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Improved AML prognosis with NPM1-positive FLT3-ITD-negative genotype contingent upon patient age
The presence of NPM1 mutations without FLT3-internal tandem duplication was associated with favorable prognosis in patients with acute myeloid leukemia aged 55 to 65 years, according to study findings.
However, this mutation status was not linked to favorable prognosis in patients older than 65 years.
The NPM1–positive and FLT3-internal tandem duplication (ITD)–negative genotype has been associated with favorable classifications in younger patients with AML. However, it was unclear whether the genotype was associated with a similar benefit in older patients, according to study background.
Fabiana Ostronoff
Fabiana Ostronoff, MD, of the clinical research division at Fred Hutchinson Cancer Research Center, and colleagues evaluated data from 156 patients with AML who were aged at least 55 years (median age, 60 years; range, 55-83) who received intensive chemotherapy on Southwest Oncology Group trials. Researchers observed NPM1 mutations in 33% of the patients and FLT3-ITDs in 24%.
In the entire cohort, the complete remission rate was 62%, 2-year OS was 31% and 2-year RFS was 32%.
Multivariable analyses indicated older age, unfavorable cytogenetics and presence of FLT3-ITDs were significantly linked to worse OS and RFS.
Researchers then divided patients into two cohorts that included those aged 55 to 65 years and those aged 65 years or older. Patients in the older-age cohort displayed lower rates for 2-year OS (19% vs. 39%; P < .001) and 2-year RFS (19% vs. 38%; P = .007), and a higher 1-year relapse rate (71% vs. 35%; P = .001) compared with younger patients.
The researchers observed the NPM1–positive/FLT3-ITD–negative genotype in 17% of the younger cohort and 26% of the older cohort. A greater proportion of patients with this genotype aged 55 to 65 years achieved 2-year OS compared with those without the genotype (70% vs. 32%; P ˂ .001). Further, this genotype was associated with significantly greater rates for 2-year OS in the younger cohort compared with the older cohort (70% vs. 27%; P ˂ .001). Among patients older than 65 years, the NPM1–positive/FLT3-ITD–negative genotype was only associated with a marginal survival benefit (27% vs. 16%).
Results of a multivariable analysis indicated the NPM1–positive/FLT3-ITD–negative genotype was independently associated with improved OS for those aged 55 to 65 years (HR = 0.2; 95% CI, 0.07-0.55) but not those older than 65 years (HR = 0.91; 95% CI, 0.39-2.1).
To confirm their findings, the researchers evaluated data from an independent cohort of 1,258 patients with AML who were treated on UK National Cancer Research Institute/Medical Research Council trials. Patients older than 65 years with the NPM1–positive/FLT3-ITD–negative genotype displayed significantly lower rates for 2-year OS (P < .001) and RFS (P < .001) compared with the younger cohort.
Analyses of 743 patients with cytogenetically normal AML from both cohorts again suggested the prognostic significance of the NPM1–positive/FLT3-ITD–negative genotype remained statistically different in the two age groups (P = .032).
Researchers acknowledged a lack of information regarding the use of allogeneic stem cell transplantation as a limitation of their study.
“The findings indicate that NPM1–positive/FLT3-ITD–negative genotype remains a favorable risk factor for patients aged 55 to 65 years but should not be considered a favorable risk factor for patients aged [older than] 65 years, at least not for those treated with standard induction followed by conventional consolidation,” Ostronoff and colleagues concluded. “… We propose that patients with AML aged [older than] 65 years with NPM1–positive/FLT3-ITD–negative genotype should not be classified as better risk. Moreover, patients aged [older than] 65 years with this genotype should be counseled about their overall poor prognosis and, if appropriate, be considered for novel clinical trials or even allogeneic stem cell transplantation in first complete remission.” – by Cameron Kelsall
Disclosure: Ostronoff reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
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Acute myeloid leukemia in elderly patients poses a significant clinical challenge, one that is expected to become increasingly more common as the population ages. Outcomes are quite poor for these patients, and the optimal management of elderly AML remains unclear, particularly for patients with good performance status and favorable risk factors. Ostronoff and colleagues nicely address this issue in older patients with AML characterized by mutated NPM1 without a FLT3-ITD mutation, a genotype that denotes favorable risk disease in younger patients with AML.
Consistent with prior studies, the older patients in this report fared worse than their younger counterparts; but interestingly, patients aged 55 to 65 years with the NPM1-positve/FLT3-ITD–negative genotype actually enjoyed outcomes comparable to those previously reported for younger patients with AML with the same risk profile. The favorable impact of the NPM1-positve/FLT3-ITD–negative genotype did not extend to patients aged older than 65 years old, and this age-related difference in outcomes was not explained by differences in performance status, other known cytogenetic/molecular abnormalities, induction chemotherapy regimen or treatment-related mortality.
Presumably, the incidence of acquired, background genetic and epigenetic lesions increases with age, and these defects may negate any beneficial impact of mutations such as NPM1 in elderly patients with AML. Relatively few patients aged older than 65 years are cured of AML by intensive chemotherapy, and existing cytogenetic/molecular risk factors offer little to no guidance in treating this population. Better therapies are desperately needed for these patients, along with better prognostic markers to appropriately personalize treatment. Whenever possible, elderly patients with AML should be encouraged to participate in clinical trials.