MRD Monitoring in Younger Patients With NPM1 Mutated AML Clinically Relevant

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Researchers have confirmed 2 clinically relevant minimal residual disease checkpoints in younger patients with acute myeloid leukemia.
Researchers have confirmed 2 clinically relevant minimal residual disease checkpoints in younger patients with acute myeloid leukemia.

ORLANDO ­– Researchers have confirmed 2 clinically relevant minimal residual disease checkpoints, after double induction therapy and after completion of therapy, in younger patients with acute myeloid leukemia (AML) with nucleophosmin (NPM1mut) mutations, a study presented at the American Society of Hematology (ASH) 57th Annual Meeting has shown.1

Because NPM1mut represent one of the most frequent gene mutations in AML and can be used for monitoring minimal residual disease, researchers sought to determine clinically relevant checkpoints and a cut-off value to identify patients with a high risk for relapse.

For the study, researchers analyzed data from 499 NPM1mut patients aged 18 to 60 years with AML. Patients had been treated with double induction therapy with idarubicin, cytarabine, and etoposide with or without ATRA or gemtuzumab ozogamicin, or 1 cycle of daunorubicin plus cytarabine followed by 1 to 4 cycles of high-dose cytarabine, autologous stem cell transplantation, or allogeneic stem cell transplantation.

Results showed that NPM1mut transcript levels before treatment were not associated with clinical characteristics like age, blood counts, and gene mutations, with the exception of lactate dehydrogenase (LDH) level (P = .006). Researchers also found that pretreatment NPM1mut transcript levels did not affect event-free, relapse-free, or overall survival.

The study demonstrated that after double induction therapy, the cumulative incidence of relapse at 4 years was 10% for patients with lower NPM1mut transcript levels vs 45% for those with higher NPM1mut transcript levels (P < .0001), which translated to a significant improvement in overall survival in patients with lower transcript levels (P = .001). After completion of therapy, 4-year cumulative incidence of relapse was 13% and 56%, respectively (P < .00001), which similarly translated to a significantly better overall survival with lower incidence of relapse (P < .00001).

“Reduction of NPM1mut transcript levels and achievement of RQ-PCR negativitiy significantly correlated with FLT3ITD/DNMT3A mutation status, especially in triple-positive patients,” Silke Kapp-Schwoerer, MD, of the University Hospital of Ulm Department of Internal Medicine III in Ulm, Germany, said during her presentation. “Outcome of triple-positive patients compared to patients with NPM1mut solely is significantly worse.”

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Multivariate analysis showed that NPM1mut transcript levels were significantly associated with shorter remission duration and shorter overall survival.

In addition, researchers determined that exceeding a cut-off value of > 200 transcript levels was highly predictive of disease relapse and found that concurrent mutations of FLT3ITD and DNMT3A significantly impact the kinetics of NPM1mut transcript levels.

“For interpretation of NPM1mut MRD monitoring, FLT3ITD and DNMT3A mutation status should be considered,” Dr Kapp-Schwoerer concluded.

Reference

  1. Kapp-Schwoerer S, Corbacioglu A, Gaidzik VI, et al. Clinical relevance of minimal residual disease monitoring in NPM1 mutated AML: a study of the AML Study Group (AMLSG). Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL.

ORLANDO ­– Researchers have confirmed 2 clinically relevant minimal residual disease checkpoints, after double induction therapy and after completion of therapy, in younger patients with acute myeloid leukemia (AML) with nucleophosmin (NPM1mut) mutations, a study presented at the American Society of Hematology (ASH) 57th Annual Meeting has shown.1

Because NPM1mut represent one of the most frequent gene mutations in AML and can be used for monitoring minimal residual disease, researchers sought to determine clinically relevant checkpoints and a cut-off value to identify patients with a high risk for relapse.

For the study, researchers analyzed data from 499 NPM1mut patients aged 18 to 60 years with AML. Patients had been treated with double induction therapy with idarubicin, cytarabine, and etoposide with or without ATRA or gemtuzumab ozogamicin, or 1 cycle of daunorubicin plus cytarabine followed by 1 to 4 cycles of high-dose cytarabine, autologous stem cell transplantation, or allogeneic stem cell transplantation.

Results showed that NPM1mut transcript levels before treatment were not associated with clinical characteristics like age, blood counts, and gene mutations, with the exception of lactate dehydrogenase (LDH) level (P = .006). Researchers also found that pretreatment NPM1mut transcript levels did not affect event-free, relapse-free, or overall survival.

The study demonstrated that after double induction therapy, the cumulative incidence of relapse at 4 years was 10% for patients with lower NPM1mut transcript levels vs 45% for those with higher NPM1mut transcript levels (P < .0001), which translated to a significant improvement in overall survival in patients with lower transcript levels (P = .001). After completion of therapy, 4-year cumulative incidence of relapse was 13% and 56%, respectively (P < .00001), which similarly translated to a significantly better overall survival with lower incidence of relapse (P < .00001).

“Reduction of NPM1mut transcript levels and achievement of RQ-PCR negativitiy significantly correlated with FLT3ITD/DNMT3A mutation status, especially in triple-positive patients,” Silke Kapp-Schwoerer, MD, of the University Hospital of Ulm Department of Internal Medicine III in Ulm, Germany, said during her presentation. “Outcome of triple-positive patients compared to patients with NPM1mut solely is significantly worse.”

Multivariate analysis showed that NPM1mut transcript levels were significantly associated with shorter remission duration and shorter overall survival. In addition, researchers determined that exceeding a cut-off value of > 200 transcript levels was highly predictive of disease relapse and found that concurrent mutations of FLT3ITD and DNMT3A significantly impact the kinetics of NPM1mut transcript levels.

“For interpretation of NPM1mut MRD monitoring, FLT3ITD and DNMT3A mutation status should be considered,” Dr Kapp-Schwoerer concluded.

Reference

1.     Kapp-Schwoerer S, Corbacioglu A, Gaidzik VI, et al. Clinical relevance of minimal residual disease monitoring in NPM1 mutated AML: a study of the AML Study Group (AMLSG). Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL.

 

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