Clinical analysis of father and son both with acute leukemia and father with triple primary malignancies

Objective To investigate the pathogenesis and clinical characteristics of familial leukemia. Methods In October 2012 and December 2018, 2 patients with acute leukemia(AL) admitted to the Department of Hematology, Taizhou People′s Hospital were included in this study. Two patients were 34 and 65 years old, respectively. Routine blood examination, bone marrow cell morphology examination, chromosome karyotype analysis, leukemia cell immunotyping, minimal residual disease (MRD) detection and fusion gene detection were performed on the 2 patients. The clinical features, diagnosis and treatment of the patients were analyzed retrospectively. The procedure of this study is accordance with the requirement of the revised World Medical Association Declaration of Helsinki in 2013. Results ① Case 1 (the son) was admitted to the Department of Hematology, Taizhou People′s Hospital on October 23, 2012, due to " dizziness, fatigue, and sleep hyperhidrosis for 3 months" . After admission, the result of bone marrow cell morphology revealed hyper-cellularity with 38.5% of lymphoblasts and prolymphocytes, and immunophenotype analysis of leukemia blasts showed that the neoplastic cells were positive for CD34, human leukocyte antigen (HLA) -DR, CD10, CD20 and CD19. No abnormal karyotype was observed in cytogenetic analysis. The patient was diagnosed with B-cell lymphoma/leukemia. Subsequently, 4 cycles of R+ hyper-CVAD (rituximab+ cyclophosphamide+ vindesine+ epirubicin+ dexamethasone)/R+ MA (rituximab+ methotrexate+ cytarabine) chemotherapy were performed, combined with 8 intrathecal injections (methotrexate combined with dexamethasone or cytarabine). Bone marrow cell morphology revealed complete remission (CR), and MRD were negative during this period of time. On April 26, 2013, autologous hematopoietic stem cell transplantation (auto-HSCT) was performed, and rituximab was used for consolidation treatment twice since then. On November 8, 2013, the result of bone marrow cell morphology reported hypercellularity with 35.0% lymphoma cells, which indicated relapse of the disease. The patient achieved CR again after VDCLP (vindazine+ daunorubicin+ cyclophosphamide+ papeurase+ prednisone) and CA (cyclophosphamide+ cytarabine) chemotherapy, but still relapsed. On March 12, 2014, the patient received haploid hematopoietic stem cell transplantation (haplo-HSCT) and then achieved CR. On April 3, 2015, the result of bone marrow cell morphology showed obviously proliferation of karyote cells with 22.0% of prolymphocyte, and immunophenotype of leukemia blasts was positive for CD34, CD22, CD19, CD33 and HLA-DR. No abnormal karyotype was observed in cytogenetic analysis. These findings led to the diagnosis of B-cell acute lymphocytic leukemia (B-ALL). The patient was then given salvage treatment of decitabine combined with VLP (vintelide+ pemetrex+ dexamethasone) chemotherapy, and CR was achieved with the MRD ratio of 0.13%. Multiple regimens of chemotherapy were given subsequently. On January 27, 2016, the patient was treated with CIOLP (cyclophosphamide+ vindesine+ mitoxantrone+ dexamethasone+ pemetrexase) chemotherapy, which caused grade Ⅳ myelosuppression and led to severe infection afterwards. Efficacy was poor despite of supportive care, and the patient died on February 20, 2016. ② Case 2 (the father) was admitted to Taizhou People′s Hospital for " abdominal bloating" in July 2001. Endoscopic biopsy was performed, which indicated poorly differentiated adenocarcinoma. A total gastrectomy was performed subsequently. In April 2018, the patient was admitted to Jiangsu Province Hospital for " painless gross hematuria" . Bladder occupied lesions was observed in CT. Then the patient underwent radical cystectomy with orthotopic ileal neobladder, in which the pathological examination showed high grade papillary urothelial carcinoma of the bladder. In November 2018, the patient received postoperative examinations, including a blood routine test in which myeloblasts were inspected, therefore the patient was transfered to the Department of Hematology, Taizhou People′s Hospital for further diagnosis. Proliferation of granulocyte with 19.0% of myeloblasts was observed in bone marrow cell morphology, and the diagnosis of myelodysplastic syndrome (MDS)-excess blasts (EB) 2 was made. On December 26, 2018, the result of bone marrow cell morphology revealed 26.0% of myeloblasts, and these primitive cells were positive for CD7, CD34, CD13, CD33, CD117, CD15, CD64, myeloperoxidase (MPO), HLA-DR by immunophenotype analysis. Normal karyotype was indicated through cytogenetic analysis, and results of fluorescence in situ hybridization (FISH) showed 86% of trisomy cen8 and 85% of TP53 deletion. Thus, the patient was diagnosed as acute myeloid leukemia (AML)-M2. Induction chemotherapy of decitabine combined with HA (homoharringtonine+ cytarabine) was given on December 28, 2018. On January 30, 2019, the result of bone marrow cell morphology showed 7.0% of myeloblasts which suggested partial remission (PR). On February 13, 2019, the patient was treated with an additional induction therapy of decitabine combined with IA (demethoxydaunorubicin+ cytarabine). It is indicated that CR was achieved based on the result of bone marrow cell morphology, performed on March 23, 2019, which showed slightly reduced proliferation of karyote cells with 1.0% of myeloblasts. Thereafter, consolidation chemotherapy of IAG (demethoxydaunorubicin+ cytarabine+ granulocyte colony-stimulating factor) was performed on March 25, 2019, and April 27, 2019, respectively. Result of bone marrow cell morphology indicated CR and negative MRD during this stage. HA chemotherapy was implemented on June 10, 2019, followed by relapse of the disease on July 19, 2019, which was manifested by 25.0% of myeloblasts observed in bone marrow cell morphology. Re-induction chemotherapy of decitabine combined with IA was given on July 20, 2019, and by August 8, 2019, bone marrow cell morphology hasn′t been reexamined. Conclusions Familial leukemia is mainly induced by genetic factors. Patients usually suffer from low remission rate, as well as high probability of relapse. The overall survival is generally short. This conclusion is limited to the clinical analysis of 2 cases, and it requires to expand sample size for further study and verification. Key words: Leukemia; Heredity; Chromosomal instability; Familial leukemia; Multiple cancer; Retrospective study