Clonal Involvement of the CD34+CD33− Progenitor Population by Leukemic Cells Harboring FLT3/ITD Correlates with High Risk of Relapse in Pediatric Acute Myeloid Leukemia.

Abstract Internal tandem duplication of the FLT3 gene (FLT3/ITD) has been associated with high risk of relapse in acute myeloid leukemia (AML) yet nearly 25–30% of the patients with FLT3/ITD have long-term disease free survival with conventional chemotherapy. We hypothesized that FLT3/ITD AML patients with poor clinical outcome may have disease that involves less mature hematopoietic precursors than patients with favorable outcome. To test this hypothesis, we isolated less mature, CD34+CD33− and more mature, CD34+CD33+ precursor cells from 24 pediatric AML patients enrolled on Children’s Cancer Group clinical trials CCG-2891 and 2961 previously identified as having a FLT3/ITD. Granulocyte/monocyte colonies (CFU-GM) were grown in methylcellulose, harvested, and analyzed for the presence of FLT3/ITD after 14 days of growth. Twenty patients yielded sufficient cells and growth of CFU-GM colonies for analysis. FLT3/ITD was detected in CFU-GM colonies derived from CD34+CD33+ cells in all patient samples (median 80% of colonies tested per patient, range 6–100%). In contrast, FLT3/ITD was detected in CFU-GM colonies derived from CD34+/CD33− cells in only 11 of the 20 patient samples (median 46% of colonies tested per patient, range 6–100%). Of the 9 patient samples without FLT3/ITD involvement of CD34+CD33− colonies, 8 achieved a CR, 6 of whom are long-term survivors, and one patient died of non-leukemic causes. In contrast, of the 11 patients with CD34+CD33− cell involvement, 9 either failed to achieve CR or relapsed after achieving CR, and 2 died of non-leukemic causes. Actuarial progression-free survival at 4 years from diagnosis for the patients with and without FLT3/ITD in the CD34+CD33− population was 0% vs. 68% respectively (p=0.017). As allelic ratio of the FLT3/ITD has been used to define high-risk patients within the FLT3/ITD cohort, we determined the FLT3/ITD allelic ratio in our study population and correlated it with the presence of FLT3/ITD in the CD34+CD33− population. Ten of the 11 (91%) of the patient samples with FLT3/ITD involvement of the progenitor cells had high allelic ratio compared to 5 of 9 (56%) of the patients without early cell involvement. Together these data suggest that clonal dominance of FLT3/ITD containing leukemia cells at the CD34+CD33− stage of hematopoietic development is correlated with a high risk of relapse. Further studies are required to determine whether clonal dominance at this hematopoietic stage is a variable that, independent of high allelic ratio, accounts for the poor clinical outcome seen in a subset of FLT3/ITD positive AML patients.

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INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia

Leukemia ◽

10.1038/leu.2015.51 ◽

2015 ◽

Vol 29 (7) ◽

pp. 1485-1495 ◽

Cited By ~ 25

Author(s):

I Dzneladze ◽

R He ◽

J F Woolley ◽

M H Son ◽

M H Sharobim ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Therapy Resistance ◽

Poor Clinical Outcome ◽

Acute Myeloid

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Next-generation sequencing–based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse

Blood ◽

10.1182/blood-2018-04-848028 ◽

2018 ◽

Vol 132 (15) ◽

pp. 1604-1613 ◽

Cited By ~ 25

Author(s):

TaeHyung Kim ◽

Joon Ho Moon ◽

Jae-Sook Ahn ◽

Yeo-Kyeoung Kim ◽

Seung-Shin Lee ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Relevant Information ◽

Longitudinal Tracking ◽

Key Points ◽

Generation Sequencing ◽

Allelic Burden ◽

Risk Of Relapse ◽

Acute Myeloid

Key Points Higher allelic burden at day 21 of post-HCT is associated with higher risk of relapse and mortality. Longitudinal tracking of AML patients receiving HCT is feasible and provides clinically relevant information.

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Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-015-0184-z ◽

2015 ◽

Vol 34 (1) ◽

Cited By ~ 32

Author(s):

Aleksandra Butrym ◽

Justyna Rybka ◽

Dagmara Baczyńska ◽

Andrzej Tukiendorf ◽

Kazimierz Kuliczkowski ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Poor Clinical Outcome ◽

Low Expression ◽

Acute Myeloid

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Acute Myeloid Leukemia With a Rare t(7;14)(q21;q32) and Trisomy 4 With Poor Clinical Outcome: A Case Report

Laboratory Medicine ◽

10.1093/labmed/lmx034 ◽

2017 ◽

Vol 48 (4) ◽

pp. 376-380

Author(s):

Seema B Jabbar ◽

Sara Monaghan ◽

Weina Chen ◽

Prasad Koduru ◽

Kirthi Kumar

Keyword(s):

Acute Myeloid Leukemia ◽

Case Report ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Poor Clinical Outcome ◽

Acute Myeloid

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Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia

Bone Marrow Transplantation ◽

10.1038/bmt.2009.348 ◽

2010 ◽

Vol 45 (8) ◽

pp. 1300-1308 ◽

Cited By ~ 13

Author(s):

R P Nelson ◽

M Yu ◽

J E Schwartz ◽

M J Robertson ◽

R Hromas ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Disease Free Survival ◽

Free Survival ◽

Disease Free ◽

Acute Myeloid

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FLAG-IDA Regimen (Fludarabine, Cytarabine, Idarubicin and G-CSF) in the Treatment of Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Blood ◽

10.1182/blood.v110.11.2866.2866 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2866-2866

Author(s):

Pau Montesinos ◽

Javier de la Rubia ◽

Guillermo Orti ◽

Jaime Sanz ◽

David Martinez ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Term Outcome ◽

Long Term Outcome ◽

First Relapse ◽

Subsequent Relapse ◽

Acute Myeloid ◽

Refractory Aml

Abstract Background: Preliminary results with the combination of fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (G-CSF) (FLAG-IDA), reported complete response (CR) rates of 47–95% in patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with acceptable toxicity. These results lead to a generalized use of FLAG-IDA regimen in this set of patients. However, these studies have been made in small series and the long-term outcome of patients have not been described. Objectives: Analyze the results of FLAG-IDA regimen, in terms of CR rate and long-term outcome, in a large series of patients with high-risk AML and MDS treated in a single institution. Methods: From 1997 to 2007, 158 adult patients (median age 60 years, range 16–79) received FLAG-IDA regimen (Fludarabine, 30 mg/m2 intravenous (iv) for 4 days, cytarabine 2 g/m2 iv for 4 days, idarubicin 10 mg/m2 iv for 3 days and glycosylated G-CSF at a daily dose of 300 mcg/m2, from day -1 until day 5). Post-remission therapy consisted of allogeneic transplantation (Allo-HSCT) in eligible patients, or consolidation (idarubicin, 10 mg/m2 iv for 3 days and cytarabine, 200 mg/m2 iv for 5 days), followed by intensification with Auto-HSCT or one cycle of carboplatin (300 mg/m2 for 4 days, as a 24 h continuous infusion). Patients were diagnosed with high-risk MDS (11%), treatment related AML (10%), AML secondary to MDS (29%), primary refractory AML (17%), AML in first relapse (27%), and AML in second or subsequent relapse (6%). Median follow-up of the cohort was 40 months (range 2–104). We calculated the Kaplan-Meier estimates curves for overall survival (OS), disease-free (DFS) and relapse-free survival (RFS). Results: CR and partial remission (PR) was achieved in 84 patients (53%) and in 19 patients (12%), respectively. Twenty-three patients (15%) died during induction, mostly due to infection (19 patients). The CR rates according to the disease status were the following: high-risk MDS 61%, treatment related AML 73%, AML secondary to MDS 52%, primary refractory AML 54%, AML in first relapse 49%, and AML in second or subsequent relapse 30%. Post-remission therapy consisted of Allo-HSCT in 16 patients (8 related and 8 unrelated), Auto-HSCT in 15 patients, and chemotherapy alone in 53 patients. The 1 and 5 year OS, DFS and RFS of the entire cohort were 36% and 11%, 40% and 11%, and 51% and 23%, respectively. The 1 and 5 year OS in patients achieving CR, PR and resistance were 64% and 22%, 26% and 7%, and 4% and 0%, respectively (p<0.0001). The 5 year RFS of patients treated with chemotherapy alone, Auto-HSCT and Allo-HSCT were 13%, 16% and 64%, respectively (p=0.09). The 5 year RFS of patients aged >55 years and ≤55 years were 4% and 53%, respectively (p=0.0005). The 5 year DFS of patients treated with chemotherapy alone, Auto-HSCT and Allo-HSCT were 7%, 13% and 35%, respectively (p=0.22). Conclusion: Our results confirm the acceptable toxicity and high response rate observed with FLAG-IDA regimen in this very high-risk subgroup of patients. This regimen can be a bridge towards Allo-HSCT, that appear to be the most curative therapy in this setting.

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Risk-Adapted, MRD-Refined Therapeutic Approach for the Treatment of Acute Myeloid Leukemia: From a Single Center Experience to the Cooperative Gimema Protocol AML1310

Blood ◽

10.1182/blood.v120.21.1422.1422 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1422-1422

Author(s):

Adriano Venditti ◽

Francesco Buccisano ◽

Luca Maurillo ◽

Maria Ilaria Del Principe ◽

Paola Fazi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Young Patients ◽

High Risk Patients ◽

Risk Patients ◽

Related Donor ◽

Family Donor ◽

Acute Myeloid

Abstract Abstract 1422 The outcome of young adult (< 60 years) with acute myeloid leukemia (AML) still remains unsatisfactory. In fact, in spite of complete remission (CR) rates ranging from 60 to 80%, only 30–40% of young patients will be long-term survivors. Advances in biologic characterization of AMLs are expected to enhance a more realistic assessment of disease aggressiveness so that therapies will be delivered in the context of a stratified approach. Cytogenetic/genetic profile is the most relevant prognostic factor established at diagnosis. Nevertheless, it is well recognized that it cannot always reliably predict outcome in individual patients. Minimal residual disease (MRD) detection promises to be an efficient tool to establish on an individual basis the leukemia's susceptibility to treatment and guide delivery of risk-tailored therapies. A further element underlying the dismal long-term outcome of young patients with AML pertains the chance to get access to allogeneic stem cell transplantation (ASCT) when carrying high-risk features. The extensive use of ASCT option is precluded by the paucity of full matched family donor (25–30%). These premises are the background to the risk-adapted approach, developed at the Institute of Hematology, University Tor Vergata, based on the following strategies: 1) combination of upfront cytogenetics/genetics and MRD status (< or ≥3.5×10−4 residual leukemic cells as counted by flow cytometry) at the end of consolidation to determine risk assignment; 2) once a given patients was categorized as high-risk (due to the expression of an unfavorable karyotype, FLT3-ITD positivity or post-consolidation positive MRD status) and therefore selected as candidate for ASCT, the transplant procedure was given whatever the source of stem cells. The present analysis includes 30 high-risk patients treated according to this design (prospective cohort = PC) and, for comparative purposes, 55 consecutive high-risk patients treated in an “old fashion” design based on donor availability (retrospective cohort = RC). The PC included 4 patients with favorable-karyotype (FK) and a MRD+ status, 12 with intermediate kayotype (IK) and a MRD+ status, 5 with unfavorable karyotype (UK) and 9 with FLT3-ITD mutation. The RC included 8 FK/MRD+, 34 IK/MRD+, 1 UK and 12 with FLT3-ITD mutation. In the PC, 22 (73%) of 30 patients received ASCT (8 matched family donor, 7 matched unrelated donor, 7 haploidentical related donor), 8 did not due to relapse (6) or because too early (2). In the RC, 12 (22%) received ASCT (11 matched family donor, 1 haploidentical related donor) whereas 24 (44%) autologous SCT (AuSCT); 19 were not transplanted at all due to relapse (13) or mobilization failure (6). Therefore, using the risk-adapted approach, 73% of high-risk patients in the PC received ASCT versus 22% of those in the RC (p <0.001). With a median follow-up of 30 and 50 months for the PC and RC, respectively, DFS is 73% vs 15% (p=0.011), OS 69% vs 20% (p=0.020), CIR 21% vs 76% (p<0.001). Based on these results, the GIMEMA Group has activated a clinical trial (AML1310, ClinicalTrials.gov.Identifier NCT01452646) of “risk-adapted, MRD directed therapy for young adult with AML”. The trial relies on a stringent disease characterization at diagnosis in terms of cytogenetic/genetic definition and identification of “leukemia associated immunophenotype” for MRD assessment at the post-consolidation time-point. The 2 parameters are exploited to qualify the category of risk which the patients belong to: low vs intermediate vs high. All patients will receive induction and consolidation according to the previous GIMEMA LAM99P protocol. After the first consolidation, patients belonging to the low-risk category (CBF+ AML without c-Kit mutations, NPM1+FLT3-ITD- AML) will receive AuSCT and those with high-risk features (UK, FLT3-ITD mutations) ASCT. Patients with FLT3-TKD mutations or c-Kit mutated CBF+ AML and those belonging to the IK category will be stratified according to the post-consolidation MRD status and will receive AuSCT or ASCT. All patients who meet the criteria for high-risk definition will be offered ASCT regardless of the availability of a HLA identical sibling, therefore all the other sources of hematopoietic stem cells will be considered. Applying this strategy, we expect a 10% survival advantage at 24 months as compared to the historical control (LAM99P protocol) where OS at 2 years was 50%. Disclosures: No relevant conflicts of interest to declare.

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Concomitant ABCG2 overexpression and FLT3-ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Cancer ◽

10.1002/cncr.25753 ◽

2010 ◽

Vol 117 (10) ◽

pp. 2156-2162 ◽

Cited By ~ 16

Author(s):

Mario Tiribelli ◽

Antonella Geromin ◽

Angela Michelutti ◽

Margherita Cavallin ◽

Annalisa Pianta ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Risk Of Relapse ◽

Acute Myeloid

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Clearance of Somatic Mutations at Remission and the Risk of Relapse in Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2017.77.6757 ◽

2018 ◽

Vol 36 (18) ◽

pp. 1788-1797 ◽

Cited By ~ 68

Author(s):

Kiyomi Morita ◽

Hagop M. Kantarjian ◽

Feng Wang ◽

Yuanqing Yan ◽

Carlos Bueso-Ramos ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Minimal Residual Disease ◽

Myeloid Leukemia ◽

Somatic Mutations ◽

Residual Disease ◽

Event Free Survival ◽

Free Survival ◽

Minimal Residual ◽

Risk Of Relapse ◽

Acute Myeloid

Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5%; MC1.0: if the VAF was < 1%; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75% v 61% in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77% v 60% in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26% v 46% in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24% v 46% in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry–based minimal residual disease revealed that patients with CMC had significantly better event-free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.

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