Comparison of Dexamethasone Versus Prednisolone Prephase in Induction Therapy of Pediatric Acute Lymphoblastic Leukemia: A Single-Center, Randomized Controlled Study from India

Background: Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. Despite advances in treatment, approximately 20% of pediatric ALL patients still relapse. Although the use of dexamethasone in induction regimen has been reported to significantly decrease CNS relapse risk & improve event-free survival (EFS) compared to prednisolone, there are concerns of significant toxicities like infection & osteonecrosis with dexamethasone.

Objectives: The aim of this single-center randomized study was to compare the efficacy and safety of dexamethasone prephase versus prednisolone prephase during the initial seven days (days 1 - 7) of induction chemotherapy in newly diagnosed pediatric ALL patients treated with ALL IC-BFM 2009 protocol,in terms of day 8 steroid response, day 15 bone marrow minimal residual disease (MRD) response, and day 33 morphological complete remission (CR) rates.

Methods: The study enrolled total 62 newly diagnosed pediatric ALL patients (age > 1 year & ≤ 18 years) between June 2019 and April 2021, after obtaining informed consent and with institutional ethics committee approval. Patients with lymphoblastic lymphoma (LBL) and infantile ALL (age < 1 year) were excluded. Patients who were randomized to dexamethasone prephase group received intravenous dexamethasone 10 mg/m²/day on days 1-7 of induction,& those in prednisolone prephase group received prednisolone 60 mg/m²/day p.o. in three divided doses on days 1-7 of induction therapy .All the patients subsequently received prednisolone 60 mg/m²/day p.o. in three divided doses on days 8 - 28 of induction, followed by prednisolone taper over next 7 days. Induction regimen of ALL IC-BFM 2009 protocol was given. The cut-off values for day 15 BM Flow-MRD were <0.1%, 0.1-10%, and >10% as per ALL IC-BFM 2009 protocol. Morphological complete remission on day 33 was defined as bone marrow blasts < 5% of total nucleated cells, with normocellular or mildly hypocellular marrow. Steroid-related toxicities in the two treatment groups were compared as per NCI-CTCAE version 5.

Results: Out of total 62 patients, 33 patients (53%) received dexamethasone prephase and 29 patients (47%) received prednisolone prephase. Forty-six patients (75%) had B-cell ALL, and 25% had T-cell ALL. The distribution of patients in standard-risk, intermediate-risk & high-risk groups as per ALL IC-BFM 2009 protocol risk stratification were 18%, 34% and 48% respectively. Twenty-nine out of 33 patients (88%) in dexamethasone prephase group achieved good steroid response on day 8 (peripheral blood absolute blast count < 1000/µl) compared to 17/29 patients (59%) in prednisolone prephase group [p = 0.018]. Day 15 bone marrow MRD assessment by flowcytometry was available in 57 patients (31/33 in dexamethasone prephase group & 26/29 in prednisolone prephase group). Nineteen out of 31 patients (61%) in dexamethasone prephase group achieved day 15 MRD < 0.1% compared to 6/26 patients (23%) in prednisolone prephase group [p = 0.02]. Twenty-eight out of 30 patients (93%) in dexamethasone group achieved morphological CR on day 33 of induction compared to 18/24 patients (75%) in prednisolone prephase group [p = 0.135]. Day 33 bone marrow Flow-MRD < 0.1% in the dexamethasone & prednisolone prephase groups were 82% and 50% respectively [p = 0.12]. At the time of analysis, 3/30 patients (10%) in dexamethasone group who achieved CR has disease relapse, compared to 8/24 patients (33%) in prednisolone prephase group [p = 0.04]. The event-free survival (EFS) at the end of study (18 months) was found to be significantly higher in the dexamethasone prephase group compared to prednisolone prephase group (p = 0.002). The incidence of steroid-related toxicities of any grade was similar in the two treatment groups.

Conclusion: In the present study, the replacement of prednisolone with dexamethasone for a relatively shorter duration in the 7-day steroid prephase of ALL IC-BFM 2009 induction regimen was associated with significantly improved day 8 steroid response, day 15 bone marrow Flow-MRD response, day 33 morphological CR rates, and EFS at 18 months, without significant increase in steroid-related toxicity in induction. To our knowledge, this is the only study to compare dexamethasone versus prednisolone prephase in pediatric ALL induction, in the context of ALL IC-BFM 2009 regimen. Long-term follow up and enrollment of larger number of patients is planned.

No relevant conflicts of interest to declare.