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.