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.