Acute myeloid leukemia secondary to acute B lymphoblastic leukemia treated with maintenance therapy in a child: A case report

Abstract Background Acute lymphoblastic leukemia (ALL) has the highest incidence among childhood hematologic cancers. Exposure to certain cytotoxic therapies for ALL is correlated with a higher risk of secondary malignancies. Case We report a rare case of a 6‐year‐old girl being diagnosed with secondary acute myeloid leukemia (AML) during her maintenance phase of treatment for ALL with TEL‐AML1 fusion gene, approximately 17 months after the primary diagnosis. Conclusion This case indicates that we should recognize the increased risk of secondary AML for pediatric ALL patients with TEL‐AML1 fusion gene if multiple alkylating drugs and inhibitors for topoisomerase II are included in induction chemotherapy.


| INTRODUCTION
Secondary acute myeloid leukemia (sAML) refers to AML whose occurrence is associated with antecedent hematologic disorders (AHDs) or therapies. Among the existing childhood hematologic cancers, acute lymphoblastic leukemia (ALL) has the highest incidence.
With multi-agent induction, consolidation, and maintenance chemotherapy, children with ALL enjoy a reasonably good survival. [1][2][3][4] However there are reports of sAML attributable to cytotoxic treatment protocol. 5,6 sAML usually occurs with a latency period after the treatment of primary malignancies. Amid the first remission of ALL, the cumulative risk of developing sAML was reported to be 1.6% and 4.7% at three-year and six-year follow-up, respectively. In addition, patients having T-cell and 11q23 chromosomal abnormalities were reported to possess a higher chance of developing sAML. 7 Therapy related AML (t-AML) is of two distinct types: type one develops following treatment with alkylating drugs (e.g., cyclophosphamide, melphalan etc.); type two develops following treatment with topoisomerase II inhibitors (e.g., etoposide, doxorubicin etc.). t-AML secondary to Topoisomerase II inhibitors is generally associated with chromosomal abnormalities, most including KTM2A at 11q23 and RUNX1 at 21q22. 8 We presented a rare case of a 6-year-old girl with sAML while she was receiving maintenance therapy for B-ALL approximately 17 months after the primary diagnosis. This was the first report that pedatric ALL patients with TEL1-AML fusion gene had rapid leukemia lineage switching. It indicated that intensive induction and consolidation combined with alkylating drugs and topoisomerase II inhibitors may enhance the risk of secondary malignancies in pediatric TEL1-AML positive ALL patients with a favorable prognosis. The patient provided written informed consent for the publication of the study.

| DISCUSSION
ALL has the highest incidence among childhood hematologic cancers.
Treatment of ALL includes induction, consolidation, and maintenance therapy, which lasts for no less than 2 years after diagnosis. The cure rate is approximately 90%. There is a risk of developing secondary leukemia following chemotherapy in some patients. The occurrence of sAML can be associated with either AHDs or therapeutic drugs including alkylating drugs and topoisomerase II inhibitors, or radiotherapy. Patients who develop sAML following alkylating drug treatment often have partially or completely deleted chromosome 5 or chromosome 7 and previous myelodysplasia with a 5-to 7-year mean latent period; while patients with topoisomerase II inhibitorassociated sAML often have chromosomal abnormalities involving chromosome band 11q23 such as KTM2A gene, [9][10][11] and develop leukemia with a relatively short latency period of 1-2 years. This patient used idarubicin and cyclophosphamide during the treatment protocol, and developed sAML 17 months after primary diagnosis. Idarubicin, a second-generation anthracycline, has been demonstrated to be effective in treating AML and recurrent ALL. [12][13][14] But in acute promyelocytic leukemia treated with idarubicin had a higher incidence of secondary cancers compared with nonchemotherapy regimen. 15 We speculate that combined with topoisomerase inhibitors and alkylating agents such as idarubicin and cyclophosphamide, which are used in induction therapy for adults, may promote this short-term disease transformation in children. 16 For now, clonal hematopoiesis with driver mutations in combination with the features of cytostatic drug metabolism and DNA damage repair are considered a comprehensive marker of an increased risk of t-AML.
So, for treating primary pediatric ALL patients, we may avoid to combine topoisomerase inhibitors with alkylating agents such as idarubicin and cyclophosphamide in induction and consolidation therapy.
It is reported that some cases of childhood leukemia arise prenatally. 17 Chromosomal translocations, especially those generate the TEL-AML1 fusion gene have been detected in peripheral blood at birth ages prior to the onset of leukemia, supporting that leukemogenesis includes multiple steps. This patient had the TEL-AML1 fusion gene at the onset of ALL, but consistently negative during maintenance therapy and onset of secondary AML, which suggested that the sAML may have little correlation with TEL-AML1 fusion gene. 18 Individuals affected by Fanconi anemia or aplastic anemia are more likely to develop sAML. According to a recent study, mutations in GATA2, RUNX1, TP53, and CEBPA genes were detected in families exhibiting an unexplained high incidence of AML, implying familial susceptibility to AML. 19,20 Human CSMD1 is a putative tumor suppressor gene. It is expressed at high levels in the cerebellum, cerebral cortex, white matter of brain, and testis, and low levels in the placenta, thyroid gland, and breast. Loss of alleles, aberrant methylation levels, and mutations of CSMD1 gene have been implicated in various cancers, including head and neck, breast, lung, liver, colorectal, prostate, and skin cancers, oral squamous cell carcinoma, chronic myeloid leukemia, and recurrent ALL. [20][21][22][23] In this patient, there was no CSMD1 gene mutation at the initial diagnosis of ALL and was detected at the onset of sAML, and the CSMD1 gene mutation in this patient may contribute to the development of sAML. 24 It was speculated that chemotherapy drugs such as idarubicin and cyclophosphamide may lead to the mutation of CSMD1 gene which resulted in the development of sAML.

| CONCLUSION
In summary, pediatric sAML rarely occurs while the patient is being treated for primary TEL1-AML positive ALL with a favorable prognosis. The early-onset sAML in our patient may be caused by the intensive induction therapy with alkylating agent and topoisomerase II inhibitor she received and the presence of a Writingreview and editing (equal).