Late relapse in acute myeloid leukemia (AML): clonal evolution or therapy-related leukemia?

Musa Yilmaz,Sanam Loghavi,Tapan Kadia,Elias Jabbour,Koichi Takahashi,Zeev Estrov,Latasha Little,Curtis Gumbs,Xingzhi Song,Gautam Borthakur,Andrew Futreal,Naveen Pemmaraju,Jianhua Zhang,Carlos Bueso-Ramos,Farhad Ravandi,Nicholas Short,Guillermo Garcia-Manero,Feng Wang,Hagop Kantarjian

doi:10.1038/s41408-019-0170-3

Musa Yilmaz, Sanam Loghavi + Show 17 more

Open Access

https://doi.org/10.1038/s41408-019-0170-3

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Abstract

Late relapse, defined as relapse arising after at least 5 years of remission, is rare and occurs in 1–3% of patients with acute myeloid leukemia (AML). The underlying mechanisms of late relapse remain poorly understood. We identified patients with AML who achieved remission with standard induction chemotherapy and relapsed after at least five years of remission (n = 15). Whole exome sequencing was performed in available bone marrow samples obtained at diagnosis (n = 10), remission (n = 6), and first relapse (n = 10). A total of 41 driver mutations were identified, of which 11 were primary tumor-specific, 17 relapse-specific, and 13 shared (detected both in primary and relapsed tumor samples). We demonstrated that 12 of 13 shared mutations were in epigenetic modifier and spliceosome genes. Longitudinal genomic characterization revealed that in eight of 10 patients the founder leukemic clone persisted after chemotherapy and established the basis of relapse years later. Understanding the mechanisms of such quiescence in leukemic cells may help designing future strategies aimed at increasing remission duration in patients with AML.

Highlights

A majority of the patients with newly diagnosed acute myeloid leukemia (AML) achieve complete remission (CR) with intensive chemotherapy
Bone marrow (BM) samples collected from patients with late relapse (n = 15) at diagnosis, CR, and at first relapse were analyzed by whole exome sequencing (WES)
Clinical characteristics Among 1962 patients with AML who received induction chemotherapy, 1188 (61%) achieved remission; 243 (20%) were alive and in remission for at least 5 years and 15 (6%) of these relapsed during follow-up

Summary

Introduction

A majority of the patients with newly diagnosed acute myeloid leukemia (AML) achieve complete remission (CR) with intensive chemotherapy. Arbitrarily defined as any relapse occurring after 5 years of remission, have been reported in 1–3% of the patients with AML1–3. Most cases of late relapse are associated with a normal karyotype[2] or lack typical cytogenetics abnormalities observed in therapy-related AML4. This raises the question whether these cases are true late relapses or they are associated with prior exposure to chemotherapy. If these are true late relapses, understanding such prolonged quiescence of AML may provide further insights into developing superior strategies for treating these patients

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