Targeted Therapies for Pediatric AML: Gaps and Perspective

Overview

Journal Front Pediatr

Specialty Pediatrics

Date 2019 Dec 6

PMID 31803695

Citations 40

Authors

Annalisa Lonetti

Andrea Pession

Riccardo Masetti

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukemia (AML) is a hematopoietic disorder characterized by numerous cytogenetic and molecular aberrations that accounts for ~25% of childhood leukemia diagnoses. The outcome of children with AML has increased remarkably over the past 30 years, with current survival rates up to 70%, mainly due to intensification of standard chemotherapy and improvements in risk classification, supportive care, and minimal residual disease monitoring. However, childhood AML prognosis remains unfavorable and relapse rates are still around 30%. Therefore, novel therapeutic approaches are needed to increase the cure rate. In AML, the presence of gene mutations and rearrangements prompted the identification of effective targeted molecular strategies, including kinase inhibitors, cell pathway inhibitors, and epigenetic modulators. This review will discuss several new drugs that recently received US Food and Drug Administration approval for AML treatment and promising strategies to treat childhood AML, including FLT3 inhibitors, epigenetic modulators, and Hedgehog pathway inhibitors.

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References

Perl A, Altman J, Cortes J, Smith C, Litzow M, Baer M . Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017; 18(8):1061-1075. PMC: 5572576. DOI: 10.1016/S1470-2045(17)30416-3. View

Downward J . Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003; 3(1):11-22. DOI: 10.1038/nrc969. View

Kruger S, Ilmer M, Kobold S, Cadilha B, Endres S, Ormanns S . Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res. 2019; 38(1):268. PMC: 6585101. DOI: 10.1186/s13046-019-1266-0. View

Alqahtani A, Choucair K, Ashraf M, Hammouda D, Alloghbi A, Khan T . Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. Future Sci OA. 2019; 5(3):FSO372. PMC: 6426170. DOI: 10.4155/fsoa-2018-0115. View

Andersson A, Miller D, Lynch J, Lemoff A, Cai Z, Pounds S . IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia. 2011; 25(10):1570-7. PMC: 3883450. DOI: 10.1038/leu.2011.133. View

Campbell V, Copland M . Hedgehog signaling in cancer stem cells: a focus on hematological cancers. Stem Cells Cloning. 2015; 8:27-38. PMC: 4325629. DOI: 10.2147/SCCAA.S58613. View

Mueller D, Bach C, Zeisig D, Garcia-Cuellar M, Monroe S, Sreekumar A . A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007; 110(13):4445-54. PMC: 2234781. DOI: 10.1182/blood-2007-05-090514. View

Briscoe J, Therond P . The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013; 14(7):416-29. DOI: 10.1038/nrm3598. View

Zahler S, Bhatia M, Ricci A, Roy S, Morris E, Harrison L . A Phase I Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33+ Acute Myeloid Leukemia. Biol Blood Marrow Transplant. 2016; 22(4):698-704. DOI: 10.1016/j.bbmt.2016.01.019. View

10.

Mosse Y, Fox E, Teachey D, Reid J, Safgren S, Carol H . A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921). Clin Cancer Res. 2019; 25(11):3229-3238. PMC: 6897379. DOI: 10.1158/1078-0432.CCR-18-2675. View

11.

Bernt K, Zhu N, Sinha A, Vempati S, Faber J, Krivtsov A . MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell. 2011; 20(1):66-78. PMC: 3329803. DOI: 10.1016/j.ccr.2011.06.010. View

12.

Stein E, Garcia-Manero G, Rizzieri D, Tibes R, Berdeja J, Savona M . The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018; 131(24):2661-2669. PMC: 6265654. DOI: 10.1182/blood-2017-12-818948. View

13.

Lin C, Smith E, Takahashi H, Lai K, Martin-Brown S, Florens L . AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010; 37(3):429-37. PMC: 2872029. DOI: 10.1016/j.molcel.2010.01.026. View

14.

Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S . Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development. Cancer Cell. 2016; 30(1):92-107. PMC: 4945461. DOI: 10.1016/j.ccell.2016.05.008. View

15.

Wouters B, Delwel R . Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood. 2015; 127(1):42-52. DOI: 10.1182/blood-2015-07-604512. View

16.

Manara E, Bisio V, Masetti R, Beqiri V, Rondelli R, Menna G . Core-binding factor acute myeloid leukemia in pediatric patients enrolled in the AIEOP AML 2002/01 trial: screening and prognostic impact of c-KIT mutations. Leukemia. 2013; 28(5):1132-4. DOI: 10.1038/leu.2013.339. View

17.

Baker S, Zimmerman E, Wang Y, Orwick S, Zatechka D, Buaboonnam J . Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia. Clin Cancer Res. 2013; 19(20):5758-68. PMC: 3878304. DOI: 10.1158/1078-0432.CCR-13-1323. View

18.

Zwaan C, Soderhall S, Brethon B, Luciani M, Rizzari C, Stam R . A phase 1/2, open-label, dose-escalation study of midostaurin in children with relapsed or refractory acute leukaemia. Br J Haematol. 2018; 185(3):623-627. DOI: 10.1111/bjh.15593. View

19.

Gruber T, Gedman A, Zhang J, Koss C, Marada S, Ta H . An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell. 2012; 22(5):683-97. PMC: 3547667. DOI: 10.1016/j.ccr.2012.10.007. View

20.

Liang J, Wu Y, Chen B, Zhang W, Tanaka Y, Sugiyama H . The C-kit receptor-mediated signal transduction and tumor-related diseases. Int J Biol Sci. 2013; 9(5):435-43. PMC: 3654492. DOI: 10.7150/ijbs.6087. View