Treatment results of children with the diagnosis of acute myeloid leukemia. Is trisomy 21 an important cause of mortality?

INTRODUCTION

Pediatric acute myeloid leukemia (AML) is the second most common pediatric leukemia characterized by clonal expansion of abnormally differentiated myeloid lineage blasts, accounts for 20% of childhood leukemia. The use of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) improve outcomes of pediatric AML.^1,2 Associations between cytogenetic changes and patient outcomes have since shifted the focus toward cytogenetic classification to distinguish between types of AML and allow for risk-stratified therapy.³ Risk stratification based on genetic abnormalities is a critical determinant for predicting outcomes of the pediatric AML.⁴

Advances in supportive care have also contributed to improving the survival rates of patients with pediatric AML. In the literature, results were reported that complete remission (CR) rates of 80-90%, relapse rates of 30-40%, event-free survival (EFS) rates of 50%, and overall survival (OS) rates of nearly 70%.² Much of this improvement is due to better supportive care, optimization of intensity of treatment including employment of HSCT in 1st complete remission (CR1) and better salvage in 2nd complete remission (CR2). Whilst the majority of children (>90%) achieve CR, the relapse rate (RR) in CR1 remains unacceptably high at 30-35%.^3,4 In this study, it was aimed to present the clinical features and treatment results of patients diagnosed with pediatric AML in the last three years.

METHODS

This is an observational retrospective clinical study; patients who received chemotherapy and HSCT with the diagnosis of AML in Istanbul Yeni Yuzyil university Gaziosmanpasa hospital pediatric hematology and oncology Service between 2018 and 2020 were evaluated. Age, gender, AML subtype, genetic characteristics, laboratory findings, treatment responses, febrile neutropenia and fungal infection frequencies of the patients were evaluated. The AML-Berlin Frankfurt Munster (AML-BFM) 2004 protocol or AML-BFM 2013 protocol was applied to the first diagnosis patients according to the year of diagnosis and the experience of the physician. Bone marrow (BM) aspiration results on day 28 and day 42 in response to treatment were evaluated. In the AML BFM 2004 protocol, the 15^th day bone marrow aspiration results were also evaluated. Two cycles of FLAG-IDA (fludarabine, ARA-C, idarubicin) regimen was used in relapsed or refractory AML. Treatment response was evaluated with the results of BM aspiration before chemotherapy courses. M1: <5% blast in assessment of BM; M2: 5-20% blast; M3: evaluated as> 20% blast. HSCT indications, pre-transplant bone marrow aspiration results, transplant type, donor characteristics, and post-transplant complications of patients who underwent HSCT were recorded. Post-treatment status and treatment success rates of the patients were evaluated. The results obtained were evaluated in the light of the literature.

The patients included in the study consisted of patients with a diagnosis of AML. Patients with other leukemia types were not included in the study. Patients who were lost at the stage of diagnosis or before treatment could be started were excluded from the study. Because of an observational retrospective data evaluation, the data were evaluated with the consent of the relatives of the patients and permission from the institution management.

Statistical analysis

Case characteristics, including diagnosis, age, and gender were calculated. The incidence as a percentage of datas were calculated. All analyses were conducted with the use of Statistical Product and Service Solutions (SPSS 22.0) software.

RESULTS

Of the 46 patients included in the study, 26 were female and 20 were male. The mean age was 8.2±5.75 years. The general characteristics of the patients are given in Table 1. The most common subtypes were AML M4 and M5 with 9 patients. AML M2 subtype followed with 7 patients. Translocation t (8;21) was detected in 6 patients diagnosed with AML M2 in morphological and immunophenotypic examination. In 6 patients diagnosed with acute promyelocytic leukemia (APL), t (15;17) translocation was detected and all-trans retinoic acid (ATRA) treatment was applied. Four patients were Down syndrome-myeloid leukemia (DS-ML). While monosomy 7 and monosomy 8 were detected in 3 patients, 5 patients had FLT3-ITD mutations. Two of the patients with FLT3-ITD mutations were continuing their chemotherapy before HSCT, while the response of one to induction treatment was good, the response of the other patient on day 28 and day 42 was found to be poor. One patient is being followed up in remission after HSCT, and when the treatment process was examined, it was seen that the bone marrow examination on the 28^th day was M2. Two of 5 patients with FLT3-ITD mutations died as a result of relapse and refractory disease after HSCT. It was observed that these patients had poor responses to induction therapy and were compatible with M2 bone marrow before HSCT.

Hyperleukocytosis was detected in 18 patients. Diagnostic laboratory mean values of the patients are shown in Table 2. At the first admission, 23 of the patients had bleeding symptoms. Two patients did not have hepatosplenomegaly on physical examination. Gingiva hypertrophy was present in four patients, according to available information. While one patient had chloroma, two patients had central nervous system involvement. Treatment-related myleoid leukemia developed in 4 of the patients. Two patients developed myeloid leukemia while being followed up with a diagnosis of myelodysplastic syndrome (MDS) and Fanconi aplastic anemia (FAA). In the treatment, AML-BFM 2004 protocol was applied in 8 of the patients, while the AML-BFM 2013 protocol was given to 24 patients. FLAG-IDA chemotherapy protocol was applied to 14 patients with relapse or poor response to treatment. When all patients were evaluated, a total of 201 febrile neutropenia attacks were observed. Suspicious or definite proven Aspergillus infection was detected in 20 of the patients.

HSCT was applied to twenty seven of the patients. In order of frequency, HSCT indications were relapse AML, high risk mutations, poor response to treatment, and secondary AML. In 4 patients who underwent HSCT, M2 bone marrow was detected before transplantation. After HSCT, twenty three patients had febrile neutropenia, four had BK virus hemorrhagic cystitis, and four had cytomegalovirus (CMV) reactivation. Veno-occlusive disease (VOD) developed in two patients. When graft versus host disease is evaluated in patients who underwent HSCT; skin involvement in 8 patients, gastrointestinal system involvement in 4 patients, pulmonary involvement in one patient, and liver involvement in one patient.

Considering the final status of the patients, 29 patients are being followed up in remission and 11 patients are still being treated. The characteristics of six patients who were lost due to disease progression or treatment complications are shown in Table 3.

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; BKV-HC: BK virus-hemorrhagic cystitis; CMV: Cytomegalovirus; CNS: Central nervous system; FAA: Fanconi aplastic anemia; GVHD: Graft-versus-host disease; HSCT: Hematopoietic stem cell transplantation; MDS: Myelodysplastic syndrome; MFD: Matched familial donor; MSD: Matched sibling donor; MUD: Matched unrelated donor; VOD: Veno-occlusive disease.

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; LDH: lactate dehydrogenase; MCV: Mean corpusculer volume

AML: Acute myeloid leukemia; HSCT: Hematopoietic stem cell transplantation; MDS: Myelodysplastic syndrome

DISCUSSION

AML in children consists of a heterogenous group; and it is classified according to morphology using the French-American-British (FAB) classification. Immunophenotyping is used in order to determine AML FAB subtypes. The minimal diagnostic requirements in childhood AML are morphology with the cytochemistry, immunophenotyping, karyotyping, fluorescence In situ hybridization (FISH), and specific molecular genetics in the bone marrow. AML is characterized by specific chromosomal abnormalities, especially translocations. Also, these abnormalities help to both classify subtypes as well as to serve as important prognostic markers.⁵ In the study by Song et al.⁴ patients with adverse cytogenetics showed significantly poorer outcomes than those with favorable cytogenetics, including t (8;21) or inv (16). Mutations frequently seen in AML were determined at the rate of 20% for t (8;21) and inv (16), and 12% for t (15;17). MLL rearrangement seen especially under the age of 2 is seen at 18%.⁶ In this study, favorable cytogenetics features such as t (8;21), inv (16), t (15;17) were found in 13 patients.

Acute promyelocytic leukemia is one of the subtypes accountings for 5%-10% of pediatric AML. Children with APL have the highest cure rates of AML, with an average overall survival (OS) 95% and event-free survival (EFS) of 90% due to the combined use of ATRA and arsenic trioxide (ATO). Increased bleeding risk must be closely monitored and aggressively treated with transfusion support in APL. Serious bleeding events were reported in 15% of pediatric APL patients with up to 10% of children in literature.^7-10 With close follow-up of coagulation values and early treatment, no fatal situation due to bleeding was observed in patients. Differentiation syndrome following the treatment with ATRA and ATO was reported in 20% of children. Patients develop fever, respiratory distress, hypotension, and renal failure due to excessive numbers of maturing myeloid cells leading to endothelial damage and edema. The early recognition and treatment of differentiation syndrome is important to prevent fatalities, and patients should be closely monitored after the initiation of therapy. Steroids and hydroxyurea are used for differentiation syndrome, leukapheresis is not recomended as it does not affect outcomes and subjects’ patients to unnecessary bleeding risk.^11,12 One of the patients developed respiratory distress, deterioration in liver function tests and fever on the second day of ATRA treatment. ATRA treatment was discontinued and steroid therapy was started. ATRA treatment was continued after the symptoms disappeared in the patient whose complaints regressed with steroid therapy. No additional findings were observed during follow-up.

Different inherited clinical conditions have been defined that predispose individuals to develop AML, constitutional chromosomal abnormalities constitute a large part of them. Trisomy 21, monosomy 7, and trisomy 8 are important causes of AML development, and trisomy 21 has a different significance, especially considering its prevalence in the population. In addition to this, children oncology group (COG) reported that presence of trisomy 21 was the primary risk factor for the development of leukemia and not associate with the presence of congenital anomalies.^13,14 In the study, when DS-myeloid leukemia patients were evaluated, 3 of 4 patients were lost due to DS-related additional comorbidities and chemotherapy adverse effects.

Association between FLT3-ITD and a high risk of relapse in childhood AML has been known from the recent studies.^15,16 One of the first reports in the literature showed that FLT3-ITDs were present in 15 of 91 childhood AML cases and were associated with an 8-year EFS estimate of only 7%.¹⁷ In this study, the results of multivariate analysis indicated that FLT3-ITD was the most important prognostic factor. Meshinchi et al reported the poor outcome of patients with FLT3-ITD in a study of 630 patients.¹⁶ Recent studies suggest that the outcome of these patients can be improved by HSCT.

Several genetic alterations in AML, including FLT3-ITD, are associated with constitutive activation of tyrosine kinases, aberrations in downstream signaling pathways, and a poor prognosis.^17,18 Therefore, sorafenib (tyrosine kinase inhibitor) is a potentially therapeutic option in AML. In a study; sorafenib, which inhibits multiple intracellular kinases, including FLT3, alone or in combination with cytarabine and clofarabine, in 12 children with refractory or relapsed leukemia. In this study, 7 days of treatment with single agent sorafenib decreased blast percentages in 10 of 11 patients with AML.¹⁹ Sorafenib is currently being evaluated in newly diagnosed patients with AML and FLT3-ITD in the St Jude AML08 and the COG AAML1031 trials. FLT3-ITD mutation was found in 5 patients. Although one of these patients was after HSCT, 2 of them had relapsed AML and were lost due to progressive disease during treatment. Sorafenib was used in these patients.

The limitation of this study was that it was a single-center study. We think that multicenter and larger number of patient analyzes can give more precise results.

CONCLUSION

In conclusion; when a general evaluation is made to results, parallel to the literature, FLT3-ITD mutation, relapse disease, and pre-HSCT M2 bone marrow were found to be highly correlated with progressive disease and mortality. In addition to these, patients with Down syndrome also had a high mortality due to additional comorbidity and drug adverse effects. Therefore, we want to emphasize that Down syndrome is an important and risky situation because of comorbidities and mortality rate in AML.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

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