scholarly journals Multigene Measurable Residual Disease Assessment Improves Acute Myeloid Leukemia Relapse Risk Stratification in Autologous Hematopoietic Cell Transplantation

2016 ◽  
Vol 22 (11) ◽  
pp. 1974-1982 ◽  
Author(s):  
Matthew P. Mulé ◽  
Gabriel N. Mannis ◽  
Brent L. Wood ◽  
Jerald P. Radich ◽  
Jimmy Hwang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Disease Assessment ◽  
Leukemia Relapse ◽  
Measurable Residual Disease ◽  
Autologous Hematopoietic Cell Transplantation ◽  
Acute Myeloid

scholarly journals Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (20) ◽  
pp. 1729-1738 ◽  
Author(s):  
Robert P. Hasserjian ◽  
David P. Steensma ◽  
Timothy A. Graubert ◽  
Benjamin L. Ebert
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Molecular Genetic ◽  
Disease Assessment ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasm ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract Current objectives regarding treatment of acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by interrogation for the presence of minimal/measurable residual disease (MRD) by molecular genetic and/or flow cytometric techniques. Although advances in molecular genetic technologies have enabled highly sensitive detection of AML-associated mutations and translocations, determination of MRD is complicated by the fact that many treated patients have persistent clonal hematopoiesis (CH) that may not reflect residual AML. CH detected in AML patients in CR includes true residual or early recurrent AML, myelodysplastic syndrome or CH that is ancestral to the AML, and independent or newly emerging clones of uncertain leukemogenic potential. Although the presence of AML-related mutations has been shown to be a harbinger of relapse in multiple studies, the significance of other types of CH is less well understood. In patients who undergo allogeneic hematopoietic cell transplantation (HCT), post-HCT clones can be donor-derived and in some cases engender a new myeloid neoplasm that is clonally unrelated to the recipient’s original AML. In this article, we discuss the spectrum of CH that can be detected in treated AML patients, propose terminology to standardize nomenclature in this setting, and review clinical data and areas of uncertainty among the various types of posttreatment hematopoietic clones.

Post-remission clonal hematopoiesis; Practical implications for measurable residual disease assessment in acute myeloid leukemia (AML).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7529-7529
Author(s):  
Sanam Loghavi ◽  
Tomoyuki Tanaka ◽  
Ken Furudate ◽  
Sa A Wang ◽  
Koichi Takahashi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Status ◽  
Leukemic Cells ◽  
Disease Assessment ◽  
Individual Gene ◽  
Clonal Hematopoiesis ◽  
Measurable Residual Disease ◽  
Acute Myeloid

7529 Background: Clonal Hematopoiesis may persist following complete remission (CR) in patients with acute myeloid leukemia (AML) but does not necessarily indicate residual AML and may represent persistence of pre-leukemic stem cells. Post-remission CH identified by NGS has not been systemically studied in parallel with measurable residual disease (MRD) detection by flow cytometric immunophenotyping (FCI). Methods: We studied bone marrow sample from AML patients at baseline and CR by targeted deep NGS of 295 genes (median 403x depth) and compared the results to FCI. Measurable residual disease (MRD) detection by FCI was performed by comparing the phenotype at CR to baseline and by detection of leukemia associated immunophenotype (LAIP) and derivation from normal (DFN) (sensitivity: 0.1%). Post-CR CH was defined as presence of mutations originally detected in AML with variant allele frequency > 2.5%. FCI results were categorized into 4 groups: a) AML MRD negative by LAIP or DFN b) AML MRD+ (similar to baseline) c) AML MRD+ (different from baseline), d) Negative for AML MRD, but aberrant phenotype suggestive of pre-leukemic cells. We correlated FCI and NGS results. Results: 101 patients were included in the study. 45 (45%) had persistent post-CR clonal hematopoiesis; 23 (51%) had phenotypic alterations detected by FCI including AML MRD+ in 18 (40%) and pre-leukemic cells in 5 (10%). Among patient with no detectable mutations by NGS (n = 56; 55%), 14 (25%) had FCI aberrancies including AML MRD+ in 4 (7%) and pre-leukemic cells in 10 (18%). CH was significantly more common in samples with residual phenotypic aberrancies detected by FCI (p = 0.004). There was no significant correlation between FCI group d and persistent CH (p = 0.4). Persistent ASXL1 (p = 0.024, OR = 7.2 ) and RUNX1 (p = 0.016; OR = 17.3) mutations were significantly associated with FCI abnormalities. The correlation coefficient between FCI abnormalities and RUNX1 mutations inferred from a Bayesian network structure was 0.66. Conclusions: NGS and FCI are complementary in evaluating post treatment disease status in AML. Post CR-CH is associated with phenotypic abnormalities that either represent residual AML or pre-leukemic cells. The latter may not have the same prognostic implications as AML MRD; however, the association with outcome needs to be elucidated. Single cell DNA sequencing technologies may be helpful in more accurately deciphering the association of individual gene mutations and their contribution to phenotypic aberrations.

scholarly journals Genomic Landscape and Risk-Stratification for De Novo Acute Myeloid Leukemia with Normal Cytogenetics and No NPM1 or FLT3-itd Mutation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1421-1421
Author(s):  
Ya-Lan Zhou ◽  
Li-Xin Wu ◽  
Robert Peter Gale ◽  
Zi-Long Wang ◽  
Jin-Lan Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Consolidation Chemotherapy ◽  
Normal Cytogenetics ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Introduction-About 25% of persons with new-diagnosed acute myeloid leukemia (AML) have normal cytogenetics and no NPM1 or FLT3-ITD mutation. The prognosis and best therapy of these persons is controversial. Methods-We evaluated 809 consecutive newly diagnosed adult with normal cytogenetics and 231 of whom had no NPM1 or FLT3-ITD mutation identified by targeted regional sequencing. 158 achieved a complete remission within 2 cycles of induction therapy and were assigned to 2 different post-remission strategies: (1) 6 courses of consolidation chemotherapy (N=95); or (2) 2-4 courses of consolidation chemotherapy and an allotransplant (N=63). Results-In multi-variable analyses a WBC ≥13·6×10E+9/L, mutated IDH2, not having a bi-allelic CEBPA mutation at diagnosis, a positive measurable residual disease (MRD)-test during consolidation and not receiving an allotransplant were independently associated with a higher cumulative incidence of relapse (CIR) and worse event-free survival (EFS). Amongst subjects with IDH2 mutations, non-bi-allelic CEBPA mutations or a positive MRD-test, subjects receiving an allotransplant had a lower 5-year CIR (16% [95% confidence interval, 6, 26%]; vs. 83% [72, 95%]; hazard ratio, HR=8·77 [4·05, 13·49]; P < 0·001) and better 5-year EFS (74% [60, 88%] vs. 15% [5, 25%]; HR=0·16 [0·09, 0·29]; P < 0·001). In contrast, in subjects with none of these adverse predictive variables there was no difference in CIR and EFS between those receiving an allotransplant and those who did not. Conclusions-Our data suggest a strategy to identify which persons with AML with normal cytogenetics and no NPM1 or FLT3-ITD mutation benefit from an allotransplant. Trial Registration: Registered in the www.clinicaltrials.gov, NCT01455272 and NCT02185261. Keywords: Acute myeloid leukemia, mutations, prognosis, targeted regional sequencing, measurable residual disease, risk stratification. *Correspondence Profs. Guo-Rui Ruan and Xiao-Jun Huang Peking University Peoples Hospital and Institute of Hematology No.11 Xi-Zhi-Men South Street, Beijing 100044, China T 86-10-88324672 F 86-10-88324672 Disclosures No relevant conflicts of interest to declare.

Preconditioning Neutropenia Is a Key Prognostic Factor in Allogeneic Hematopoietic Cell Transplantation for High Risk Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3411-3411
Author(s):  
Philippa J Rohman ◽  
Richard M Szydlo ◽  
Emily Hobbs ◽  
Renuka Palanicawandar ◽  
Belen Sevillano ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Prognostic Factor ◽  
Cell Transplantation ◽  
Neutrophil Count ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract Identification of prognostic indicators to predict outcomes of hematopoietic cell transplantation (HCT) is important for selection of patients most likely to benefit from the procedure. Widely validated systems such as the HCT-Comorbidity Index (HCT-CI) and the modified EBMT risk score provide consistent prediction of outcomes, in particular non-relapse mortality (NRM) and survival. In this retrospective study we identified neutropenia prior to initiation of conditioning regimen as an additional prognostic factor in 117 adults with high risk acute myeloid leukemia (AML) who received HCT at a single institution from January 2005 to December 2015. The main endpoints of the study were day 100 non-relapse mortality and survival at 5 years. The median age at HCT was 50 years (range 21-68); 65% had an EBMT score of ≥4. In total 107 (91%) patients had poor risk disease, with classification for poor risk including; patients undergoing HCT due to failure to achieve complete remission (CR) after induction chemotherapy, patients in 2nd CR, patients in 1st CR with adverse karyotype, patients with standard karyotype but with a FLT-3 mutation, patients with measurable residual disease (MRD) by immunophenotyping or molecular monitoring and patients with secondary AML. Conditioning was myeloablative (Cy-TBI: N=41, Bu-Cy: N=3) for patents younger than 51 years with good performance status; the intensity of conditioning was reduced for the others (N=73). Standard methotrexate and cyclosporine was used as graft versus host disease prophylaxis in recipients of sibling cells, and unrelated graft recipients also received alemtuzumab. With a median follow-up of 3.1 years (range 0.3 - 10.0), day 100 NRM for the whole group was 17.3% (95% confidence interval (CI) 11 - 25) and the probability of survival at 5 years was 40.3% (95% CI 31 - 50). The effects of patient, disease and transplant factors were analysed in univariate analyses on both NRM and survival. Significant factors were then entered into multivariate analyses which yielded significant associations with improved NRM for preconditioning absolute neutrophil count (ANC) >= 1000/microL and HCT-CI < 3 (Figure) (hazard ratio (HR) 0.36; 95% CI 0.1 - 0.9 and HR 0.39; 95% CI 0.2 - 0.9 respectively). The factors associated with improved survival in multivariate analysis included preconditioning neutrophil count >= 1000/microL (HR 2.9; 95% CI 1.6 -5.4, P= 0.01), absence of any measurable disease prior to conditioning (HR 2.1; 95% CI 1.1 -4.2, P= 0.03), and less than 2 disease risk defining criteria (HR 15.8; 95% CI 2.0 -124.4, P= 0.01). In conclusion, patients with ANC of 1000/microL and above prior to initiation of conditioning and those with HCT-CI below 3 had significantly better day 100 NRM. ANC of 1000/microL or above was also associated with better survival at 5 years together with disease specific factors, absence of measurable residual disease prior to initiation of condition and less than two adverse prognostic factors. A simple measurement such as the neutrophil count helps to predict outcome: this might reflect the presence of on-going disease but it is also possible that delaying transplant until neutrophil count recovery might impact favourably on the results. Our findings therefore advocate integration of preconditioning neutrophil count into existing risk assessment tools when considering HCT. Figure Figure. Disclosures Milojkovic: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria.

scholarly journals Role of Minimal (Measurable) Residual Disease Assessment in Older Patients with Acute Myeloid Leukemia

Cancers ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 215 ◽  
Author(s):  
Francesco Buccisano ◽  
Richard Dillon ◽  
Sylvie Freeman ◽  
Adriano Venditti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Assessment ◽  
Measurable Residual Disease ◽  
Acute Myeloid
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