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Randomized Controlled Trial
. 2014 May 20;32(15):1586-94.
doi: 10.1200/JCO.2013.52.3480. Epub 2014 Apr 7.

Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia

Friederike Pastore  1 , Annika Dufour  2 , Tobias Benthaus  2 , Klaus H Metzeler  2 , Kati S Maharry  2 , Stephanie Schneider  2 , Bianka Ksienzyk  2 , Gudrun Mellert  2 , Evelyn Zellmeier  2 , Purvi M Kakadia  2 , Michael Unterhalt  2 , Michaela Feuring-Buske  2 , Christian Buske  2 , Jan Braess  2 , Maria Cristina Sauerland  2 , Achim Heinecke  2 , Utz Krug  2 , Wolfgang E Berdel  2 , Thomas Buechner  2 , Bernhard Woermann  2 , Wolfgang Hiddemann  2 , Stefan K Bohlander  2 , Guido Marcucci  2 , Karsten Spiekermann  2 , Clara D Bloomfield  2 , Eva Hoster  2
Affiliations
Randomized Controlled Trial

Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia

Friederike Pastore et al. J Clin Oncol. .

Abstract

Purpose: Cytogenetically normal (CN) acute myeloid leukemia (AML) is the largest and most heterogeneous cytogenetic AML subgroup. For the practicing clinician, it is difficult to summarize the prognostic information of the growing number of clinical and molecular markers. Our purpose was to develop a widely applicable prognostic model by combining well-established pretreatment patient and disease characteristics.

Patients and methods: Two prognostic indices for CN-AML (PINA), one regarding overall survival (OS; PINAOS) and the other regarding relapse-free survival (RFS; PINARFS), were derived from data of 572 patients with CN-AML treated within the AML Cooperative Group 99 study (www.aml-score.org).

Results: On the basis of age (median, 60 years; range, 17 to 85 years), performance status, WBC count, and mutation status of NPM1, CEBPA, and FLT3-internal tandem duplication, patients were classified into the following three risk groups according to PINAOS and PINARFS: 29% of all patients and 32% of 381 responding patients had low-risk disease (5-year OS, 74%; 5-year RFS, 55%); 56% of all patients and 39% of responding patients had intermediate-risk disease (5-year OS, 28%; 5-year RFS, 27%), and 15% of all patients and 29% of responding patients had high-risk disease (5-year OS, 3%; 5-year RFS, 5%), respectively. PINAOS and PINARFS stratified outcome within European LeukemiaNet genetic groups. Both indices were confirmed on independent data from Cancer and Leukemia Group B/Alliance trials.

Conclusion: We have developed and validated, to our knowledge, the first prognostic indices specifically designed for adult patients of all ages with CN-AML that combine well-established molecular and clinical variables and that are easily applicable in routine clinical care. The integration of both clinical and molecular markers could provide a basis for individualized patient care through risk-adapted therapy of CN-AML.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Definition of PINAOS and PINARFS. biCEBPA, biallelic CEBPA mutation; ECOG, Eastern Cooperative Oncology Group performance status; FLT3-ITD+, presence of an internal tandem duplication of the FLT3 gene; HiR, high risk; IntR, intermediate risk; LowR, low risk; NPM1+, mutation in the nucleophosmin gene; OS, overall survival; PINA, prognostic index in cytogenetically normal acute myeloid leukemia; RFS, relapse-free survival.
Fig 2.
Fig 2.
Outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML) according to the new prognostic indices in the German AML Cooperative Group (AMLCG) cohort. (A) Overall survival (OS) according to the prognostic index for CN-AML for OS (PINAOS). (B) Relapse-free survival (RFS) according to the prognostic index for CN-AML for RFS (PINARFS). The hazard ratios (HRs) were corrected for overfitting; see Data Supplement. For patient selection, see Data Supplement. In the AMLCG cohort, the median PINAOS score was 4.5 (range, 2.1 to 6.3), and the median PINARFS score was 2.5 (range, 0.8 to 4.0). CR, complete remission; HiR, high risk; IntR, intermediate risk; LowR, low risk; PINA, prognostic index in cytogenetically normal acute myeloid leukemia.
Fig 3.
Fig 3.
Outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML) according to the new prognostic indices stratified by age in the German AML Cooperative Group (AMLCG) cohort. (A) Overall survival (OS) according to the prognostic index for CN-AML for OS (PINAOS) in patients younger than 60 years old. (B) OS according to the PINAOS in patients ≥ 60 years old. (C) Relapse-free survival (RFS) according to the prognostic index for CN-AML for RFS (PINARFS) in patients younger than 60 years old. (D) RFS according to the PINARFS in patients ≥ 60 years old. In patients younger than 60 years old, the median PINAOS score was 3.9 (range, 2.1 to 5.6), and the median PINARFS score was 2.2 (range, 0.8 to 3.7). In patients ≥ 60 years old, the median PINAOS score was 5.0 (range, 3.0 to 6.3), and the median PINARFS score was 2.9 (range, 1.2 to 4.0). CR, complete remission; HiR, high risk; HR, hazard ratio; IntR, intermediate risk; LowR, low risk; PINA, prognostic index in cytogenetically normal acute myeloid leukemia.
Fig 4.
Fig 4.
Outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML) according to the new prognostic indices among European LeukemiaNet (ELN) genetic groups in the German AML Cooperative Group (AMLCG) cohort. (A) Overall survival (OS) according to the prognostic index for CN-AML for OS (PINAOS) in patients in the ELN favorable genetic group. (B) OS according to the PINAOS in patients in the ELN intermediate-I genetic group. (C) Relapse-free survival (RFS) according to the prognostic index for CN-AML for RFS (PINARFS) in patients in the ELN intermediate-I genetic group. CR, complete remission; HiR, high risk; HR, hazard ratio; IntR, intermediate risk; LowR, low risk; PINA, prognostic index in cytogenetically normal acute myeloid leukemia.
Fig 5.
Fig 5.
Validation of the prognostic indices for cytogenetically normal acute myeloid leukemia (CN-AML) for overall survival (OS; PINAOS) and relapse-free survival (RFS; PINARFS) in an independent data set of patients with CN-AML from the Cancer and Leukemia Group B. (A) OS according to the PINAOS. (B) RFS according to the PINARFS. In the validation cohort, the median PINAOS score was 4.3 (range, 1.7 to 6.9), and the median PINARFS score was 2.0 (range, 0.6 to 4.0). CR, complete remission; HiR, high risk; HR, hazard ratio; IntR, intermediate risk; LowR, low risk.
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References

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