CASE DESCRIPTION
A 6-year-old Chinese male with no significant family history was admitted to the hematology department for a high fever of unknown origin and an abnormal blood test. He was diagnosed with HLH in the same department for lymph node swelling three years ago. Initial laboratory tests, including mutational analyses, were positive (TABLE 1). He was treated with VP16, steroids and cyclosporin. His symptoms improved, and he achieved complete remission in eight weeks and finished chemotherapy in twelve weeks. At an intermittent follow-up of 1 year after discharge, his symptoms had gone. However, he was lost to follow-up in the next two years. While three years later, he was readmitted for fever, anemia and leukocytosis. His laboratory tests showed a decreased HB level of 92 g/dL and WBC count of 105.4×109/mL (differential count: neutrophils 25%, lymphocytes 10%, metamyelocytes 6%, basophils 6%, myelocytes 20%, stab granulocyte18%, and blasts 3%). A bone marrow smear revealed myeloid hyperplasia without evidence of hemophagocytosis. Flow cytometry indicated that 81.5 % of leukocytes were positive for CD10, CD11, CD13, CD15, CD16, CD33, CD58 and CD64. Karyotyping of the bone marrow was positive for 46, XY, t (9; 22)(q34;q11). Polymerase chain reaction confirmed BCR-ABL (P210) positive. He was diagnosed with chronic phase CML, and an imatinib 400mg tablet was given once daily. At a follow-up appointment one month after discharge, his blood test showed that WBC count decreased to 9.02×109/L, and hematological, cytogenetic and molecular achieved complete remission in three months. He continues on imatinib now.
DISCUSSION
Patients with CML account for 2% to 3% of leukemia in children and adolescents6, 7. Secondary CML in children is rare and reported in a few cases, including Pineal germinoma, Langerhans cell, Diffuse large B-cell lymphoma, Nasopharyngeal carcinoma, B-ALL and AML8. Similarly, the development of secondary malignancies seems rare in HLH3. Here, we report a 9-year-old male with CML occurring three years following treatment for HLH, harboring de novo heterozygous UNC13D , LYST and ITK variant. To our knowledge, the first report of a child with HLH developing CML.
CML originates from abnormal multiple bone marrow stem cells; chromosomal aberrations result from an unfaithful repair of two DNA double-strand breaks by a random event9. Treatment-related CML (Tr-CML) is associated with chemotherapy, radiotherapy and immunotherapy, accounting for 3% of 452 CML cases10. VP16 is an essential cornerstone of the HLH-2004 protocol as one of the topoisomerase Ⅱ inhibitors; it could break the DNA chain, cause gene rearrangement, DNA damage and induce leukemia11. VP16-related second leukemia is related to many risk factors, including the cumulative dose higher than 3000 mg/m2, frequency of application (weekly or twice-weekly doses) and combined platinum agent in HLH12. The patient in our case with HLH received VP16 treatment weekly or twice-weekly; the cumulative dose of VP16 was 1380 mg/m2. So we speculate that the dose and frequency of VP16 seem to be an induced factor for secondary CML in our case.
Cytotoxic T lymphocytes and natural killer cells eliminate malignant cells that are dependent on cytotoxic granule-mediated killing; genetic defects in the cytolysis pathway are associated with malignant tumors13. Genetic deficiencies mediated cellular cytotoxicity pathways in HLH, including secretion of lymphocyte granule and expansion and T cells’ cytolytic capacity14. Without using known leukemogenic agents, one patient carrying a heterozygous UNC13D variant developed AML15. One patient with a heterozygous PRF1 variant progressed to primary aggressive DLBL16. STX11 gene mutations may be linked with secondary malignancies (MDS/AML)17. The patient with HLH harbored UNC13D , LYST and ITKheterozygous variants, but the significance of the gene variant is uncertain; functional assays of the gene were not performed. We speculate that the patient with genetic deficiencies of the cytolytic pathway may contribute to the development of CML through impairment of immune surveillance for malignant cells.
Patients with CML present typically with leukocytosis, a condition before the chronic phase defined as pre-clinical CML with a mildly or normal elevated WBC18. A 64-year-old female with refractory Primary Intraocular Lymphoma (PIOL) is incidentally-detected t(9;22)/BCR-ABL1-positive clones without leucocytosis of the CML chronic phase, Who accepted systemic treatment (chemoimmunotherapy and brain radiotherapy) for PIOL. After 48 months, she confirmed the diagnosis of the CML chronic phase19. The patient in our case reported without leucocytosis or blood/marrow feature of CML during staging for HLH. Unfortunately, the philadelphia chromosome or fusion gene study did not perform.
In conclusion, the risk of secondary leukemia in HLH patients is low but realistic. We believe that the screening of genetic background should strengthen if the initial conditions of HLH diagnosis permit; the dose and frequency of essential VP16 should be controlled. Secondary leukemia should be closely recognized in the late follow-up of chemotherapy for HLH.