DISCUSSION
The presenting clinical picture of this patient with pallor, persistent fever, cervical lymphadenopathy, hepatosplenomegaly and hyperleukocytosis directed to hematological malignancy. The peripheral blood smear showed less than 20% blasts. The myeloblast predominance in blood smear suggested a diagnosis of the myeloid lineage. This patient was initially diagnosed as chronic myeloid leukemia, shortly treated with hydroxyurea, until further workups showed negative BCR-ABL gene and increased HbF. The diagnosis of JMML is based on diagnosis criteria per 2016 revision to World Health Organization Classification (Table 1).8,9
This patient fulfilled all of the items in Category 1 (peripheral blood monocyte count >1000/uL, blast in peripheral blood <20%, splenomegaly, absence of BRC-ABL gene) and two items in the Category 3 (circulating myeloid precursors and increased HbF for age). This patient also had the epidemiologic characteristics of JMML, i.e. male sex and age less than 6 years old. The pathogenesis of JMML involves disruption of signal transduction along the RAS pathway, with resultant selective hypersensitivity of JMML cells to GM-CSF. Unfortunately, we could not perform laboratory tests to find aberrations in the RAS pathway.
Marked splenomegaly and hepatomegaly are usually found and may cause abdominal discomfort and breathing difficulty. Lymphadenopathy is observed in about half of the patients and leukemic infiltrates may give rise to enlarged tonsils. Peribronchial and interstitial pulmonary infiltrates may be evident on chest x-ray and manifests as cough and respiratory distress. Central nervous system involvement is uncommon in JMML. Cutaneous involvement is frequent and most often appeared as eczematous eruptions or indurated raised lesions with a central pale area.10
Allogenic hematopoietic stem cell transplantation (HSCT) is the only curative regimen for JMML. Currently, no therapy other than HSCT has been proven to result in long-term remission. HSCT can achieve long-term event-free survival in about 50% of patients, but it still has a high relapse rate at 30-40%.11 In the absence of treatment, the progression of JMML is highly variable, including blast crisis, acute leukemia or even spontaneous partial or complete remission.12
Currently, there is no proven chemotherapy known to achieve complete remission for JMML.13 AML protocols for intensive chemotherapy can induce temporary remission in JMML, but this approach is also very toxic. The European Working Group (EWOG-MDS) trial reported no significant difference in event-survival rate and mortality of AML-type chemotherapy compared to less intensive treatment.11 For many decades, cytoreductive therapy with 6MP at a 50 mg/m2 dose or low dose i.v. cytarabine in a 40 mg/ m2 dose for 5 days have been used to control the JMML symptoms before HSCT.14 In aggressive cases, high dose fludarabine 30 mg/m2 and cytarabine 2 g/m2 daily for 5 consecutive days have been adopted by some centers.15 JMML sometimes was sensitive to 6MP, and cytosine arabinoside (Ara-C) was added, because of its efficacy in AML. However, neither intensive nor low dose chemotherapy have been demonstrated to improve the outcome of patients with JMML.13 Various combinations of busulfan (BU), melphalan (MRL), cyclophosphamide (CY) and fludarabine (FLU) have been tested as conditioning regimens.13 Shakashita et al. found that BU/L-PAM/CY and BU/L-PAM/FLU combinations were associated with higher overall survival rate that total body irradiation or BU alone.16 Due to unavailability of HSCT in our center, we opted for chemotherapy for controlling the disease. We used mercaptopurine and cytarabine due to its wide studies and availability in our center.
Jin Kang, et al. in Korea proposed a novel regimen for newly diagnosed JMML lacking access to transplantation. They proposed a standard regimen in 3-weeks interval consisting the combination of chemotherapy (Ara-C, etoposide, and vincristine) and differentiation therapy (isotretinoin). If disease relapsed or progressed, they continued to salvage regimen consisting of chemotherapy (Ara-C, etoposide) and differentiation therapy (low-dose Ara-C) in 3-4 weeks interval. This regimen was found to be safe and effective, but the study was only done in 5 JMML patients.17 Another regimen was tested by Feng X et al. in China, consisting of decitabine, cytarabine, and fludarabine. They reported that this regimen is safe, effective, and feasible with a response rate of 97%. Although, the complete remission rate was low and mostly partial.18 Given that DNA hypermethylation of certain genes is contributing to the aggressiveness of JMML, azacytidine (AZA), a DNA hypomethylating agent, has been tested as potential treatment for JMML. Cseh, et al. in their retrospective study treated 9 JMML patients with low-dose azacytidine prior to HSCT and highlighted two full remissions and two partial remissions. However, there were several adverse events (severe neutropenia, skin rash, and gastrointestinal problems).19 Further study by Leoncini, et al. suggested that azacytidine is particularly beneficial in JMML patients with high methylation levels.20Fabri, et al. in Slovakia tested a novel approach using azacytidine 75 mg/m2 i.v. on days 1 to 7 of a 28-day cycle as a bridging therapy before HSCT and reported good response and favorable toxicity.21
Age, platelet count, and percentage of HbF at diagnosis are the main prognostic factors in JMML. Age >2 years at diagnosis, platelet count <33 x 106/mm3, and HbF >10% are related to short survival.5 The reasons as to why these factors portend a poor prognosis is still unknown. This patient had bad prognosis due to his age at diagnosis was older than 2 years old, initial low platelet count, and cachexia. In most patients, JMML is a rapidly progressive fatal disorder if untreated. The probability of survival without allogenic HSCT is less than 10%. Left untreated, JMML is fatal with 80% of patients surviving less than 3 years. Median survival rate is 0.9 – 1.4 years. Most untreated patients die from respiratory failure due to pulmonary infiltration with leukemic cells and progression to acute leukemia is observed in fewer than 20% of patients.5
In the setting of a terminal illness with limited available therapy, palliative care is an appropriate approach. Palliative care is a patient-centered approach that aim to improve the quality of life of patients and the family through prevention and relief of sufferings by means of early identification and treatment of pain and other physical, psychosocial, and spiritual problems.22 Palliative care may or may not include the use of cytostatic drugs to improve the clinical condition and to extend life, however thia approach has the risk of severe side effects too. Provision of palliative care for children is different from adults based on several reasons: (1) evaluation of pain severity and quality of life is difficult, (2) communication with children about disease, treatment, and death is under influence of their developmental stages.23 The application of palliative care in cancer patients can decrease the number of unnecessary procedures, length of hospital stays, the need for intensive care, facilitate pain management, and improve communication among parents and health care team.24
Our patient had a history that suggested he was suffering from JMML already for about 2 years before he reached the Estella Clinic for Children with Cancer and Blood Diseases. He came from a small town about 400 km or 10 hours car drive away from Manado. After making the diagnosis of JMML, when he was in cachectic condition, he was treated with a simple palliative chemotherapy course, 6MP orally daily plus Cytarabine subcutaneously weekly. He improved greatly, both clinically and in laboratory values. After 2 months he came home with his family and had a good quality of life until in the end probably low WBC counts and low platelets led to his death 4 months after the start of palliative chemotherapy.
Unfortunately, access to pediatric palliative care in low- or middle-income countries is limited and mostly focused on adult patients. Lack of knowledge about the principle of palliative care and misperceptions about palliative care are the major barriers that limit the development of palliative service in low- and middle-income countries.25 Therefore, providing education and training on clinicians working in pediatric oncology department is one of the initial steps necessary to develop palliative care for pediatric cancer patients.