Letter to the editor
Hemophagocytic lymphohistiocytosis
(HLH) is a life-threatening disease characterized by acute onset,
critical condition, and high mortality rate1. Since
the adoption of the HLH protocol, mortality rates associated with HLH
have markedly decreased2. As survival rates increase
in HLH, some individuals who initially had HLH subsequently develop
long-term secondary leukemia, such as secondary acute myeloid
leukemia(AML), secondary acute lymphoblastic leukemia (ALL) and
secondary myelodysplastic syndromes(MDS)3-5.
However, Chronic Myelogenous Leukemia (CML) is not reported as a common
secondary leukemia in HLH. CML accounts for 2% to 3% of leukemia cases
in the pediatric and adolescent population6, 7.
Secondary CML in children is rare and has been reported in a few cases,
including pineal germinoma, langerhans’cell histiocytosis(LCH), diffuse
large B-cell lymphoma(DLBCL), nasopharyngeal carcinoma(NPC), B-ALL
and AML8. In this study, we present the case of a
patient who developed CML approximately two years post-completion of HLH
treatment.
A 6-year-old Chinese male with no significant family history, was
admitted to the hematology department due to a high fever of unknown
origin and an abnormal blood test. Initial laboratory tests, including
de novo heterozygous UNC13D, LYST and ITK variants (the significance of
the gene variants is uncertain; functional assays of the gene were not
performed), yielded positive results (Table 1). Flow cytometry analysis
of the bone marrow did not indicate the presence of neoplastic lesions.
Consequently, he underwent treatment with vp16 (1380
mg/m2), steroids and cyclosporine, achieved complete
remission in eight weeks and completing chemotherapy in twelve weeks. At
an intermittent follow-up one year post-discharge, his symptoms had
disappeared. Due to economic factors, the child didn’t undergo
hematopoietic stem cell transplantation (HSCT).
Two years later, the patient was readmitted to the hospital due to
persistent fever, anemia, and leukocytosis, with no recurrence of HLH.
Laboratory tests revealed a hemoglobin level of 92 g/dL and a WBC count
of 105.4×109/mL with a differential count indicating
neutrophils (25%), lymphocytes (10%), metamyelocytes (6%), basophils
(6%), myelocytes (20%), stab granulocytes (18%), and blasts (3%).
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 (PCR) analysis confirmed the
presence of BCR-ABL (P210) positivity, so the patient was diagnosed with
chronic phase CML. In accordance with standard treatment protocols, the
patient was started on daily administration of 400mg imatinib tablets.
At the follow-up appointment one month after discharge, the blood test
results showed a decrease WBC count to 9.02×109/L.
Within three months, the patient achieved hematological, cytogenetic,
and molecular remissions. The patient continues to take imatinib as part
of his ongoing treatment plan.
Treatment-related
CML (Tr-CML) is associated with the administration of chemotherapy,
radiotherapy, and immunotherapy, accounting for approximately 3% of the
total 452 CML cases reported9. Vp16 is a critical
component of the HLH-2004 protocol, serving as a topoisomerase II
inhibitor cleaving the DNA chain, inducing gene rearrangement and DNA
damage, and ultimately leading to the development of
leukemia10. The development of secondary leukemia
associated with vp16 is influenced by various risk factors, including a
cumulative dose exceeding 3000 mg/m2, the frequency of
administration (weekly or twice-weekly dosing), and the concomitant use
of platinum agents11. In our case, the patient with
HLH received weekly or twice-weekly vp16
treatment,
accumulating a dose of 1380 mg/m2. Although this
cumulative dose is lower than the threshold of 3000
mg/m2; the frequency of administration and the
specific treatment protocol used may have contributed to the development
of secondary CML in this case.
Cytotoxic T lymphocytes and natural killer cells play a crucial role in
eliminating malignant cells12. Genetic deficiencies in
HLH can mediate cellular cytotoxicity pathways, affecting lymphocyte
granule secretion and T cell cytolytic capacity13.
Without the use of known leukemogenic agents, one patient carrying a
heterozygous UNC13D variant developed AML14. One
patient harboring a heterozygous PRF1 variant progressed to primary
aggressive DLBL15. Additionally, mutations in the
STX11 gene may be associated with secondary malignancies
(MDS/AML)16.
The patient with HLH had heterozygous variants in UNC13D, LYST, and ITK,
which may weaken immune surveillance against malignant cells,
contributing to CML development. Genetic studies primarily serve to
assess the risk of HLH recurrence2. HSCT is performed
to prevent potentially fatal recurrences of HLH; HLA typing and
preliminary donor searches be conducted early after diagnosis to HSCT if
necessary17. Genetic risks are often unknown during
the initial presentation of a patient with HLH. Unfortunately, the
patient with HLH was unable to undergo HSCT treatment in the early
stages.
In conclusion, the risk of secondary leukemia in patients with HLH is
low but still exists. Genetic screening should be intensified, if
possible, during the initial stages of HLH diagnosis. Additionally, it
is essential to regulate the dose and frequency of essential drugs like
vp16. The prompt administration of HSCT is essential for the treatment
of primary HLH, while secondary CML requires meticulous identification
and management during the follow-up period.