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.