Base line characteristics at the time of diagnosis

French American British classification and cytogentic abnormalities of all 7 patients

Treatment and outcome details

Results

Outcomes of treatment have been summarized in [Table 3]. Early response to treatment was evaluated by peripheral blood blast clearance after end of induction chemotherapy at D + 7. Granulocyte colony stimulating factor (G-CSF) was used in all patients in dose of 5 mcg/kg subcutaneously. G-CSF was started on D + 8 of chemotherapy. G-CSF was administered till two consecutive reports of ANC > 500/mm3. Median days of use were 10 days (Range 4–14 days) during induction cycles. No patients were given prophylactic antibiotics or antifungals. All 7 patients are currently under follow-up, patient number 1 and 2 have been followed up for more than 60 months. Remaining 5 children have been under follow-up for median duration of 24 months (9–48 months) at the time of writing. Assessment for minimal residual disease was not done for any of these children during follow-up because as it is not part of our institutional protocol.

Discussion

Incidence of AML among pediatric population is estimated to be 7.7 cases per million,[9] accounting for 18% of all childhood leukemia.[10] Unlike Acute lymphoblastic leukemia, treatment of AML is associated with poor prognosis and significant relapse rates. Almost 50%–80% patients in India suffer severe toxicity, relapse or refractory disease.[11] Radhakrishnan et al. evaluated and found twodrug induction regimen to be more suitable then the conventional three drug induction regimen in order to reduce treatment related toxicity among sick patients.[12] In India cure rates have been inferior for pediatric malignancies when compared to developed countries.[13] With improvement is supportive care and standardization of treatment protocols, improved survival has also been reported in pediatric AML management in India.[14] Abandonment of therapy is common in the Indian/low middle income country scenario. Socioeconomic factors and long-term morbidity associated with DS also play part in failure to complete therapy in AML.[15] Historically patients with DS with AML were considered to have high risk disease and patients with DS who developed AML were not administered protocol based therapy largely owing to DS per se In a large multi centre study from India 54% patients of AML were not given any form of therapy due to various reasons.[16] Though there is no study from India, one can safely assume that higher percentage of DS with AML do not get any form of treatment due to reasons discussed above. In last three decades outcomes have improved dramatically once patients with DS were treated according to tailor made protocols for them.[17] Initial study of 12 patients with DS published in 1992 was first one to show excellent outcomes with chemotherapy protocol with AraC as backbone. In this study 3-year event free survival (EFS) was 100% for patients of DS compared to only 28% for non DS patients.[18] Since then more than 10 studies have been published studying patients of DS with AML and all have reported significantly better outcome in these patients in comparison to non DS AML.[17] One of recently published results is from COG-A2971 study which included 132 patients of DS with AML. In this study induction consisted of oral thio guanine (T), continuous infusion of AraC (A) and daunorubicin (D) also known as TAD protocol. Consolidation was as per Capizzi regimen with high dose AraC (3 g/m2) and L asparginase. There was no maintenance chemotherapy. Five-year overall survival and EFS rates were impressive 84% and 79%.[19] Therapy reduction and its outcome were studied in 170 patients treated with International Ml-DS 2006 trial. In this study, lower cumulative dose of etoposide was used along with AraC and Idarubicin (AIE) during induction. There was no maintenance chemotherapy. Despite being less intensive, there were comparable results as far as disease outcomes were concerned.[20] This proved the concept that altered drug metabolism in myeloid leukemic-DS cells and the altered capacity for DNA repair in normal DS cells both permit and necessitate reduced exposures to cytotoxic therapies for optimal survival benefit. Two groups have published findings after studying large number of DS with AML. Based on these findings we have modified our induction protocol to less intensive 3 + 7 or ADE from 2017 onward. Anthracycline cardiotoxicity is more pronounced in children with DS. Cardiac assessment in all patients was done by baseline echocardiography and repeated at 06 monthly intervals till the follow-up period. No patient exceeded cumulative threshold dose of anthracycline and we did not find any evidence of cardiac toxicity in any of the patient. In present study all patients developed febrile neutropenia during induction, out of which 4 patients who received 3 drug induction developed severe complications necessitating intensive care. All patients successfully recovered with good supportive care. Though these are small numbers, they do indicate that addition of third drug during induction increases severe neutropenic complications. In our study, we used prophylactic G-CSF in all patients with no adverse outcomes even though some studies have documented higher risk of relapse with G-CSF.[21],[22] Our policy of use of G-CSF in children with AML post induction chemotherapy is guided by various publications in literature where G-CSF has not been associated with increased risk of relapse.[23] In a Cochrane review where 19 studies with more than 5000 patients were analyzed, relapse rates did not increase due to use of CSFs.[24] Shortening the duration of neutropenia in children with AML is very important in our setting but authors would like to caution that long-term follow-up is required to assess the risk of relapse in these children due to use of G-CSF. With advances in cytogenetics it is clear that besides trisomy 21, DS children with AML may show additional chromosomal abnormalities.[25] Recent study has suggested that normal karyotype, besides trisomy 21 may indicate poor prognosis among this specific group of children.[26] In our study only 2 children (Patient number 2 and 4) did not have additional cytogenetic anomaly while other 5 had additional trisomy (Patient number 1 and 6), deletion (Patient number 3 and 7), or translocation (Patient number 5). However, this is too small a series to comment on significance of these anomalies in terms of management or prognosis. Additional cytogenetic abnormalities are important especially in long-term outcome. We intend to follow-up these children to better understand effects of additional cytogenetic abnormalities.

Conclusion

DS children are particularly susceptible to AML, which is relatively uncommon disorder among children without DS. However, prognosis among DS children is much better than non-DS children for AML. During this time period, 65 non DS AML children were also treated. At 2 years of follow-up, 38 children were in remission giving an OS of 58.4% in this cohort. To conclude all patients of DS with AML should be offered chemotherapy, as they show excellent response to AraC, which was remains keystone in any chemotherapy protocol. Endeavour should be to give less aggressive chemotherapy protocol to bring down treatment related mortality. G-CSF should be judiciously used from D + 8 during induction to bring down duration and complications of febrile neutropenia in these patients.

Conflict of Interest

There are no conflicts of interest.

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Address for correspondence

Publication History

Received: 20 April 2020

Accepted: 19 August 2020

Article published online:
14 May 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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