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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.
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.
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.
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.
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.
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*
|
Criteria |
---|---|
Group 1 |
True MDS with <5% blasts without known high risk mutations or cytogenetic |
Group 2 |
True AML with PML-RARA, RUNX1-RUNX1T1, or CBFB-MYH11 gene fusions, NPM1 |
Group 3 |
Cases with high-risk mutations that are common to both AML and MDS, and other |
AML, acute myeloid leukemia; MDS, myelodysplastic syndromes. |
There is evidence to support defining AML primarily according to genetic features, rather than basing mainly on a fixed blast count.
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.
Table 2. Patient characteristics and clinical responses*
Characteristic, % |
MDS-EB2 |
WHO AML |
All patients |
p value† |
---|---|---|---|---|
Age (range), years |
62 (22–85) |
63 (18–91) |
62 (18–91) |
|
Disease status |
|
|
|
|
De novo |
89 |
72 |
75 |
|
Secondary |
11 |
28 |
25 |
|
Mean morphologic blasts (range) |
14 (10–19.8) |
45 (0–100) |
34 (0–100) |
<0.001 |
ELN 2017 risk group |
|
|
|
<0.001 |
Favorable |
5 |
25 |
21 |
<0.0001 |
Intermediate |
49 |
38 |
40 |
0.009 |
Adverse |
44 |
36 |
37 |
0.03 |
Induction intensity |
|
|
|
0.038 |
High |
68 |
75 |
75 |
|
Low |
32 |
25 |
26 |
|
CR |
|
|
|
|
CRMRD- |
29 |
47 |
43 |
<0.001 |
CR or CRi |
58 |
69 |
67 |
0.0043 |
Allo-HSCT |
45 |
35 |
37 |
0.02 |
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. |
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.
Table 3. Clinical outcomes assessed using multivariate models*
Variable |
OS |
EFS |
CR or CRi |
RFS if CR/CRi |
||||
---|---|---|---|---|---|---|---|---|
HR |
p |
HR |
p |
HR |
p |
HR |
p |
|
WHO AML (ref MDS-EB2) |
0.89 (0.74–1.07) |
0.21 |
0.89 (0.75–1.06) |
0.2 |
1.06 (0.99–1.13) |
0.11 |
0.66 (0.53–0.83) |
<0.001 |
Age (per 10 year) |
1.3 (1.22–1.38) |
<0.001 |
1.19 (1.13–1.26) |
<0.001 |
0.98 (0.96–1.00) |
0.02 |
1.13 (1.05–1.20) |
<0.001 |
Performance Status 2–4 (ref Performance Status 0–1) |
2.0 (1.68–2.37) |
<0.001 |
1.68 (1.42–1.99) |
<0.001 |
0.87 (0.82–0.93) |
<0.001 |
1.21 (0.96–1.51) |
0.11 |
ELN 2017 risk |
|
|
|
|
|
|
|
|
Intermediate (ref favorable) |
1.7 (1.34–2.15) |
<0.001 |
1.72 (1.38–2.14) |
<0.001 |
0.86 (0.80–0.93) |
<0.001 |
2.15 (1.67–2.76) |
<0.001 |
Adverse (ref favorable) |
2.28 (1.80–2.88) |
<0.001 |
2.29 (1.84–2.85) |
<0.001 |
0.78 (0.73–0.84) |
<0.001 |
3.07 (2.35–4.00) |
<0.001 |
Secondary AML (ref de novo) |
1.3 (1.10–1.55) |
0.002 |
1.28 (1.08–1.50) |
0.004 |
0.93 (0.87–0.99) |
0.02 |
1.16 (0.93–1.43) |
0.18 |
Low-intensity induction (ref high intensity) |
1.3 (1.08–1.55) |
0.004 |
1.62 (1.36–1.93) |
<0.001 |
0.7 (0.66–0.75) |
<0.001 |
1.07 (0.82–1.38) |
0.63 |
Allo-HSCT (ref no allo-HSCT) |
0.48 (0.39–0.60) |
<0.001 |
0.39 (0.31–0.47) |
<0.001 |
NA |
NA |
0.29 (0.23–0.36) |
<0.001 |
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. |
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.
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