Call for papers

alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol; 32:752-759. 17. Chi-Hang Wong, Gigi Lam, Connie Hui, Rachel C.T. Lam, K.W. Lo, Edwin P. Hui, Anthony T.C. Chan, Brigette B.Y. Ma (2021). In vivo evaluation of VEGF/ Ang-2 bispecific nanobody BI836880 in nasopharyngeal carcinoma (NPC). https://www.inoncology.com/events/ congresses/aacr-2021. Poster. 18. Yunsik Choi, Sanghyuk Lee, Kapyoul Kim, SooHyun Kim, Yeun-Jun Chung and Charles Lee (2018). Studying cancer immunotherapy using patient-derived xenografts (PDXs) in humanized mice. Exp. Mol. Med; 50:99 19. Yue Zhao,Timothy Wai Ho Shuen, Tan Boon Toh, Xue Ying Chan, Min Liu, Sue Yee Tan, Yong Fan et al. (2018). Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy. Gut; 67:1845–1854. 20. Zheng Hu, Jinxing Xia, Wei Fan, Jennifer Wargo and Yong-Guang Yang (2016). Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice. Oncotarget; 7:No. 64486459. 21. Breslin S, O’Driscoll L (2013). Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today. 18(5–6):240–9.

Acute Myeloid Leukemia Updates

Written by Dr. Rabiatul Basria S. M. N. Mydin1* (Ph.D) and Dr. Eman S. Algariri1,2 (MD) 1Oncological and Radiological Sciences Cluster, Advanced Medical and Dental Institute Universiti Sains Malaysia 13200, Pulau Pinang, Malaysia 2Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Hadhramout University, Mukalla, Hadhramout, Yemen. *Corresponding author email: rabiatulbasria@usm.my

In the last decade, the incidence of acute myeloid leukemia (AML) has increased worldwide. In Malaysia, AML represented the highest incidence and mortality rate among other leukemia type, as shown in Figure 1 (Global Health Data Exchange, 2019). AML is more common in adults, with a median age of 67 and around 30% of AML patients over 75 years. However, Pediatric AML is the fifth most common cancer in children and its prognosis is still poor compared to ALL, the most common type of leukemia in children (Chen et al., 2019). AML is characterized as a highly heterogeneous hematologic malignancy and is associated with the clonal expansion of immature (blast) myeloid precursors and disturbance of hematopoiesis in the bone marrow. Figure 1. Incidence and mortality rate of leukemia subtypes in Malaysia in 2019. Comparison of incidence and mortality rate between leukemia subtypes in Malaysia in 2019. AML: Acute myeloid leukemia, ALL: Acute lymphocytic leukemia, CML: Chronic myelogenous leukemia, CLL: Chronic lymphocytic leukemia. Data was obtained from Global health data exchange (2019).

Recently, the AML survival rate revealed certain improvements that were prominent across all age groups, except for the age group older than 70 years. From 2010 to 2017, the estimated 5-year survival rate was 65 %-70 % in childhood AML, 50-63 % in patients less than 40 years old, and 40% for patients aged 40-60 years old. The survival rate did not show any change among elderly AML patients, where the survival rate

remained just around 5% (Sasaki et al., 2021). Despite the higher AML survival rate among childhood AML, it is still less than the childhood ALL survival rate that reached 90% (Chen et al., 2019). Relapse is another big challenge in AML, which occurs in 40-50% of younger and the great majority of elderly patients (Thol & Ganser, 2020).

Survival rates for AML have improved in tandem with advances in molecular characterization and therapeutic strategy. AML mutations such as the FMS-like tyrosine kinase 3 (FLT3) that is found in around 30% of AML patients and the IDH mutations that happen in 15-20% of newly diagnosed AML patients are currently targeted with approved targeted therapy such as midostaurin and Ivosidenib, which when added to standard therapy results in improving the complete remission and survival rate of AML patients, especially for those with very poor prognosis (relapsed and refractory AML) and the elderly (Puccini et al., 2021; Wu et al., 2018). The therapeutic targets that have recently been approved for subgroups of AML are presented in Table 1. In summary, AML treatments is still a major medical challenge, especially for adult and elderly patients. Since AML has a complex etiology, multiple targeted therapies could be a promising therapeutic strategy to overcome the AML challenges. Further comprehensive studies on relapse, precision medicine and targeted therapy are critically needed better AML managements.

Acknowledgements

The authors would like to thank The Ministry of Higher Education Malaysia for sponsoring this work under the Fundamental Research Grant Scheme (FRGS) with Project Code: FRGS/1/2019/SKK15/USM/02/2.

References

1. Global health data exchange. (2019). GBD results tool. http://ghdx.healthdata.org/gbd-resultstool. 2. Chen, X., Pan, J., Wang, S., Hong, S., Hong, S., & He, S. (2019). The epidemiological trend of acute myeloid leukemia in childhood: a population-based analysis. Journal of Cancer, 10(20), 4824.

Drug Class Target Inclusion criteria

Midostaurin Tyrosine kinase inhibitor

Gilteritinib Tyrosine kinase inhibitor FLT3, KIT, PDGFRα/β, SYK, VEGFR1/2 Adult, newly diagnosed, untreated AML with FLT3 mutation 74.7 months in the midostaurin group vs. 25.6 months in the control group 8.2 months in the midostaurin group and 3.0 months in the control group 58.9% in the midostaurin group and 53.5% in the control group (7)

Highly specific FLT3 inhibitor Adult R/R AML with FLT-3 mutation Longer among the gilteritinib group than the chemotherapy group (9.3 months vs. 5.6 months 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group. 34% in the gilteritinib group and 15.3% in the chemotherapy group. (8,9)

Ivosidenib Small-molecule inhibitor

Venetoclax Small-molecule inhibitor

Gemtuzumab ozogamicin (GO) Monoclonal antibody CD33 transmembrane protein Newly diagnosed de novo adult AML patients 27.5 months in the GO group and 21.8 months in the control group longer for the GO group (median 17.3 months) than in the control group (median 9.5 months) No significant difference in the rate of CR in the GO group compared with the control group (12)

Mutated IDH1 Adult R/R AML with IDH1 mutation 9.0 months after follow-up 15.3 months - 24% (with 10.1 months median CRD) (10)

Bcl-2 > 65 years, newly diagnosed AML patients, ineligible for intensive chemotherapy 10.1-month in the venetoclax plus LDAC group vs. 5.5 months in the LDAC group - 54% in the venetoclax plus LDAC group vs. 11% to 19% in the LDAC group (11)

Out come

Median OS Median EFS CR Reference

3. Sasaki, K., Ravandi, F., Kadia, T. M., DiNardo, C. D., Short, N. J., Borthakur, G., ... & Kantarjian, H. M. (2021). De novo acute myeloid leukemia: A population‐based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results (SEER) database, 1980 to 2017. Cancer, 127(12), 2049-2061. 4. Thol, F., & Ganser, A. (2020). Treatment of relapsed acute myeloid leukemia. Current Treatment Options in Oncology, 21(8), 1-11. 5. Puccini, M., Pilerci, S., Merlini, M., Grieco, P., Scappini, B., Bencini, S., ... & Gianfaldoni, G. (2021). Venetoclax-Based Regimens for Relapsed/Refractory Acute Myeloid Leukemia in a Real-Life Setting: A Retrospective Single-Center Experience. Journal of Clinical Medicine, 10(8), 1684. 6. Wu, M., Li, C., & Zhu, X. (2018). FLT3 inhibitors in acute myeloid leukemia. Journal of hematology & oncology, 11(1), 1-11. 7. Stone, R. M., Mandrekar, S. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., ... & Döhner, H. (2017). Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. New England Journal of Medicine, 377(5), 454-464. 8. Perl, A. E., Martinelli, G., Cortes, J. E., Neubauer, A., Berman, E., Paolini, S., ... & Levis, M. J. (2019). Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. New England Journal of Medicine, 381(18), 1728-1740. 9. McMahon, C. M., & Perl, A. E. (2019). Gilteritinib for the treatment of relapsed and/or refractory FLT3-mutated acute myeloid leukemia. Expert review of clinical pharmacology, 12(9), 841-849. 10. Megías-Vericat, J. E., Ballesta-López, O., Barragán, E., & Montesinos, P. (2019). IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood and lymphatic cancer: targets and therapy, 9, 19. 11. Wei, A. H., Strickland Jr, S. A., Hou, J. Z., Fiedler, W., Lin, T. L., Walter, R. B., ... & Roboz, G. J. (2019). Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. Journal of Clinical Oncology, 37(15), 1277. 12. Lambert, J., Pautas, C., Terré, C., Raffoux, E., Turlure, P., Caillot, D., ... & Castaigne, S. (2019). Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica, 104(1), 113.

Malaysian Journal of Human Genetics

The Malaysian Journal of Human Genetics (MJHG) (eISSN: 2716-649X) is the official journal of Malaysian Node of the Human Variome Project and Malaysian Society of Human Genetics. The MJHG publishes high quality peer reviewed original research, case report, short report and review articles that covers all aspect of human genetics including molecular, clinical, pharmacogenetics, population genetics and functional genomics. MJHG is now indexed in MyJurnal and Google Scholar.