3. DISCUSSION
We present three cases of ML-DS, of whom two are in continuous complete
remission until now, and one died on the last day of the chemotherapy
treatment. We used a two-cycle protocol using systemic vincristine,
daunorubicin, and cytarabine (ara-C) plus triple intratechal
chemotherapy.
Vincristine has been a standard of chemotherapy regimens for many
childhood cancers but was rarely used especially in patient with AML and
ML-DS.8 A study in Japan showed vincristine was toxic
to the terminal divisions and self-renewal of the AML blast progenitor
within in-vitro setting. The results showed vincristine can inhibit the
growth of blast progenitors in dose- and time-dependent manners. In the
repeated exposure, only vincristine in high-dose shown a reduction of
clonogenic cells. Suggesting if vincristine combined with other drugs,
the success of treatment can be achieved easily.9
Recent in-vitro study for drug resistance profile shown the ML-DS cells
were significantly more sensitive to cytarabine, anthracyclines,
etoposide, and vincristine. This study suggested the benefit of
vincristine in ML-DS, as this drug had the highest toxicity to the ML-DS
blast cells.10 Our patients who were treated using
vincristine, cytarabine and daunorubicin showed an improvement in blood
counts profile after the first cycle of chemotherapy, suggesting the
efficacy of these drugs combinations. Vincristine was also well
tolerated by children with DS variant of
leukemia.11,12
Al Ahmari et al.13 used vincristine for their ML-DS
patients, comparing between a very low-dose, long-term ara-C regimen,
and standard High-dose ara-C (HD-ara-C) regimens from contemporary
protocols. The low dose regimen consisted of ara-C 10
mg/m2 twice-a-day subcutaneous injection for 7 days,
with vincristine 1 mg/m2 and retinylpalmitate 25,000
units/m2/day. This regimen was repeated every 2 weeks
for 2 years, with 5-years EFS between low-and high-dose regimens not
being different at all (67 and 75%, respectively) and neither was the
OS (77 and 80%, respectively).
Chidren’s Oncology Group AAML0431 trial for AML-DS patients was focusing
on curative chemotherapy dose intensity while minimizing
treatment-related toxicity with ara-C and daunorubicin. The treatment
protocol consists of 4 induction cycles and 2 intensification therapy
cycle, with HD-ara-C was used in the second induction and 25% dose
reduction in daunorubicin. For 204 patients, 5-year EFS was 89.9% and
overall survival was 93%. Prolonged ANC recovery, severe febrile
neutropenia and severe sterile-site bacterial infection were
common.14
The ML-DS 2006 trial focused on therapy reduction intensity using a
lower cumulative dose of chemotherapy. This trial applied intrathecal
CNS prophylaxis without any maintenance therapy and still showed a
satisfying result. The total cumulative dose of cytarabine was 27,400
mg/m2 instead of 29,400 mg/m2 used in AML-BFM 98
trial, meanwhile etoposide was 450 mg/m2 rather than
950 mg/m2. The results of this trial showed a 5-year
overall survival rate (OS) of 89%, EFS of 87%, and cumulative
incidence of relapse/nonresponse of 6% ± 3%; similar to the historical
control arm (AML-BFM 98) which consist of longer duration and a higher
dose of therapy.15 We use an even lower cytarabine
with total cumulative dosage 2,000 mg/m2, and also
omitting maintenance therapy, but with vincristine added to cytarabine
and daunorubicin. Where we have a good result as well, but in only two
patients.
Another study from Brazil, as one of LMICs, reported ML-DS patients (age
< 19 years old) had a survival rate of 62.5%. The patients
received two induction cycles chemotherapy of daunorubicin, cytarabine
and etoposide followed by low-dose cytarabine for 21
days.6 We used an innovative regimen with regular dose
of vincristine, ara-C and daunorubicin for a shorter duration with a
good result, although the patient number is small.
In conclusion, ML-DS is curable in LMICs with limited resources
pediatric oncology setting like Indonesia. Further study of more
patients is needed to evaluate the effectiveness of our protocol.