Managing the chromosomal subtypes of AML

02 Jul 2021

Acute myeloid leukemia (AML) is a heterogenous disease characterized by chromosomal variability. Typically, patients with the core binding factor AML (CBF-AML) subtype have a better prognosis than those with cytogenetically normal AML (CN-AML). On the other hand, patients with complex/monosomal karyotype AML (CK/MK-AML) have the worst prognosis among all AML subtypes. Despite having varied prognosis between each subtype, all AML subtypes are conventionally treated with the same treatment paradigm of induction and consolidation. Afterwards, AML patients would receive either close observation or hematopoietic stem-cell transplantation (HSCT) during first complete remission (CR).

Per 2017 European LeukemiaNet (ELN) recommendations, AML patients are now stratified into favorable, intermediate or adverse risk groups based on their genetic abnormalities including NPM1, FLT3 and CEBPA.1 However, a local study found that the leukemia-free survival (LFS) and overall survival (OS) of AML patients between risk groups are similar when the 2017 ELN prognostic model was used (p=0.22 and 0.13, respectively).2 Instead, the incorporation of another gene mutation, DNMT3A, allowed a clear LFS and OS distinction between each risk group (both p<0.0001).2 “When treating AML in Hong Kong, you really have to consider DNMT3A as an adverse risk group,” commented Prof. Leung, Yu-Hung Anskar.

With a more detailed stratification strategy, a more personalized treatment can now be given to patients in the first-line setting. For young and fit patients, Prof. Leung stated that the treatment goal is to reduce relapse and prolong survival. Where midostaurin plus chemotherapy is indicated for FLT3-mutated AML patients, gemtuzumab ozogamicin (GO) plus chemotherapy is also an option for AML in the first-line setting. However, Prof. Leung noted that GO has only demonstrated benefit among patients with favorable or intermediate risks and should be prescribed with care.3

In old and unfit patients, the treatment goal is shifted towards the induction of durable response as AML is unlikely to be cured. For these patients, GO monotherapy and glasdegib plus low-dose cytarabine can be considered. For those with therapy-related AML, CPX-351 can be chosen instead. Ivosidenib monotherapy in IDH1-mutated AML, venetoclax plus HMA and oral azacitidine as maintenance therapy are also the approved treatment options for old and unfit AML patients in the firstline setting. Of note, venetoclax is associated with a significant composite CR of 66.4% and an OS improvement of 34% when compared to azacitidine alone.4 “Importantly, 30-40% of these patients can survive in remission in 3 years, which is much better than what we can offer in best supportive care,” commented Prof. Leung.

For patients with relapsed/refractory AML (rrAML), the treatment goal is to induce a durable response and bridge towards HSCT. For patients with FLT3-mutated AML, gilteritinib monotherapy and quizartinib monotherapy are indicated. However, quizartinib is only approved in Japan and can only be used on a named-patient basis. Otherwise, GO monotherapy, ivosidenib monotherapy for IDH1-mutated AML and enasidenib for IDH2-mutated AML are also available for patients with rrAML.

Despite the availability of multiple treatment options, Prof. Leung commented that certain unmet medical needs remain for FLT3- mutated AML patients especially in those who are old and unfit. Similarly, patients with heavily pre-treated rrAML and TP53- mutated CK/MK-AML would require better treatment options for disease control in the future.

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