The intermediate-risk cytogenetic group is heterogeneous and includes cytogenetically normal disease as well as those with karyotypic abnormalities not meeting criteria for good- or poor-risk AML. It previously constituted the largest risk category, accounting for approximately 40% to 50% of adult AML patients less than 60 years of age, but more recently with the refinement of molecular risk predictors, this category has shrunk. Long-term disease-free survival of approximately 40% to 45% is anticipated after consolidation chemotherapy in intermediate-risk AML. However, identification of mutations with prognostic importance such as mutant FLT3 internal tandem duplication (FLT3-ITD), NPM1, and CEBPA (CCAAT/enhancer-binding protein-α) have further individualized treatment decision-making, including allogeneic transplantation.
Over the past decade, “normal” karyotype AML (NK-AML, the largest category within intermediate-risk AML) has been documented to encompass molecular abnormalities with divergent risk. The presence of an isolated NPM1 or biallelic CEBPA mutation improves disease prognosis to slightly below that of AML with CBF translocations, placing them in the favorable-risk category, and most investigators do not offer HSCT in first remission. The favorable impact of NPM1 mutations appears to persist albeit to a lesser extent in older patients, and allogeneic HSCT may be a consideration in older AML. In contrast, patients with an isolated FLT3-ITD mutation and NK-AML have outcomes similar to those with poor-risk karyotype. In a report evaluating the 2010 ELN risk classification in a large cohort of patients, for those in the “intermediate I” risk group (includes all patients with NK-AML with FLT3 abnormalities and those lacking both FLT3 and NPM1 mutations), relapse-free survival (RFS) was improved with allogeneic HSCT (94 vs. 7.9 months without allogeneic HSCT).
Although the better-prognosis subgroup within NK-AML may not benefit from early allogeneic transplantation, HSCT appears to be the preferred post-remission therapy for other intermediate risk AML patients at higher risk for relapse, including those lack ing favorable gene mutations like NPM1 without FLT3-ITD, or double mutant CEBPA. However, the dissection of disease complexity requires detailed analysis to identify optimal therapy. For instance, Dohner et al. validated the 2017 NPM1/FLT3-ITD ELN AML risk classification, documenting that allogeneic HSCT benefit is restricted to patients in the “adverse-risk” group (NPM1wt/ FLT3-ITDhigh; NPM1mut/FLT3-ITDhigh with high-risk molecular mutations (RUNX1, ASXL1, TP53); and NPM1wt/FLT3-ITDlow AML with high-risk molecular markers and/or adverse-karyotype). For the “intermediate-risk” group (NPM1mut/FLT3-ITDhigh; and NPM1wt/FLT3-ITDlow, both without adverse-risk karyotype), allogeneic HSCT benefit was restricted to patients who did not receive midostaurin-based treatment on the CALGB 10603/RATIFY trial. Of note, this finding is relevant to AML patients aged 18 to 60 years and requires validation in independent datasets prior to its routine incorporation in clinical decision making. Further, extrapolation to patients aged above 60 years is not warranted, given their overall worse disease outcomes.
Poor-Risk Acute Myeloid Leukemia
In poor-risk AML, relapse rates are high and survival rates are anticipated to be 15% or lower with conventional therapy. Allogeneic HSCT with a matched sibling or unrelated donor results in long-term survival of 30% to 40% and is considered the treatment of choice for adults less than 60 years of age with poor-risk AML. There remains, however, a subgroup of poor-risk AML that may have particularly adverse prognosis, for whom additional novel therapeutic strategies may be necessary.
The monosomal karyotype (MK) is defined by the presence of a single autosomal monosomy, in association with at least one additional monosomy or non-good-risk structural chromosomal abnormality (i.e., excluding CBF mutation AML).16 In the original report, MK-positive AML patients had a long-term survival of only 3% to 4%, and these generally dismal chemotherapeutic outcomes have been confirmed by other investigators. Allogeneic transplantation appears to only partly ameliorate the impact of MK-positive karyotype, which remained an adverse prognostic factor after HSCT, and was associated with a relapse risk of 62% and poor survival of 15% at 4 years.
Importantly, some if not all of the negative impact of MK and complex karyotype (CK) AML is its association with deletions of chromosome 5 (−5/5q−) and especially with abnormal (abnl)17p (site of TP53 gene). In a retrospective analysis of 236 high-risk AML-CR1 patients of whom nearly half (49%) received reduced intensity allogeneic HSCT, patients with abnl(17p) had a 2-year EFS of 11%, those with −5/5q− but no abnl(17p) had a 2-year EFS of 29%, and those with high-risk AML (including MK or CK) without either abnl(17p) or −5/5q− had a 2-year EFS of 49%. Further, in updated analyses, the negative impact of abnl(17p) appears minimally improved after allogeneic HSCT. Improving HSCT outcomes in TP53 mutant and other extremely poor-risk AML remains a high priority for the future, and clinical trials of novel conditioning (e.g., Venetoclax-based) and post-transplant maintenance (e.g., APR-246) approaches are strongly encouraged for such patients.
