BCR-ABL1-positive acute lymphoblastic leukemia following successful treatment of acute promyelocytic leukemia: case report

Acute promyelocytic leukemia (APL) is currently considered a disease with a higher cure rate. And cases of secondary malignant tumors following successful APL treatment are rare. Here we described a rare case of a 29-year-old man who was treated for APL in 2019 and developed BCR-ABL1-positive acute lymphoblastic leukemia 2 years later. The patient responded well to tyrosine kinase inhibitors and chemotherapy, and achieved a molecular remission. Although APL usually has a good prognosis, the prognosis of its secondary malignancies is uncertain. There are no effective measures to prevent the occurrence of secondary tumors. Continuing to increase the monitoring frequency of laboratory tests, especially the molecular biomarkers, is essential for the diagnosis and treatment of secondary malignancies after the patients achieving complete remission.


Introduction
Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia (AML), which is designated as M3 subtype by French-American-British classification (Krause, 2000). It is characterized by a large number of abnormal promyelocytic cells in the bone marrow, accompanied with the typical chromosomal translocation t(15; 17) (q22; q12-21). As a result, a fusion gene of the promyelocytic leukemia (PML) gene and the retinoic acid receptor alpha (RARα) gene was formed by this chromosomal abnormality (Tan et al., 2021;Yilmaz et al., 2021). The application of target specific agents, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) with or without chemotherapy, is an internationally recognized standard therapy regime for APL patients (Ferrara et al., 2022;Jamy et al., 2022). Despite the success of ATRA and ATO in the treatment of patients with APL, secondary malignant tumors after complete remission (CR) of patients are worthy of attention. BCR-ABL1 fusion protein has two major isoforms, BCR-ABL1 (p190) and BCR-ABL1 (p210). And the BCR-ABL1 (p190) mainly occurs in acute lymphoblastic leukemia (ALL) patients (El Fakih et al., 2018;Adnan-Awad et al., 2021). Here, we reported a rare patient who developed secondary BCR-ABL1 (p190)-positive ALL following successful treatment of APL, and provide a literature review to summarize the characteristics of this subset of patients.

Case report
A 29-year-old man was admitted to our hospital for pancytopenia and clustered petechiae and ecchymoses on his left arm in January 2019. The laboratory features of the patient were shown in Table 1. Complete blood count at diagnosis showed white blood cell (WBC) counts 1.0 × 10 9 /L, hemoglobin level 95.0 g/L, platelet counts 20.0 × 10 9 /L. The bone marrow (BM) morphologic evaluation revealed 80.4% typical promyelocytes ( Figure 1A). Bone marrow pathology analysis showed a large number of blasts in the hematopoietic tissue ( Figure 1B). Immunophenotyping studies of BM cells revealed that the blasts expressed CD45dim, CD117, CD33, CD38, CD13, CD64 and CD15; no lymphoid antigens were expressed ( Figure 1C). Cytogenetic analysis result showed an abnormal karyotype of t(15; 17) (q22; q21) ( Figure 1D), and PML-RARa fusion gene was also detected in the patient's bone marrow cells. BCR-ABL1 fusion gene was not detected (Table 1). Normalized PML-RARα/ABL1 by qRT-PCR was 100% ( Figure 2E). The patient was diagnosed with APL, and evaluated as low risk, therefore he was treated by ATRA and ATO without chemotherapy for three courses. Then he treated with ATO alone for five courses due to ATRA intolerance. He achieved molecular remission (MR) 3 months after diagnosis and remained MR status.
In order to determine the specific time of the patient's secondary leukemia, we retrospectively tested his BM samples before November 2021, and the results showed that the positive expression of the BCR-ABL1 (p190) gene could be detected as early as August 2021. However, the patient's blood counts and bone marrow characteristics was normal at that time, and the PML-RARα gene was also negative, so the chemotherapy regimen was not changed.

Discussion
Since the combination of ATRA and ATO with or without chemotherapy, the survival rates of APL patients have been dramatically improved, exceeding 80%-95% Ferrara et al., 2022). However, some patients developed therapy-relate myeloid neoplasms (t-MN), such as therapyrelated AML or myelodysplastic syndrome (t-AML/MDS), with an incidence of 1%-9.8% (Gaut et al., 2018). And others developed secondary solid tumors (Huang et al., 2001;Au et al., 2007;Eghtedar et al., 2015). Secondary lymphoid neoplasms following treatment for APL were rare, and only four cases have been reported. One case developed precursor T-lymphocytic lymphoma (Szotkowski et al., 2009), two cases developed T-ALL (Liso et al., 1998;Bee et al., 2004), and one case developed early pre-B ALL with MLL/AF-1p fusion gene (Tsujioka et al., 2003). To our knowledge, the case we reported here was the first one who developed a secondary ALL with BCR-ABL1 fusion gene. The BCR-ABL1 fusion protein is sensitive to TKI, such as dasatinib (Shen et al., 2020), and the patient we reported achieved MR after 3 months of TKI and chemotherapy.
There are many hypotheses regarding the mechanism of secondary malignant neoplasms after successful treatment of APL. One of the hypotheses recognized by the majority of people is that APL induces therapy-related malignancies due to exposure to cytotoxic drugs during treatment (Wang Z. et al., 2019). While it is still unclear which drug may lead to it. In our case, the patient only received ATRO and ATO, without any other chemotherapy. ATRO and ATO maybe the possible reason. The underling possible mechanism is clonal selection. After exposure to APL treatment, the preexisting somatic mutation in hematopoietic stem cell may development to secondary neoplasms. The preexisting somatic mutations mainly tend to DNA damage, such as TP53 or PPM1D mutations (Martin et al., 2020). Moreover, there were also some cases about co-expression of t(15; 17) and other chromosome translocations, such as t(8; 21) (Uz et al., 2013). While the incidence of chromosomal rearrangements in addition to t(15; 17) was rare, and the role of additional translocations was still unclear. The current literature reviews tended to similar prognosis between additional abnormality and t(15; 17) alone. We detected the next-generation sequencing and chromosomal examination of this case before treatment, but no additional rearrangements or mutations were positive. The other possible reason is lineage switch. However, "Lineage switch" is a Frontiers in Pharmacology frontiersin.org term used to describe the phenomenon of acute leukemias that meet standard criteria for a specific lineage (either lymphoid or myeloid) at the time of initial diagnosis, but later switch to another lineage upon relapse, including changes in cell morphology, histology, and immunotype (Rossi et al., 2012). While in our case, we detected the fusion gene of BCR/ABL at initial diagnosis which was negative, so the possibility of lineage switch was small. Furthermore, the PML-RARα fusion gene in our case remained continuous negative, and neither the clinical symptoms nor laboratory data exhibited typical features of APL. We supposed that this secondary ALL might be related to therapy.
In conclusion, we reported a rare case of secondary BCR-ABL1 positive ALL after successful APL treatment. The patient responded well to TKI and chemotherapy and achieved a MR. Although APL usually has a good prognosis, the therapeutic effects of secondary malignant tumors are different. At present, there are no effective measures to prevent the occurrence of secondary tumors. For this subset of patients, the monitoring frequency of molecular biomarkers (not only PML-RARα) should be increased after receiving CR, in order to achieve the purpose of early detection and early treatment.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Ethics statement
Written informed consent was obtained from the participants/ patient for the publication of this case report, including the images and data in this article.

Author contributions
SF and HW performed the study concept and design. SF developed the methodology and wrote the paper. SF and ML acquired, analyzed and interpreted the data and performed the statistical analysis. HW reviewed and revised the paper. All authors contributed to the article and approved the submitted version.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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