Leukemia fusion gene analysis demonstrated positive EVI1 and negative IgH and TCR gene rearrangement. Furthermore, the patient was secondary, but not concurrent, ALL-L2 (former B type). Bone marrow examination was performed (12th of November 2012). Then, 1 cycle of VDCLP (vincristine, pirarubicin, cyclophosphamide, L-asparaginase, dexamethasone) chemotherapy was initiated on the 18th of October 2012. The results indicated that patient symptoms disappeared, and bone marrow and blood indexes recovered. Flow cytometry revealed that minimal residual disease (MRD) was negative, suggesting that patient response was CR1complete remission for the first time (CR1).
The patient was discharged from the hospital after 1 additional cycle of VDCLP consolidation therapy. Then, the patient received 14 cycles consolidation therapy, as follows: MTX + L-ASP (methotrexate, L-asparaginase), mitoxantrone, cytarabine (MA), cyclophosphamide, cytosine arabinoside, granulocyte stimulating factor (CAG) and VDCLP consolidation therapy. She received 6-MP and MTX as a maintenance treatment. The bone marrow of the patient was monitored. MRD was negative, and at present, ALL has been sustained at CR1 for more than 5 years.
3 Ethics statement
As a case report with written consent, our hospital does not require formal ethical approval. Written informed consent was obtained from the patient and her husband for publication of this case report.
Eighty-five percent of secondary leukemia patients receive alkylating agent treatment, and 65% of chemotherapy-induced leukemia is caused by melphalan, chlorambucil, and cyclophosphamide. The incidence of secondary leukemia in MM patients is 0.7% to 25%, which is 100 to 200 times higher than the incidence of leukemia in the normal population. Although acute leukemia-related treatment is common, ALL related treatment accounts for only approximately 12%. Among ALL related treatments, the use of alkylating agent accounted for only 0.5% to 1%. Recently, Tan et al reviewed a case series in which patients receiving lenalidomide maintenance therapy developed secondary ALL. Consistent with their report, the patient in the present study continued to take thalidomide as a maintenance treatment for many years, which may have caused the development of secondary ALL.
Lau et al reported 1 case of MM (IgG type) patient, who developed into earlier B-ALL at 3 years after autologous stem cell transplantation. A high dose of melphalan was used before transplantation, and the authors believed that the alkylating agent might have lead to gene instability in myeloma cells or lymphocytes, and the occurrence of acute leukemia. Ueda and Yamamoto reported an MM (IgD type) patient who received autologous stem cell transplantation. The patient transformed to ALL, which was related to the alkylating agent treatment after 1 year, in which high-dose melphalan was administered before transplantation. Chimerism studies were performed using Short tandem repeat (STR) makers, showing that leukemic cells in the bone marrow were derived from the donor. Igarashi and Chou reported a refractory MM patient who received allogeneic bone marrow transplantation, and developed ALL after 6 years. Short tandem repeat (STR) analysis suggested that leukemic cells in the bone marrow were derived from the donor.
In the present case, the MM (IgG type) patient was treated with multiple chemotherapy regimens, including alkylating agents, and developed ALL after 11 years. The cumulative amount of cyclophosphamide was 1.2 g and the sum of melphalan was 64 mg. Although the chromosome karyotype of the patient was abnormal after conversion into ALL and IgH gene rearrangement was negative, it could not be confirmed whether MM and ALL developed from different clones due to the lack of results on chromosomes and bone marrow examination at the onset of MM.
The prognosis of leukemia is related to many factors, such as leukemia fusion gene, chromosome, immunophenotyping, and age. Leukemia fusion gene EVI1 is an oncogene, and its expression is associated with the acute change of AML and chronic myeloid leukemia (CML). The lifespan of EVI1-positive patients is significantly shorter than that of EVI1-negative patients. It has been reported that chromosome translocation may lead to the activation of EVI1, and chromosomal abnormalities may be correlated to the use of alkylating agents. Alkylating agents with anti-tumor effects induce chromosome mutation, especially Chromosomal 5 and 7 abnormalities, leading to the activation of oncogene Ras and the inactivation of tumor suppressor gene p53, as well as uncontrolled cell proliferation and leukemia. Reddi and Lu reported that the abnormal Chromosome 5 and 7 were related to the use of multiple chemotherapy programs, especially melphalan and cyclophosphamide. Therefore, it could be speculated that the use of alkylating agents in this patient might be 1 cause of the abnormal EVI1 gene on Chromosome 5 and 7, leading to the occurrence of ALL.
CD34 is a marker of the poorly differentiated stage of acute leukemia cells, and a high CD34 expression indicates low tumor cell differentiation, less sensitivity to chemotherapy and poor prognosis. Myeloid antigen CD33 is an indicator of poor prognosis for ALL. The patient in the present case had a high expression of HLA-DR, CD34, and CD33, which suggested that the patient had ALL with poor prognosis. B-ALL can be divided into 4 hypotypes: Pro-B-ALL, c-ALL, Pre-B-ALL, and Mature-B-ALL. The CR rate of B-ALL and cell differentiation were negatively correlated. The remission rate of Pro-B-ALL was the highest, followed by c-ALL, Pre- B-ALL, and Mature-B-ALL. The patient in the present case was older than 50 years old, and developed secondary ALL, which was Pre-B-ALL with Chromosome 5 and 7 abnormalities and positive CD34 and EVI1 expression, all of which suggests poor prognosis. However, the patient reached complete remission after 1 cycle of VD-CLP chemotherapy, and no recurrence occurred after consolidation therapies with VDCLP MA, CAG, and other chemotherapy regimens. ALL (CR1) has been maintained for more than 5 years until now.
The present case suggests that we should pay attention to MM secondary to ALL and take proper measure of treatment.
This study was supported by the General Project Funds from the Health Department of Zhejiang Province (2015KYB264)
Conceptualization: Zhiying Zheng
Data collection and drafting of the original article: Tonglin Hu.
Development of the idea and editing of the final draft: Zhiying Zheng.
Development of the idea and the treatment plan: Wenbin Liu.
Formal analysis: Wenbin Liu.
Funding acquisition: Jianping Shen.
Investigation: Tonglin Hu, Jianping Shen, and Wenbin Liu.
Methodology: Wenbin Liu and Zhiying Zheng.
Project administration: Jianping Shen.
Project administration: Tonglin Hu, Jianping Shen, Wenbin Liu, and Zhiying Zheng.
Resources: Tonglin Hu, Jianping Shen, Wenbin Liu, and Zhiying Zheng.
Validation: Jianping Shen.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
acute lymphoblastic leukemia; multiple myeloma