Favorable prognosis of NPM1 mutations in AML lost in patients with poor cytogenetic risk
Click Here to Manage Email Alerts
Patients with acute myeloid leukemia and adverse-risk cytogenetics had an unfavorable prognosis regardless of whether they harbored mutated or wild-type NPM1, according to results of a pooled analysis of patient data published in Journal of Clinical Oncology.
Thus, although NPM1 mutations typically have been associated with a favorable prognosis in AML, poor cytogenetic risk appeared to override this association.
“Mutations in the NPM1 gene have been associated with a favorable prognosis in the absence of concomitant internal tandem duplications (ITD) of the FLT3 gene in cytogenetically normal AML,” Linus Angenendt, MD, of the department of medicine at University Hospital Münster in Germany, and colleagues wrote. “It was later observed that patients with an NPM1 mutation and a low allelic ratio FLT3-ITD had similar outcomes to patients with an NPM1 mutation but no FLT3-ITD. Thus, both groups are now being classified as favorable risk in the 2017 update of the European LeukemiaNet (ELN 2017) recommendations on genetic risk classification.”
A change in the ELN 2017 guidelines also sought to consider patients with mutated NPM1 and negative or low allelic ratio (FLT3-ITDneg/low) as having favorable risk, regardless of coexisting chromosomal abnormalities. However, limited evidence exists to support this change and previous studies have not evaluated the co-occurrence of NPM1 mutations and adverse-risk karyotype abnormalities, such as such as deletions or monosomies of chromosomes 5 or 7, abnormalities of chromosome 17p, or complex or monosomal karyotypes.
“Even though the combination of an NPM1 mutation with these abnormalities is rare, the prognostic effect of adverse cytogenetics in [NPM1-mutated] AML has important implications for postremission treatment decisions, in particular, the current recommendation that patients who are [NPM1-mutant]/FLT3-ITDneg/low not receive allogeneic hematopoietic stem cell transplantation, given their presumed low risk [for] relapse might be altered if the adverse karyotype increased the risk,” the researchers wrote.
Thus, Angenendt and colleagues examined the validity of the guidelines’ assumption that prognosis was favorable regardless of coexisting chromosomal abnormalities by analyzing the association between karyotype and clinical outcomes among 2,426 intensively treated patients with NPM1-mutated, FLT3-ITDneg/low AML. The researchers collected patient data from registries of nine international AML study groups or treatment centers.
Among these patients, 2,000 (82.4%; median age, 56 years; 56.2% women) had a normal karyotype and 426 (17.6%) had an abnormal karyotype. Among those with an abnormal karyotype, 329 (median age, 56 years; 55% men) had intermediate-risk chromosomal abnormalities, 83 (median age, 62 years; 60.2% men) had adverse-risk chromosomal abnormalities and 14 had favorable core-binding factor cytogenetics.
The researchers compared these patients with data from 1,845 patients (median age, 58 years; 54.6% men) with wild-type NPM1/FLT3-ITDneg/low AML and adverse-risk cytogenetics.
Median follow-up was 4.23 years (95% CI, 4.05-4.46).
Results showed the 83 patients with NPM1-mutated, FLT3-ITDneg/low AML and adverse cytogenetics had lower complete remission rates (66.3%) than those with a normal karyotype (87.7%) or intermediate-risk cytogenetic abnormalities (86%; P < .001), as well as inferior 5-year OS (19.5% vs. 52.4% vs. 44.8%; P < .001), inferior 5-year EFS (18.1% vs. 40.6% vs. 36%; P < .001), and higher 5-year cumulative incidence of relapse (51.9% vs. 43.6% vs. 44.2%; P = .0012).
The associations remained significant (P < .001) in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors.
However, patients with NPM1-mutated, FLT3-ITDneg/low AML and adverse cytogenetics had similar outcomes as patients with wild-type NPM1, FLT3-ITDneg/low AML with regard to risk for death, experiencing an event and risk for relapse.
“This international collaborative study clearly shows that cytogenetic abnormalities are important determinants of outcome in [NPM1-mutated], FLT3-ITDneg/low AML,” Angenendt and colleagues wrote. “Most importantly, patients with NPM1 mutations with the FLT3-ITDneg/low genotype and adverse-risk cytogenetics share the same unfavorable prognosis as their counterparts with [wild-type] NPM1 and should be classified accordingly.” – by John DeRosier
Disclosures: Angenendt reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Jonathan M. Gerber, MD
Molecular testing and subsequent risk stratification are now routine in the management of AML, substantially adding to longstanding cytogenetic-based risk factors. However, there remain significant gaps in our knowledge of the interactions of these various risk factors and, thus, uncertainty persists as to how best manage patients with complex molecular and/or cytogenetic profiles.
Angenendt and colleagues nicely address the confusion surrounding NPM1 mutations in combination with abnormal cytogenetics, particularly adverse cytogenetic risk features.
In this large patient series, adverse cytogenetics appeared to dictate prognosis — irrespective of NPM1 mutational status — fully neutralizing any beneficial impact of an NPM1 mutation. The presence of an adverse karyotype in combination with an NPM1 mutation yielded a roughly twofold increased risk for death among older patients (age 60 or older) and — even more profoundly — a nearly fourfold increased risk for death among younger patients (< 60 years).
That said, the allelic ratios for NPM1 mutations were not reported; thus, it is not known whether the NPM1-mutant population represented only a minor fraction or the dominant clone of the total leukemic burden. Indeed, the NPM1-mutant clone and the adverse karyotype clone may have been exclusive populations.
Outcomes did not support allogeneic HSCT for patients with NPM1 mutations who lacked coincident adverse risk features, as nonrelapse mortality canceled out the survival benefit of HSCT. Allogeneic HSCT in first complete remission did confer an OS benefit to younger patients with NPM1-mutated AML who harbored adverse cytogenetics, although the cumulative incidence of relapse was not significantly different for these patients. Of note, the number of transplanted patients with NPM1 mutations and adverse cytogenetics was small, and there was no randomization for HSCT, so these conclusions should be interpreted with caution.
These data suggest that NPM1 mutations confer a favorable risk only in the absence of any adverse risk features. In fact, among patients with NPM1-mutant AML, the presence of adverse cytogenetics seems to yield an even worse prognosis than a concomitant FLT3-ITD mutation. As a result, patients with adverse cytogenetic features — regardless of NPM1 mutational status — should be managed as unfavorable, with consideration of allogeneic HSCT in first complete remission. That said, the outcomes of patients with adverse cytogenetics remain quite poor with intensive chemotherapy and even allogeneic HSCT, emphasizing the need for novel therapeutic approaches for these patients.
Read more about
Click Here to Manage Email Alerts