Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine-containing chemotherapy and stem cell transplantation in selected genetic high-risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%–10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity.

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Pediatric AML: From Biology to Clinical Management

Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes.

/pdf/genetic-predisposition-to-myelodysplastic-syndrome-and-acute-24sewntazt.pdf

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hypomethylating agents (azacitidine and decitabine) in AML patients are presented. Novel hypomethylating agent (guadecitabine) and experimental DNMT inhibitors in AML are also discussed. In summary, hypermethylation of tumour suppressors mediated by DNMT1 or DNMT3B contributes to the progression and severity of AML (except MLL-AF9 and inv(16)(p13;q22) AML for DNMT3B), while mutation affecting DNMT3A represents an early genetic lesion in the pathogenesis of AML. In clinical trials of AML patients, expression of DNMTs is downregulated by hypomethylating agents while the clinical response predictive roles of DNMT biomarkers remain unresolved. Finally, nucleoside hypomethylating agents have continued to show enhanced responses in clinical trials of AML patients, and novel non-nucleoside DNMT inhibitors have demonstrated cytotoxicity against AML cells in pre-clinical settings.

https://journals.sagepub.com/doi/pdf/10.1177/1177271919846454

Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia.

DNA-hypomethylating agents are a viable treatment option for AML/myelodysplastic syndrome (MDS) relapse after allograft by upregulating Ags on blasts before DLI. Seventy-two patients with relapsed AML (n=62), MDS (n=8) and other myeloid neoplasms (n=2) after allograft were treated with low-dose 5-azacytidine and, if feasible, DLI. Patient characteristics: median age 62 years (range 20–75), 42% with adverse cytogenetics, 82% not in remission at transplant and 83% received fludarabine-based reduced-toxicity conditioning. Median duration from transplant to 5-azacytidine was 289 days (range 59–2133). Response criteria: CR, temporary disease control or treatment failure. A median of 2.7 courses (range 1–10) were administered; 65 out of 72 patients also received DLI (41 already before 5-azacytidine). Ten patients developed acute GVHD and two succumbed to treatment-related sepsis. CR rate was 9.7% (in two patients lasting >5 years), 44% had temporary disease control (median duration 71 days, range 31–380). Median survival from 5-azacytidine was 108 days, 21 patients proceeded to subsequent transplant. In multivariate analysis, peripheral blood blasts <1% were predictive of longer OS (P=0.03). Taken together, long-term remissions can be induced by this well-tolerated outpatient treatment, particularly in patients without peripheral blood blasts.

5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft

In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n = 35) or molecular relapse (n = 1) of acute myeloid leukemia (AML, n = 29) or myelodysplastic syndrome (MDS, n = 7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2 DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10 months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (± 6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure.

Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI—a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group

Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2.5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.12268

William Blum

Papers

Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults