The hallmarks of hematopoietic stem cell transplantation for pediatric acute myeloid leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) has significantly improved the outcome of children with high-risk (HR) acute myeloid leukemia (AML). Implementing allogeneic HSCT depends on numerous factors, including adverse cytogenetics, molecular abnormalities, poor response to first-line treatment, or relapsed or primary refractory disease. In HR AML, allogeneic HSCT is considered to be the consolidation strategy of choice in first complete remission (CR1) and offers the best chance of cure for patients with relapsed disease. Advances in donor/recipient typing, conditioning regimens, graft-versus-host-disease (GvHD) management, and supportive care have contributed to this improvement in overall-and transplant-outcome. This review will comprehensively discuss indications for HSCT and its modalities in pediatric AML by examining past, current, and future strategies for disease- and response-related stratification. We will examine the key importance of low/negative measurable residual disease (MRD) before transplantation and discuss conditioning regimens and graft variables, as well as novel approaches to harness the graft-versus-leukemia (GvL) effect, including targeted immunotherapy. The review will also address toxicities associated with HSCT, GvHD prophylaxis, and the management of treatment failure. Ultimately, this review seeks to inform clinical practice and highlights how improved outcomes have been achieved through the collective efforts of international study groups.

Fig. 1. Factors affecting eligibility to and outcome of allogeneic HSCT in children with acute myeloid leukemia.

Schematic representation of the variable influencing eligibility criteria, donor and graft selection, conditioning regimens, and graft-versus-host-disease prophylaxis choices in children with AML.

Fig. 2. Factors indicating eligibility for HSCT in newly diagnosed pediatric AML.

High-risk features in pediatric AML are defined by cytogenetic and molecular abnormalities, as well as poor response to treatment as indicated by measurable residual disease: ¹Karyotypic Abnormalities: Complex karyotype (≥3 aberrations including at least one structural abnormality), excluding cases with recurrent translocations; monosomal karyotype, such as monosomy 7 or deletion 5q (-7, -5/del(5q)). ²Chromosomal Translocations: t(16;21)(p11;q22)→FUS::ERG; t(9;22)(q34;q11.2) → BCR::ABL1; t(6;9)(p22;q34) → DEK::NUP214; t(7;12)(q36;p13) → MNX1::ETV6; inv(3)(q21q26)/t(3;3)(q21;q26) → RPN1::MECOM; inv(16)(p13q24) → CBFA2T3::GLIS2; t(5;11)(q35;p15.5) → NUP98::NSD1; t(11;12)(p15;p13) → NUP98::KDM5A; 12p abnormalities; 11q23/KMT2A rearrangements, including: t(4;11)(q21;q23) → KMT2A::AFF1; t(6;11)(q27;q23) → KMT2A::AFDN; t(10;11)(p12;q23)→KMT2A::MLLT10. ³Monogenic HSCT Classifiers: FLT3-ITD with an allelic ratio (AR) ≥ 0.5, either alone or in combination with other recurrent abnormalities or NPM1 mutations. ⁴Measurable Residual Disease (MRD): Multiparametric flow cytometry (MFD)-MRD ≥0.1% after first or second induction or (if MFC-MRD result is not available/ informative) blast count ≥5% at second induction. HR high-risk, KMT2A Histone-Lysin-N-Methyltransferase 2A, AFD Afadin, Adherents Junction Formation Factor, MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor, FUS RNA Binding Protein, ERG ETS transcription factor, BCR Breakpoint cluster region, ABL1 Abelson Murine Leukemia Viral Oncogene Homolog 1, DEK protoonko-gene, NUP nucleoporin, MNX1 Motor Neuron And Pancreas Homeobox 1, ETV6 ETS Variant Transcription Factor 6, RPN1 Ribophorin I, MECOM MDS1 And EVI1 Complex Locus, FLT3 FMS-like tyrosine kinase 3, ITD internal tandem duplication, NPM1 nucleophosmin 1, WT1 Wilms Tumor 1, CBFAT3 CBFA2/RUNX1 Partner Transcriptional Co-Repressor 3, GLIS2 GLIS Family Zinc Finger 2, NSD1 Nuclear Receptor Binding SET Domain Protein 1, KDM5A Lysine Demethylase 5A, MFC multiparametric flow cytometry, MRD measurable residual disease, MRD.

Fig. 3. To transplant or not to transplant in pediatric AML?

Retrospective analyses have demonstrated that HSCT in CR1 improves OS with reduced RR in high-risk and r/r pediatric AML patients. The prognostic significance of NR or MRD-positivity before HSCT, as well as the association of subsequent HSCT with poorer survival outcomes, has been confirmed by various study groups. Numeric details are provided below: ¹AML-BFM (2010-2012): 5-year pOS: 76% [183]; AIEOP-2002/01: 8-year pOS: 74% [205]. ²AML-BFM (2011-2012): CIR: 25.1% (SE 3.9), NR: 12.3% (SE 2.8) [183]; AIEOP-2002/01: CIR: 17% [205]. ³AML-BFM 2004/2012 and AML-BFM registry 2012: 5-year pOS 54.5%, SE = 4.4; COG (AAML0531 and AAML1031) (2013–2017): 5-year pOS 40%; 5-year pOS 24%, MRD⁺_, COG: 5-year pOS 41%, MRD⁻ [106]. ⁴BFM 2004/2012 and AML-BFM registry 2012: NR patients: 5-year pOS 26.7%, SE = 9.0 [106]. ⁵AML-SCT-BFM: CR1/CR2: 4-year pOS and pEFS 61 and 70%, CIR 22%, NRM 15% [107]. ⁶2-year pLFS: CR 33%, NR 19%, 8-year pLFS: CR 24%, NR, 10% [206]. 4-year pOS w HSCT: 31% w/o 3%, CIR and NRM at 4 years: 45% and 22% [177]. *Consider maintenance therapy. AML acute myeloid leukemia, AML-MRC AML-myelodysplasia-related changes, PIF primary induction failure, s/t-AML secondary/therapy-related AML, r/r AML relapsed/refractory AML, MRD measurable residual disease, CR complete remission, NR no response, BFM Berlin–Frankfurt–Münster Study Group, COG Children’s Oncology Group, HSCT hematopoietic stem cell transplant, OS overall survival, RR relapse rate, CIR cumulative incidence of relapse, SE standard error, LFS leukemia-free survival, NRM non-relapse mortality.

Fig. 4. Overview of treatment targets currently available or under development in acute myeloid leukemia.

Immunotherapy initiatives include ADC antibody (Abs)-drug conjugates, bispecific Abs, mAbs monoclonal Abs, CI checkpoint inhibitors, and cellular therapies (DLI donor lymphocyte infusion, CTL cytotoxic T lymphocytes, CAR chimeric antigen receptor approaches, NK natural killer, CIK cytokine-induced killer). Targeted therapies are summarized as RTK receptor tyrosine kinase inhibitors, BH3 mimetics selective small-molecule B-cell lymphoma 2 (Bcl-2) Homology 3, and inhibitors involved in protein degradation. WT1 Wilms tumor protein, PRAME preferentially expressed antigen in melanoma, ADGRE2 adhesion G protein-coupled receptor E2, FLT3 FMS‐like tyrosine kinase 3, TIM-3 T cell immunoglobulin and mucin-domain containing-3, GO gemtuzumab ozogamicin, PVEK pivekimab sunirine, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, PD-1 programmed cell death protein 1, XPO1 exportin 1, HDACs histone deacetylases, HMA DNA hypomethylating agents, BTK Bruton’s tyrosine kinase, JAK Janus kinase, CDK cyclin-dependent kinase, mTOR mammalian target of rapamycin, IDH isocitrate dehydrogenase, FOLR1 folate receptor alpha, MDM2 mouse double minute 2 homolog, PROTAC proteolysis targeting chimera.

Fig. 5. A Guide to personalized therapy: HSCT in pediatric AML.

The choice of donor and conditioning regimes for patients with an indication for allogeneic HSCT for pAML. Conditioning regimes are considered “reduced intensity/toxicity (RIC)” if the dose of Busulfan is less than 8 mg/kg PO or IV, Melphalan is less than 150 mg/m², total body irradiation (TBI) dose is ≤500 as a single dose, or 800 cGy administered as fractionated doses. Other regimens are considered myeloablative (MAC). pAML pediatric acute myeloid leukemia, HR high-risk, AML-MRC AML-myelodysplasia-related changes, s/t-AML secondary/therapy-related AML, r/r AML relapsed/refractory AML, MRD measurable residual disease, RD residual disease, CR complete remission, HSCT hematopoietic stem cell transplant, HLA human leukocyte antigen, MSD matched sibling donor (second choice in case of a minor child), MFD matched family donor, MUD matched unrelated donor, MMFD mismatched family donor, MMUD mismatched unrelated donor, BM bone marrow, PBSC peripheral blood stem cells, UCB umbilical cord blood, GvHD graft-versus-host disease, GvL graft-versus leukemia, CNI calcineurin inhibitor, MTX methotrexate, MMF mycophenolate mofetil, MAC myeloablative conditioning, RIC reduced intensity conditioning, Bu Busulfan, Cy Cyclophosphamide, Mel Melphalan, Treo Treosulfan, Flu Fludarabine, TT Thiotepa, (LD)-TBI (low dose) total body irradiation, Clo Clofarabine.