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Editorial theme | Impact of using a fixed blast percentage threshold on AML and MDS treatment options

Feb 16, 2022

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Whilst treatment for acute myeloid leukemia (AML) has historically been more intense than that for myelodysplastic syndromes (MDS), reduced-intensity induction therapeutic options for AML have recently been successful. Nevertheless, the difference in treatment remains, guided by the 2001 World Health Organization (WHO) classification of myeloid neoplasms, which states that the presence of ≥20% myeloblasts in marrow or peripheral blood is diagnostic of AML, a criterion which has been retained in both the 2008 and 2016 revisions of the guidelines. This has limited patients’ eligibility for novel drug treatments within clinical trials, as patients with 19% blasts are deemed ineligible for AML studies, and those with 21% blasts are not able to participate in MDS studies.

Here we present the first article in our editorial theme looking at diagnostic and prognostic techniques in AML and MDS, summarizing the key findings and recommendations from a recent review in Blood by Estey, et al.1 The review collated biologic and clinical data from existing studies, alongside a cohort of patients with either WHO-defined AML or MDS excess blast 2 (MDS-EB2), to assess the role of the blast percentage threshold when distinguishing AML from MDS.

Biologic data

AML-associated genetic abnormalities can also present as MDS

The presence of core binding factor (CBF) or PML-RARA rearrangements, NPM1 mutations, and Inv(3)/t(3:3) would usually lead to a diagnosis of AML, regardless of blast count. However, these can also present in MDS or chronic myelomonocytic leukemia, albeit rarely; therefore classification based on mutational landscape may be helpful in some cases.

Genetic overlap between high grade MDS and secondary AML

Patients with AML-associated mutations in genes regulating ribonucleic acid splicing (SRSF2, SF3B1, U2AF1, and ZRSR2), chromatin modification (ASXL1, STAG2, BCOR, KMT2aPTD, EZH2, and PHF6), or transcription (RUNX1) often have a hematologic disorder and/or dysplastic marrow morphology, and experience poorer outcomes.

  • The chromatin/spliceosome AML subgroup has also been described in high-grade MDS, suggesting secondary AML and high-grade MDS are biologically very similar and may both surpass the 20% blast threshold.
  • Genetic mutations involved in at least six major pathways, including cytogenetic abnormalities, occur in both MDS and secondary AML.
  • A group of MDS-associated cytogenetic abnormalities are diagnostic of AML with myelodysplasia-related changes (AML-MRC), even in de novo cases without prior MDS diagnosis. 
    • These abnormalities are also common in MDS, and lead to poor/very poor risk classification by the MDS Cytogenetic Scoring System and revised International MDS Prognostic Scoring System.
    • These scoring systems group together patients with MDS and those with AML developed from MDS who have 20–29% blasts.

MDS progression to AML

Paired samples from 60 patients revealed mutations in TP53, splicing factor, and epigenetic modifying genes in both MDS and secondary AML.

These were more frequent in patients in the MDS stage, with mutations in transcription factors and activating signal genes becoming more prominent at the AML progression stage, suggesting de novo/pan-AML mutations from pre-existing MDS clones drives progression.

Secondary vs de novo AML

Comparison of mutation patterns in 93 and 180 patients with secondary AML and de novo AML, respectively, found mutations in eight genes (SRSF2, ZRSR2, SF3B1, ASXL1, BCOR, EZH2, U2AF1, and STAG2) that were >95% specific for secondary AML, and three alterations (NPM1 mutations, KMT2a rearrangement, and CBF gene fusions) were specific for de novo AML.

  • A related study demonstrated that TP53 mutations were more common in patients with MDS excess blasts (MDS-EB; 39%) and patients with AML-MRC/therapy related-AML (t-AML; 29%), compared to patients with de novo AML (2%; p < 0.00001).  
  • NPM1 and FLT3-internal tandem duplication (ITD) mutation frequencies were also more similar between patients with MDS-EB and AML-MRC/t-AML than with de novo AML.   

Blast percentage and tumor burden

Although blast percentages differ between MDS-EB and AML-MRC/t-AML, no difference in the distribution of variant allele frequency of individually mutated genes has been found.

Paired bone marrow samples from patients with MDS and AML progression also showed that, despite increase in morphologic blast count, ~85% of the cells were clonal at both stages.

Altogether, the biologic data suggests that rather than classifying solely based on blast percentage, disease categorization may be more accurately based on biologic and genetic features (Table 1).

Table 1. Recommendation for disease categorization*



Group 1

True MDS with <5% blasts without known high risk mutations or cytogenetic
abnormalities leading to low-risk progression of AML.

Group 2

True AML with PML-RARA, RUNX1-RUNX1T1, or CBFB-MYH11 gene fusions, NPM1
mutations, KMT2A gene rearrangements, or biallelic CEBPA mutations, irrespective
of blast percentage.

Group 3

Cases with high-risk mutations that are common to both AML and MDS, and other
cases with >5% blasts.

AML, acute myeloid leukemia; MDS, myelodysplastic syndromes.
*Adapted from Estey et al.1

Clinical data

There is evidence to support defining AML primarily according to genetic features, rather than basing mainly on a fixed blast count.

  • Clinically, patients with de novo AML and secondary type mutations or t-AML with secondary mutation patterns, have poorer outcomes, similar to those with secondary AML.
  • According to WHO criteria, patients with genetic abnormalities including RUNX1-RUNX1T1 t(8;21) (q22.q22.1) and CBFB-MYH11 inv(16)(p13.1q22), or t(16;16)(p13.1;q22) are considered to have AML, irrespective of blast count.
  • Comparison of AML-type induction chemotherapy with MDS-type therapy (usually hypomethylating agents) in 21 patients with NPM1-mutated MDS or chronic myelomonocytic leukemia (median blast count, 10%), found:
    • Complete remission rates of 90% with AML-type induction and 28% with hypomethylating agents (p = 0.004).
    • At median follow-up of 30 months, AML-type induction was associated with longer progression free survival (p = 0.023) and overall survival (p = 0.047) compared with MDS-type therapy.
  • Although GATA2 MECOM (EVI1) inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2) are commonly found in AML, they share the same biology and poor outcomes whether treated as MDS or AML; similarly, TP53 is associated with dismal outcomes irrespective of MDS- or AML-type treatment.
  • FLT3-ITD mutations are an adverse prognostic factor in patients with de novo MDS, similar to findings in FLT3-ITD-mutated AML.    

Seattle patient cohort

The Fred Hutchinson Cancer Research Center, Seattle, considers patients with MDS-EB2 (excess blasts in 10%–19% bone marrow) eligible for AML-type therapy. Data from 769 patients with WHO-defined AML and 202 patients with MDS-EB2, treated between 2008 and 2016, were analyzed, with a median follow-up of 4.2 years in patients alive or alive in remission.

  • In total, 95% of patients with WHO-defined AML had ≥20% morphologic blasts in either marrow or peripheral blood, and secondary disease was more common with AML than with MDS (28% vs 11%).
  • Treatment with low-intensity induction therapy and allogeneic hematopoietic stem cell transplantation were more common in patients with MDS-EB2 (Table 2).

Table 2. Patient characteristics and clinical responses*

Characteristic, %
(unless otherwise

(n = 202)

(n = 769)

All patients
(N = 971)

p value
(MDS-EB2 vs

Age (range), years

62 (22–85)

63 (18–91)

62 (18–91)


Disease status





              De novo










Mean morphologic blasts (range)

14 (10–19.8)

45 (0–100)

34 (0–100)


ELN 2017 risk group




















Induction intensity

























              CR or CRi










allo-HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; CRMRD-, CR MRD negative; ELN, European Leukemia Network; MDS-EB2, myelodysplastic syndromes excess blasts 2; MRD, minimal residual disease; WHO, World Health Organization.
*Adapted from Estey, et al.1
Values in bold are statistically significant.

Although patients with AML who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) but not minimal residual disease negative CR (CRMRD-) showed superior survival outcomes, after adjustment for factors such as age, disease status, performance status, European Leukemia Network (ELN) 2017 risk group, and induction intensity (Table 3), overall and event-free survival rates were similar between patients diagnosed with AML and MDS-EB2.

  • The effect of AML on relapse-free survival rates in patients reaching CR/Cri and on the rate of CRMRD- was less than that of having ELN intermediate- or adverse-risk disease.
  • Attainment of CR/CRi was not affected by whether patients had AML or MDS-EB2.
  • Although patients with AML were more likely to achieve CRMRD-, relapse-free survival rates were similar between diagnoses.

Table 3. Clinical outcomes assessed using multivariate models*




CR or CRi











0.89 (0.74–1.07)


0.89 (0.75–1.06)


1.06 (0.99–1.13)


0.66 (0.53–0.83)


Age (per 10 year)

1.3 (1.22–1.38)


1.19 (1.13–1.26)


0.98 (0.96–1.00)


1.13 (1.05–1.20)


Performance Status 2–4 (ref Performance Status 0–1)

2.0 (1.68–2.37)


1.68 (1.42–1.99)


0.87 (0.82–0.93)


1.21 (0.96–1.51)


ELN 2017 risk









              Intermediate               (ref favorable)

1.7 (1.34–2.15)


1.72 (1.38–2.14)


0.86 (0.80–0.93)


2.15 (1.67–2.76)


              Adverse (ref               favorable)

2.28 (1.80–2.88)


2.29 (1.84–2.85)


0.78 (0.73–0.84)


3.07 (2.35–4.00)


Secondary AML (ref de novo)

1.3 (1.10–1.55)


1.28 (1.08–1.50)


0.93 (0.87–0.99)


1.16 (0.93–1.43)


Low-intensity induction (ref high intensity)

1.3 (1.08–1.55)


1.62 (1.36–1.93)


0.7 (0.66–0.75)


1.07 (0.82–1.38)


Allo-HSCT (ref no allo-HSCT)

0.48 (0.39–0.60)


0.39 (0.31–0.47)




0.29 (0.23–0.36)


allo-HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; EFS, event-free survival; ELN, European Leukemia Network; HR, hazard ratio; MDS-EB2, myelodysplastic syndromes excess blasts 2; ref, reference; RFS, relapse-free survival; WHO, World Health Organization.
*Adapted from Estey, et al.1
Values in bold are statistically significant.


This review of biologic and clinical data demonstrated that, although the 20% blast threshold remains important in the diagnosis of AML and MDS, its use has significant implications for patient treatments and outcomes. The authors recommended creating a 10%–30% AML/MDS category, allowing patients with low blast count AML to access treatments currently used in MDS-EB2 and providing them with access to a wider range of therapies. Moreover, patients with NPM1, FLT3 or TP53 mutations, KMT2a rearrangements, or inv(3)/t(3:3) should be eligible for AML trials regardless of their blast count.

There were limitations to the data obtained from the Seattle cohort of patients, such as selection bias, a high proportion of MDS-EB2 patients receiving high intensity induction therapy, and high rates of allogeneic hematopoietic stem cell transplantation in first remission. Therefore, AML studies which also include patients with MDS-EB2 are needed to validate the findings here.

  1. Estey E, Hasserjian RP, Döhner H. Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal. Blood. 2022;139(3):323-332. DOI: 1182/blood.2021011304


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