Atypical chronic myeloid leukemia (aCML) is a rare
Currently, the diagnosis of aCML is based on morphology because its clinical and molecular features overlap with those of other myeloid neoplasms, such as chronic myelomonocytic leukemia, chronic neutrophilic leukemia (CNL), and unclassifiable MDS/MPN [1,3]. The main features of aCML are the principal involvement of neutrophil lineage (≥10% of the leukocyte) with leukocytosis (>13,000/μL). According to the World Health Organiza-tion, 2016 diagnostic criteria, prominent granulocytic dysplasia, <20% blasts in the peripheral blood (PB) and bone marrow (BM), and minimal absolute basophils (<2% of leukocytes) and monocytes (<10% of leukocytes) should be entertained . In addition, to rule out Philadelphia-positive CML and other myeloid-lymphoid neoplasms associated with eosinophilia,
In contrast to
Here, we report a pediatric case of aCML with
A 13-year-old boy in a stupor was admitted. He experienced a headache, vomiting two days ago, and weight loss of 5 kg (11.6% of baseline weight) during the last 6 months. At the time of admission, his Glasgow coma scale score was 7 and his blood pressure was 164/78 mmHg. His left pupil was dilated and showed no reflex to the light. Physical examination revealed multiple bruises and spleen was palpable to 7 cm below the costal margin. The laboratory findings were as follows: white blood cells (WBC) of 296,500/μL, neutrophils of 177,900/μL (60% of WBC), lymphocytes of 14,800/μL (5% of WBC), basophils of 3,560/μL (1.2% of WBC), hemoglobin level of 7.4 g/dL, platelet counts of 27,000/μL, prothrombin time of 15.8/55.7/1.38 secs/%/INR, and activated partial thrombin time of 26.8 secs.
Brain computed tomography (CT) showed an acute lobar intracranial hemorrhage (ICH) in the left frontal lobe with the midline shifting to the right (Fig. 1A). After platelet transfusions, evacuation of the hematoma was attempted.
A PB smear showed left-shifted myeloid hyperplasia with dysplasia, blasts of 2%, increased granulocytic precursors (myelocytes of 20% and metamyelocytes of 3%), and an absence of both basophilia and monocytosis (Fig. 1B). A BM aspiration revealed increased granulocytic series with 8.7% blasts (Fig. 1C). The blasts cells expressed CD13, CD33, CD34, CD56, CD117, and myeloperoxidase O. These led to a putative diagnosis of chronic CML. Hydroxyurea and imatinib were initially administered to reduce leukocytosis. On the third day of hospitalization (HD), fluorecence in situ hybridization (FISH) for
BM cytogenetics was 46, XY, and the multiplex real-time polymerase chain reactions for 28 chromosome translocations, including
After the initial aspiration of ICH, conservative measures using mannitol, dexamethasone, levetiracetam, and platelet transfusions were continued. On HD3, however, abrupt dilatation (8 mm) and loss of light reflex in the left pupil were noted, and a repeat brain CT revealed increased amount of ICH. Repeat aspiration of the hematoma resulted in decrease of ICH. The impaired patient’s memory, orientation, and motor function of the right side gradually recovered over 2 weeks. The spleen was no longer palpable and leukocytosis and blast counts in the BM were normalized 4 weeks after the patient was started on hydroxyurea (Fig. 2).
On HD 28, upon the identification of
The patient received planned allogeneic peripheral blood stem cell transplantation from an 8/8 allele-matched unrelated donor. The conditioning regimen consisted of fludarabine (40 mg/m2 for 5 days) and busulfan (3.2 mg/kg for 3 days). Graft versus host disease (GvHD) prophylaxis consisted of rabbit antithymocyte globulin (1.25 mg/kg for 3 days), tacrolimus, and low doses of methotrexate. The time to neutrophil and platelet engraftment were 11th day, 12th day after transplant, respectively. Post-transplant 6 months, at one month after tacrolimus-off, he developed stage 3 gut GvHD which was treated with steroid and ruxolitinib.
Currently, his motor function has fully recovered, although magnetic resonance imaging of his brain showed encephalomalacic changes with hemosiderin deposit in the left frontal lobe and corpus callosum, sequelae of previous ICH (Fig. 1E). He remains in hematologic remission with complete donor chimerism at 8 months after transplant with manageable gut GvHD.
Making the diagnosis of aCML in children is quite challenging, as they are extremely rare, and they may share clinical, morphologic and molecular similarities with other MDS/MPDs. Mutation in the
The natural history of aCML is characterized by an increasing leukemic cell burden, organomegaly, and a high rate of transformation to acute myeloid leukemia in 37-40% of aCML cases [1,2,9,10]. There is no current standard of care, but the only curative treatment option is allogeneic HSCT [1,2]. Traditionally, treatments used in MDS/MPN cases (such as hypomethylating agents, hydroxyurea, pegylated-interferon-alpha, and erythropoietic stimulating agents) have been utilized to control leukocytosis and symptomatic splenomegaly . Recently, owing to the discovery of mutations in aCML, promising targeted therapies were investigated, including the JAK inhibitor ruxolitinib, SRC kinase inhibitor dasatinib, and MEK inhibitor trametinib [1,11].
CSF3R mutation has two types [1,6]. First, membrane proximal mutations, such as
In this case, after the identification of
To date, the largest study of allogeneic HSCT for aCML has been reported from the European Society for Blood and Marrow Transplantation registry . In 42 adult patients with aCML between 1997 and 2006, the 5-years relapse-free survival following HSCT was 36%, and non-relapse mortality was 24%, while relapse occurred in 40%. Their median time from diagnosis to transplant was 7 months. There are no current recommendations on the optimal timing of HSCT for aCML. However, the finding of increasing blast counts despite ruxolitinib treatment in this case might justify early intervention with allogeneic HSCT if a donor is available.
In conclusion, ruxolitinib for aCML with
The authors have no conflict of interest to declare.