Prognostic Significance of the French-American-British (FAB) Morphologic Subclassification of “Acute Myeloid Leukemia, Not Otherwise Specified” in the 2008 WHO Classification: Analysis of 5,848 Newly Diagnosed Patients From HOVON, MRC/NCRI, SWOG, and MD Anderson Cancer Center

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 540-540
Author(s):  
Roland B. Walter ◽  
Megan Othus ◽  
Alan K. Burnett ◽  
Bob Löwenberg ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Who Classification ◽  
Prognostic Significance ◽  
Early Death ◽  
Cancer Center ◽  
Newly Diagnosed ◽  
Not Otherwise Specified ◽  
Fab Classification ◽  
Md Anderson ◽  
French American British

Abstract Abstract 540 Background: The World Health Organization (WHO) classifies acute myeloid leukemia (AML) via genetic, immunophenotypic, biologic, and clinical features. Nevertheless, in the subgroup “AML, not otherwise specified (NOS)”, cases are subdivided based on morphologic criteria similar to those of the previous French-American-British (FAB) classification, but the clinical relevance of this practice is unknown. Assuming that part of a classification system's value derives from its clinical relevance, we used data from adults with newly diagnosed AML treated on trials conducted by the Dutch-Belgian Cooperative Trial Group for Hematology/Oncology (HOVON), the U.K. Medical Research Council/National Cancer Research Institute (MRC/NCRI), the U.S. cooperative group SWOG, and MD Anderson Cancer Center (MDA) to assess the prognostic significance of FAB in the WHO “AML, NOS” category. Patients and Methods: We reviewed information on patients with newly diagnosed AML other than acute promyelocytic leukemia receiving curative-intent treatment on HOVON (1987-2008), MRC/NCRI (1988-2010), or SWOG (1987-2009) protocols or at at MDA (2000-2011) and had information on FAB classification available. We used multivariate analyses to assess whether the FAB type was independently associated with early death (i.e. death within 28 days of initiation of chemotherapy or study registration), achievement of complete remission (CR), relapse-free survival (RFS), and overall survival (OS). The following pre-treatment covariates were used in the regression modeling: FAB category, age at diagnosis, white blood cell count, platelet count, bone marrow blast percentage, gender, performance status (0 vs. 1 vs. ≥2), karyotype (normal vs. abnormal), and treatment site. Results: After exclusion of patients with therapy-related neoplasms, AMLs with myelodysplasia-related changes, and leukemias with recurrent cytogenetic abnormalities but ignoring information on NPM1 and CEBPA, our cohort included 5,848 predominantly adult patients (median age: 54 years [range: 12–91 years] with “AML, NOS”. After multivariate adjustment, FAB M0 AML was independently associated with significantly lower likelihood of achieving CR and inferior RFS as well as OS as compared to FAB M1, M2, M4, M5, and M6 (FAB “M1-M6”), and inconclusive data regarding M7. Specifically, relative to patients with FAB M1-6, those with FAB M0 the hazard ratios (HRs) were 1.66 (95% confidence interval: 1.30–2.12) for achievement of CR (p<0.001), 0.86 (0.73–1.01) for RFS (p=0.068), and 0.82 (0.72–0.92) for OS (p=0.0013). In contrast, FAB M0 was not associated with risk of early death (HR: 1.01 [0.67–1.53], p=0.96). After exclusion of cases fitting the entity of “AML with mutated NPM1” (n=987) and cases with unknown NPM1 status (n=3,584), FAB M0 was no longer associated with worse outcome relative to other FAB subtypes in the remaining 1,277 patients, with HRs of 1.19 (0.75–1.91; p=0.46) for achievement of CR, 0.98 (0.74–1.31; p=0.89) for RFS, 0.91 (0.72–1.16; p=0.45) for OS, and 1.03 (0.35–3.03; p=0.95) for early death. Although data were limited by sample size, additional exclusion of cases fitting the provisional entity of “AML with mutated CEBPA” and cases with unknown CEBPA status did not further affect this result. Conclusion: In the 2008 WHO classification scheme, our data suggest that FAB subclassification of “AML, NOS” cases does not provide prognostic information if molecular data on the mutational status of NPM1 and CEBPA are available. This finding leads us to question the utility of continued use of the FAB system in this subset of AML patients. Disclosures: No relevant conflicts of interest to declare.

Prediction Of Therapeutic Resistance In Adult Acute Myeloid Leukemia: Analysis Of 4,550 Newly Diagnosed Patients From MRC/NCRI, HOVON/SAKK, SWOG, and MD Anderson Cancer Center

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 64-64
Author(s):  
Roland B Walter ◽  
Megan Othus ◽  
Alan K. Burnett ◽  
Bob Löwenberg ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Cancer Research ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Cancer Center ◽  
Therapeutic Resistance ◽  
Refractory Disease ◽  
Newly Diagnosed ◽  
Md Anderson ◽  
Acute Myeloid

Abstract Background Primary failure of induction chemotherapy or disease recurrence after short remission duration (“therapeutic resistance”) remains the principal problem in adult acute myeloid leukemia (AML). Although cytogenetic and molecular abnormalities have proven useful in the identification of subsets of patients with distinct disease risks, it is unclear to what degree therapeutic resistance can be predicted for individual patients. Patients and Methods We used information on patients with newly diagnosed AML other than acute promyelocytic leukemia receiving curative-intent treatment on trials conducted by the U.K. Medical Research Council/National Cancer Research Institute (MRC/NCRI; 1988-2010; n=2,615), the Dutch-Belgian Cooperative Trial Group for Hematology/Oncology and the Swiss Group for Clinical Cancer Research (HOVON/SAKK; 1987-2008; n=1,098), the U.S. cooperative group SWOG (1987-2009; n=428), and MD Anderson Cancer Center (2000-2011; n=409). Achievement of a complete remission (CR) with the initial 1-2 courses of induction chemotherapy was defined as therapeutic success. Patients who failed to achieve CR were defined as primary refractory for the purpose of this analysis; patients who experienced treatment-related mortality (i.e., death within 28 days of treatment initiation) were excluded from this analysis. We used logistic regression analyses to assess the relationship between individual covariates and various measures of therapeutic resistance. The following pre-treatment covariates were used in the regression modeling: age at diagnosis, gender, white blood cell (WBC) count, platelet count, bone marrow blast percentage, disease type (primary vs. secondary), cytogenetic risk, FLT3/NPM1 status, and treatment site. We then used the area under the receiver operator characteristic curve (AUC) to quantify a model’s ability to predict therapeutic resistance; in this approach, an AUC of 1 indicates perfect prediction while an AUC of 0.5 indicates no prediction; AUC values of 0.6-0.7, 0.7-0.8, and 0.8-0.9 are commonly considered as poor, fair, and good, respectively. Results A total of 4,550 patients (median age: 52 years [range: 15-90 years]) were included in this study. A CR to the initial 1-2 courses of induction chemotherapy was achieved in 3,597 (79.1%) of patients, whereas 953 (20.9%) were primary refractory; 1,304/4,497 patients (29.0%) with sufficient follow-up time were either primary refractory or had a relapse-free survival (RFS) of 3 months or less after CR achievement, 1,774/4,445 patients (39.9%) with sufficient follow-up time were either primary refractory or had a RFS of 6 months or less after CR achievement, and 2,523/4,386 patients (57.5%) with sufficient follow-up time were primary refractory or had a RFS of 12 months or less after CR achievement. Increasing age (p<0.001) and WBC (p<0.001), secondary disease (p<0.001), FLT3/NPM1 status (p<0.001), and cytogenetic risk (favorable or intermediate vs. adverse, p<0.001) were independently associated with being primary refractory to induction chemotherapy in a combined analysis of all patients. In the total patient cohort, a bootstrap-corrected multivariate model predicting primary refractoriness yielded an AUC of 0.79; removal of FLT3 and NPM1 from the model minimally, but statistically significantly, decreased the AUC (0.77). Between individual treatment sites, these AUCs varied from 0.82/0.81 to 0.69/0.67. Prediction of therapeutic resistance, as defined as primary refractoriness or relapse after short remission duration, was more difficult. Specifically, when analyzing the entire study cohort, the AUCs for models predicting primary refractory disease or relapse within 3 months were 0.76/0.74 (with/without inclusion of FLT3/NPM1 data) and further decreased to 0.76/0.73 and 0.75/0.71 for models predicting primary refractory disease or relapse within 6 or 12 months, respectively. Conclusion Our ability to predict therapeutic resistance based on routinely available clinical covariates, even with inclusion of commonly used molecular data on FLT3 and NPM1, is relatively limited. This finding would support the continued use of randomization to assign patients between standard and investigational therapies, and argues for the integration of early treatment response measures (e.g. minimal residual disease) to optimize prediction of therapeutic resistance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

scholarly journals Simultaneous or sequential expression of lymphoid and myeloid phenotypes in acute leukemia

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 142-148 ◽  
Author(s):  
PB Neame ◽  
P Soamboonsrup ◽  
G Browman ◽  
RD Barr ◽  
N Saeed ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Differentiation Markers ◽  
Lymphoid Leukemia ◽  
Chromosome Marker ◽  
Fab Classification ◽  
Blast Cells ◽  
French American British

Abstract Acute mixed myeloid-lymphoid leukemia is uncommon. We report four cases in which myeloid and lymphoid cell markers were observed simultaneously or sequentially when 94 patients with acute leukemia were phenotyped according to the French-American-British (FAB) classification system, with cytochemical stains, and with immunologically defined differentiation markers (identified by monoclonal antibodies and antiterminal deoxynucleotidyl transferase [TdT]). In one case, conversion from acute lymphoblastic leukemia to acute myeloid leukemia was noted (FAB L1, TdT+ to FAB M4, Auer rods, TdT-). In another patient, two distinct populations of myeloid and lymphoid blast cells were observed simultaneously (TdT-, LeuM1+/TdT+, LeuM1-). In two additional patients, acute leukemia was characterized by the expression of both lymphoid and myeloid markers on the same cell (TdT+/Leu M1+, B4+/Leu M1+ and greater than or equal to 70% TdT+, T11+, My9+). The Philadelphia (Ph1) chromosome was negative in all cases, though other chromosomal abnormalities were noted in three out of four cases. Malignant transformation of a pluripotential stem cell for both lymphoid and myeloid lineages, with or without the Ph1 chromosome marker, could explain the coexistence of distinct populations of lymphoblasts and myeloblasts in acute leukemia. Acute leukemia with a biphenotypic profile may reflect genome depression accompanying neoplasia.

scholarly journals Prognosis of aggressive lymphomas: a study of five prognostic models with patients included in the LNH-84 regimen

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 558-564 ◽  
Author(s):  
B Coiffier ◽  
E Lepage
Keyword(s):  
Performance Status ◽  
Prognostic Significance ◽  
Staging System ◽  
Prognostic Models ◽  
Cancer Center ◽  
Malignant Lymphomas ◽  
Prognostic System ◽  
Ann Arbor ◽  
Md Anderson ◽  
Better Than

Abstract Four prognostic models described for aggressive malignant lymphomas and the classical Ann Arbor staging system were used to compare the survival of 737 patients treated with the LNH-84 regimen. The aim of the study was to determine the optimal prognostic system at the time of diagnosis. Three institutions have described these models after multivariate analyses: the Dana Farber Cancer Institute (DFCI1 and DFCI2), the MD Anderson Hospital (MDAH), and the Memorial Sloan- Kettering Cancer Center (MSKCC). The models were constructed with the following variables: performance status, LDH level, and tumor extension. The latter is the most difficult to assess: it was considered as the number of extranodal sites and the diameter of the largest mass in DFCI1, stage and the diameter of the largest mass in DFCI2, the number of extranodal and extensive nodal sites in MDAH, and the number of nodal sites and their localization in MSKCC. Univariate studies with LNH-84 regimen patients showed all these variables to have major prognostic significance (logrank tests: P less than 10(-4)). All five prognostic systems divided patients into three subgroups: good, intermediate, and poor prognosis. Logrank analyses of survival showed highly significant differences (X2 greater than 90 and P less than 10(- 6)) between the subgroups. No gross difference was found between the models, and none was better than the others. A new, internationally accepted prognostic system for the expression and comparison of treatment results in aggressive malignant lymphomas should include major univariate prognostic parameters and must be reliable and easy to use in clinical practice. Until such time, stage or LDH level are the best alternatives.

Cellular Vascular Endothelial Growth Factor Is a Predictor of Outcome in Patients With Acute Myeloid Leukemia

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3717-3721 ◽  
Author(s):  
Alvaro Aguayo ◽  
Elihu Estey ◽  
Hagop Kantarjian ◽  
Taghi Mansouri ◽  
Cristi Gidel ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Vascular Endothelial ◽  
Newly Diagnosed ◽  
Endothelial Growth Factor ◽  
Vegf Level ◽  
Acute Myeloid

Abstract Vascular endothelial growth factor (VEGF) is a potent mitogen for vascular endothelial cells. It has been associated with angiogenesis, growth, dissemination, metastasis, and poor outcome in solid tumors. To assess cellular VEGF levels and their prognostic significance in newly diagnosed acute myeloid leukemia (AML), we used a radioimmunoassay (RIA) to quantify VEGF levels in stored samples obtained before treatment from 99 patients with newly diagnosed AML treated at the MD Anderson Cancer Center from 1996 to 1998. Outcome in the 99 patients was representative of that observed in all patients seen at this institution with this diagnosis during these years, but the 99 patients had higher white blood cell (WBC) and blast counts than the other patients. Results of the RIA were confirmed by Western blot. There was a relationship between increasing VEGF levels and shorter survival (P = .01), as well as shorter disease-free survival, both from start of treatment and from complete response (CR) date. In contrast, there was no relationship between VEGF level and WBC or blast count, or between VEGF level and such established prognostic factors as age, cytogenetics, performance status, or presence of an antecedent hematologic disorder, and multivariate analysis indicated that VEGF was still prognostic for the above outcomes after accounting for these factors, as well as treatment. Our results suggest that at least in AML patients with higher WBC and blast counts, cellular VEGF level is an independent predictor of outcome.

Evaluation of the Gene Xpert DX System for Molecular Monitoring in CML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4794-4794
Author(s):  
Ghayathri Jeyakumar ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Elias J. Jabbour ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Real Time ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Great Variability ◽  
Molecular Diagnostic ◽  
Cancer Center ◽  
Molecular Monitoring ◽  
Simple Method ◽  
Two Samples ◽  
Md Anderson

Abstract Abstract 4794 Background: The diagnosis of chronic myeloid leukemia (CML) and the monitoring during therapy requires identification and quantification of the BCR-ABL1 transcripts. Molecular monitoring has become a requirement as therapy has become more efficient in inducing cytogenetic and molecular remissions. Unfortunately, there is great variability in the methodologies used for molecular monitoring, with various levels of expertise, great variability of the results between different laboratories, and frequently limited access. A simple method for rapid detection and quantification of BCR-ABL1 transcripts would benefit patients and improve outcomes. The GeneXpert DX System rapidly detects and quantifies BCR-ABL1 mRNA transcripts (type e13a2/b2a2 or e14a2/b3a2) in patients diagnosed with CML via an automated, quantitative real-time reverse transcription polymerase chain reaction. Results are available within 2 hours and adjusted to the international scale. We assessed the correlation between the GeneXpert system with the results from the Molecular Diagnostic Laboratory (MDL) at MD Anderson Cancer Center. Methods: Peripheral blood specimens were collected from 55 patients with CML, acute lymphoblastic leukemia and acute myeloid leukemia and used for assay development, analytical validation and precision studies that compared the GeneXpert BCR-ABL1 Monitor Assay versus the standard MD Anderson MDL real-time PCR protocol. CML Ph positive was assessed as belonging to categories based on the BCR-ABL1 mRNA transcript level (Category I, >1%; Category 2, >0.1–1%; Category 3, >0.01%–0.1%; Category 4, ≤0.01%). Patients who had tyrosine kinase therapy resulting in stable disease were in categories 3 or 4, whereas newly diagnosed patients or those with acute disease were in categories 1 and 2. Ph-negative patients with ALL (n=2) and AML (n=4) were the negative controls. Results: Of the 55 patients whose blood was tested by the GeneXpert monitoring assay, 49 patients with CML fell into categories 1–4 (3, 7,4,35 respectively). The remaining 6 patients had a diagnosis of ALL or AML and acted as negative control. These patients had undetectable transcript levels by the GeneXpert system. The median time to obtaining results with the GeneXpert system was 1 hour and 30 min (range 1:29:51 to 1:31:16). There was a strong correlation between the results achieved with the GeneXpert system and those obtained at the MDACC MDL (R=0.7597; P=< 0.0001). Only two samples showed clearly discordant values and these likely represent swapping of the samples which were run at the same time. Excluding these samples the correlation is even tighter (R=0.8937; P= < 0.0001). Conclusion: Results from GeneXpert system BCR-ABL1 are rapid and reliable and can be obtained with little training required. These results suggest that this methodology can be used to expand access and reproducibility to molecular monitoring in CML. Disclosures: Cortes: Cepheid: Research Funding.

Prognostic impact of trisomy 8 cytogenetic abnormality in acute myelogenous leukemia: Analysis of a large cohort (N=2187) of newly diagnosed patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7089-7089
Author(s):  
Gautam Borthakur ◽  
Cecilia Ysabel Arana Yi ◽  
Jorge E. Cortes ◽  
Wei Qiao ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Remission Rate ◽  
Myelogenous Leukemia ◽  
Cancer Center ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Trisomy 8 ◽  
Acute Myelogenous ◽  
Md Anderson

7089 Background: Trisomy 8 is grouped as intermediate risk in cytogenetic (CG) classifications of acute myelogenous leukemia (AML). In a multi-variate analysis of MRC data, trisomy 8 was associated with worse overall survival (OS). Methods: Between years 1993-2012, 2,187 patients (pts) with newly diagnosed AML presented at MD Anderson Cancer Center and 21 (10%) were with a trisomy 8 CG abnormality. The median age of trisomy 8 pts was 63 years (range, 17-89 years) and 59% were males. Sixty four (30%) had isolated trisomy 8, 45 (21%) had trisomy 8 +≤2 additional cytogenetic abnormalities and 102 (49%) had trisomy 8 + ≥3 additional abnormalities. Thirty three percent of pts with trisomy 8+≤2 additional abnormalities, had secondary AML compared to 21% of diploid CG (p=.007). Mutations in the FLT3 gene was seen in 9% and N or KRAS gene in 8%. Results: The overall remission rate (RR) was 47%, 53% and 43% among pts with trisomy 8 alone, trisomy 8+≤2 and trisomy 8+≥3 abnormalities respectively. Among pts <60 years of age and with trisomy 8 + ≤2 abnormalities, RR was 71% and the same was 77% for pts with diploid CG. For pts ≥ 60 years, the RRs were 26% and 57% respectively. Among pts ≥ 60 years and trisomy 8 with complex CG (≥3 additional abnormalities) the RR was 38% and that for patients with complex (non-trisomy 8) CG was 41%. Patients with trisomy 8 either alone or ≤2 additional abnormalities had a shorter OS (p= .04 and .05 respectively, median 10.8 and 8.6 months vs 16.5 months) compared to those with diploid CG. Event free survival was also shorter among patient with isolated trisomy 8 versus those with diploid CG (p=.008, median 2.9 versus 7.5 months). On the other hand, patients with trisomy 8+≥3 abnormalities had outcomes comparable to non-trisomy 8 CG group. Conclusions: Non-complex CG trisomy 8 is associated with worse clinical outcome in patients with AML than those with diploid CG and its inclusion in intermediate risk group may need reconsideration. The most adverse impact appears to be from lower RR among patients with trisomy 8+≤2 additional abnormalities and ≥60 years of age.

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