (CR) at the end of induction course 1 were similar for fusion-positive and -negative patients (68.9% vs. 77.7%; P=0.17). However, fusion-positive patients were more likely to have minimal residual disease (MRD) by flow cytometry at this time point (50% vs. 28.9%; P=0.006) with a correspondingly higher relapse rate (RR) from remission of 58% vs. 35% (p=0.005). Disease-free survival for those with and without fusion was 42% vs. 58% (p=0.060) In a subset analysis of 193 patients with CN-AML, the prevalence of CBFA2T3-GLIS2 was 4.7%. Fusion-positive patients were younger than fusion-negative patients (1.6 vs. 13.1 years; P<0.001) and more likely to have MRD at the end of induction (85.7% vs. 40.8%; P=0.043). CN-AML fusion-positive patients had significantly worse 5-year OS (36% vs. 67% P=0.025) and EFS (18% vs. 51%, P=0.017) than fusion-negative patients. All fusion-positive patients in CR had a higher 5-year RR than fusion-negative patients (88% vs. 33%; P<0.001), with a corresponding disease-free survival (DFS) of 13% vs. 59% (P<0.001). Implications of CBFA2T3-GLIS2 were evaluated in 71 cases of children with FAB M7 AML where the fusion was identified in 12 patients (17%). Fusion-positive FAB M7 patients had significantly lower CR rate than fusion-negative patients (33.3% vs. 77.6%, P=0.005) and all were MRD positive at the end of induction (100% vs. 30%, P=0.001). All FAB M7 fusion-positive patients relapsed (100% vs. 36%, P=0.007), with a DFS of 0% vs. 60% (p=0.013). As CBFA2T3-GLIS2 was most common in younger patients, we compared clinical implications in children <2 years of age. Although CR rates in fusion-positive and -negative patients were similar (68.2% vs. 74.9%; P=0.50), fusion-positive patients were more likely than fusion-negative patients to have MRD at the end of course 1 (63.2% vs. 24.8%, P=0.006). Five-year RR rates in fusion-positive and -negative patients were 71% vs. 39% (P=0.012), with corresponding DFS of 29% vs. 56% (P=0.030). This study provides a comprehensive evaluation of incidence and prognostic implications of the CBFA2T3-GLIS2 fusion in pediatric de novo AML. Along with MLL rearrangements, 12p abnormalities, and the recently described NUP98-JARID1A fusion, this cryptic inversion 16, as defined by presence of the CBFA2T3-GLIS2 fusion, represents a distinct, recurrent chromosomal abnormality associated with poor prognosis in infant AML and is a potential therapeutic target. Disclosures No relevant conflicts of interest to declare.

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