IDH1/2,   TET2,  DNMT3A,  NPM1,  FLT3

Establishing precision medicine and novel molecular target therapies in Japanese patients with AML

The (HM)-SCREEN-Japan 01 program aims to establish precision medicine and novel molecular target therapies in Japanese patients with AML.

The prognosis of younger patients with acute myeloid leukemia (AML) has improved with the development of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and advancement in supportive care. However, in the majority of elderly patients with AML, the outcome of treatment remains poor. Therefore, less toxic targeted agents that can be used alone or in combination with other treatments are needed.

Kenichi Miyamoto and Yosuke Minami, from the Department of Hematology, National Cancer Centre Hospital East, Kashiwa, JP, report on the (HM)-SCREEN-Japan 01 program which investigates molecular targets in AML in Japan.1

Chromosomal gene abnormalities and genetic mutations in AML have become more apparent in recent years, along with the impact they have on treatment outcomes. The use of next-generation sequencing (NGS) for the analysis of AML has identified recurrent somatic mutation, with one study identifying one or more mutations in 96% of patients using comprehensive myeloid gene panels comprising of 111 genes.2

Whole genome or exosome sequencing has resulted in the identification of numerous genetic mutations that are involved in epigenetic control mechanisms in AML, such as ASXL1 or EZH2 involved in chromatin modification, IDH1/2, TET2 or DNMT3A involved in the methylation of DNA and histones, STAG2 or RAD21 involved in the formation of cohesin complexes during cell division, and SF3B1 or U2AF1 involved in RNA splicing.3,4

More than 10% of mutations observed in a study in 20135 were found to be only three genes, FLT3, NPM1 and DNMT3A. Race also plays a part in the frequency of each gene seen in a patient, as seen in the AML201 study performed by the JALSG analysing 55 genes in 197 Japanese patients with AML, where 5 gene mutations (FLT3, NPM1, DNMT3A, CEBPA, and KIT) were seen in more than 10% of patients. Therefore, it will be important to evaluate biologically homogenous populations in order to help develop optimized therapies.

Application of gene mutation analysis to allo-HSCT

Genetic mutation profiling prior to beginning therapy helps physicians decide whether proceed with post-remission allo-HSCT. Cytogenetic abnormalities are effective predictors and prognostic factors. A recent study6 that enrolled 872 patients younger than 60 years of age demonstrated that patients with NPM1 mutation without FLT3 internal tandem duplication (ITD) would not receive the clinical benefit allo-HSCT.

Another recent study7 looking at FLT3-ITD positive patients found that the clinical benefit of allo-HSCT was shown, but that the overall survival (OS) was not significantly different between FLT3-ITD positive and negative patients. RUNX1 mutations were analyzed in a group of 53 patients, where 32 attained complete remission (CR) after induction chemotherapy.8 Patients with RUNX1 mutations who underwent allo-HSCT had a better RFS in the analysis (52% vs 0%, P < 0.0001).

Survival of patients with TP53 alterations was inferior in multivariate analyses in comparison to patients with wild type TP53 (3-year OS, 3% vs 28%), with TP53 alterations being a poor prognosis factor in patients who received allo-HSCT in first CR.9

A number of mutations, such as IDH1/2 and ASXL1, have been found as effective prognostic factors, however, larger sample sizes are needed to examine the clinical significance of a combination of these mutations using comprehensive sequencing.

Application of gene mutation to novel agents

Small molecule FLT3 tyrosine kinase inhibitors (such as midostaurin and quizartinib) have been developed, and have resulted in better median OS in patients with FTL3-mutated AML, when used in combination with cytotoxic chemotherapy.10

For IDH1/2 mutations isocitrate dehydrogenase (IDH) inhibitors, have shown good efficacy.11 AG-120  acts against mutated IDH1 showed efficacy (33% CR; median duration of response, 8.2 months (95% CI)). More recently, ivosidenib has been approved by the FDA for the treatment of patients with IDH1-mutated AML in the relapsed/refractory setting.11

In a phase I study enrolling patients with relapsed/refractory (RR) AML investigating the effect of IDH305 on mutated IDH1R132, the overall response rate was found to be 33% (7/21).12 Enasidenib, a selective inhibitor of the mutant form of IDH2, has been approved by the FDA for patients with RR AML. More targeted agents are currently being developed and approved to be used in the RR AML setting. Should a targetable mutation be detected in older patients with AML, a frontline treatment with a targeting agent, which is less toxic than intensive chemotherapy, should be considered for future clinical trials.

Necessity of mutation profiling

With the majority of elderly patients with AML, intensive chemotherapy only prolongs life for a few months when compared with palliative care. The long-term survival rate of elderly patients with AML has remained around 10—25%, and the standard treatment may not be sufficiently effective in this group of patients.

Genetic mutation profiling with performed at high quality and with swift turnaround times could influence the prognosis of elderly patients with newly diagnosed AML, as physicians would be able to make informed decisions regarding treatment options. However, most studies on genetic mutations in elderly patients with AML have been conducted in western countries where the genetic profile is likely to be different to comparable Asian populations. The availability of data in elderly Japanese patients with AML is scarce.

HM-SCREEN-Japan

Hematologic malignancies (HM)-SCREEN-Japan is a genetic sequencing project (UMIN 000035233) conducted by the National Cancer Center Hospital to develop effective drugs against AML, and to facilitate the rapid introduction of new diagnostic techniques. The comprehensive genome profiling assay (FoundationOne®Heme, F1H) was evaluated. F1H provides a comprehensive genetic profile that applies NGS to identify somatic genomic alterations. Patient’s enrolled need to have histologically confirmed newly diagnosed AML, be elderly and unfit for standard treatment. Also, the specimens provided have to be fit for genetic analysis

Estimating the frequency of each leukemia gene alteration is the primary focus, with the secondary outcome to evaluate the association between each leukemia genome mutation and clinicopathological characteristics or prognosis.

Conclusion

The data from studies looking at genetic mutations in AML could help to shape prognosis through better testing of targeted treatment options for elderly patients with AML. The HM-SCREEN-Japan program aims to help identify and treat targetable mutations in elderly Japanese patients with AML However, further large scale studies in biologically homogenous populations are needed to reach these objectives.

References
  1. Miyamoto K., & Minami Y. Precision medicine and novel molecular target therapies in acute myeloid leukemia: the background of hematologic malignancies (HM)-SCREEN-Japan 01. International journal of clinical oncology. 2019 May 20. DOI: 1007/s10147-019-01467-1
  2. Papaemmanuil E., et al. Genomic classification and prognosis in acute myeloid leukemia. New England Journal of Medicine. 2016 Jun 9. 374(23):2209-21. DOI: 1056/NEJMoa1516192
  3. Ley T.J., et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008 Nov. 456(7218):66. DOI: 1038/nature07485
  4. Naoe T. & Kiyoi H. Gene mutations of acute myeloid leukemia in the genome era. International journal of hematology. 2013 Feb 1. 97(2):165-74. DOI: 1007/s12185-013-1257-4
  5. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New England Journal of Medicine. 2013 May 30. 368(22):2059-74. DOI: 1056/NEJMoa1301689
  6. Schlenk R.F., et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. New England Journal of Medicine. 2008 May 1. 358(18):1909-18. DOI: 1056/NEJMoa074306
  7. Bornhäuser M., et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. 2007 Mar 1. 109(5):2264-5. DOI: 1182/blood-2006-09-047225
  8. Gaidzik V.I., et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. Journal of Clinical Oncology. 2011 Feb 22. 29(10):1364-72. DOI: 1200/JCO.2010.30.7926
  9. Schlenk R.F., et al. The value of allogeneic and autologous hematopoietic stem cell transplantation in prognostically favorable acute myeloid leukemia with double mutant CEBPA. Blood. 2013 Aug 29. 122(9):1576-82. DOI: 1182/blood-2013-05-503847
  10. Stone R.M., et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. New England Journal of Medicine. 2017 Aug 3. 377(5):454-64. DOI: 1056/NEJMoa1614359
  11. DiNardo C.D., et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study. 2017 Dec 7.130:725.
  12. DiNardo C.D., et al. A phase I study of IDH305 in patients with advanced malignancies including relapsed/refractory AML and MDS that harbor IDH1R132 mutations. 2016 Dec 1. 128(22):1073.
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