Measurable Residual Disease Results & Survival with Augmented Early Intensification Therapy in Intermediate-Risk & High-Risk Group Pediatric Acute Lymphoblastic Leukemia Patients Treated with ALL IC-BFM 2009 Protocol: A Single-Center Study from India

Introduction

Measurable residual disease (MRD) has proven to be one of the most effective disease monitoring responses in ALL. Multiple treatment groups have demonstrated End-of-Induction (day 33) flow MRD of <0.01% has excellent disease-free survival (DFS). Patients with end-of-consolidation MRD of <0.01% has an overall DFS of 75 % as per COG AALL1131 including the very high-risk B-ALL genotypes. We conducted a study to assess the efficacy & toxicity of augmented early intensification therapy (phase IB) in ALL IC-BFM 2009 protocol for intermediate-risk & high-risk group pediatric ALL patients.

Objectives

1. To evaluate efficacy of augmented early intensification therapy (phase IB) in ALL IC-BFM 2009 in terms of achievement of day 78 MRD negative status.
2. To determine the event-free survival in intermediate-risk & high-risk group patients.
3. To appraise the adverse events (AEs) of augmented phase IB Induction.

Methodology

The study enrolled treatment-naïve ALL patients of 1-25 years’ age between April 2021 to February 2023 at AIIMS Rishikesh, India. Patients were risk stratified into Standard (SR), Intermediate (IR) & High risk (HR) groups as per ALL IC BFM 2009 protocol. All patients received Augmented phase IB protocol. The regimen comprised of cyclophosphamide (2 doses), four blocks of cytarabine & 6-mercaptopurine, augmented with vincristine (4 doses), and L-Asparaginase (12 doses). Day 78 bone marrow flowcytometric MRD was performed in all patients irrespective of day 33 marrow morphology & MRD. The study defined complete remission as BM blasts <5% with no extramedullary disease and MRD negativity as <0.01%. The AEs was monitored as per NCI-CTCAE v5.

As per the study protocol, patients of B-ALL with day 33 MRD >0.01%, ph-positive ALL, hypodiploidy and T-ALL with day 78 MRD > 0.01% was considered as HR & treated with High-risk blocks consolidation followed by transplant or delayed intensification & maintenance.

Results

A total of 75 patients enrolled in the study. The M: F ratio was 1.6:1. The median age was 8 years (range 1-25 yrs). B & T-ALL constituted 80% & 20% respectively. ph-positivity accounted 22% of B-ALL. The median Lansky performance was 40 & ECOG was 3 among the participants. The median hb, total white counts, and platelets were 5.9 g/dl, 28 x10⁹/L and 30 x10⁹/L respectively. At diagnosis, 28% of patients had hyperleukocytosis, 15% with bacterial sepsis, 8% with invasive fungal infections, and 8% with CNS leukemia.

At baseline, the distribution of patients in SR, IR & HR was 15%, 68% & 17% respectively. The final risk strata at end-of-induction were 8%, 49% & 43% in SR, IR & HR groups. CNS leukemia accounted for 8% of all patients.

Of the total evaluable patients, 86% achieved day 8 good steroid response (absolute blasts count <1000/cu.mm), 73% & 38% achieved day 15 marrow M1 response (<5%blasts) and MRD < 0.1%, 97% & 77% achieved day 33 M1 marrow response and day 33 MRD <0.01% respectively. Among the study participants who were MRD positive on day 15, three-fourths (75%) of them accomplished MRD negativity at day 33.

Of the 23% patients with day 33 MRD positivity, 80% achieved day 78 MRD negativity of <0.01% with Augmented phase IB with 3 participants being persistent MRD positive.

The median follow-up was 24 months and the overall survival was 74%. The mean survival time was 16.7 months (12.7-20.6) for HR & 21.2 months (18.3-24.1) for IR patients. The subgroup analysis demonstrated an overall survival of 80% for SR, 84% for IR & 64% for HR groups. Nevertheless, the proportion of patients in the SR group (8%) was lower compared to the others.

The commonest hematological adverse events were hypofibrinogenemia (22%), followed by febrile neutropenia (19%), anemia (19%), and thrombocytopenia (18%) respectively. The commonest non-hematological AEs were peripheral neuropathy (5%) and typhlitis (5%).

Conclusion

In our single-center experience, the use of augmented early intensification therapy (phase IB) in ALL IC-BFM 2009 protocol in intermediate-risk & high-risk pediatric ALL patients was associated with achievement of day 78 MRD negative status in 80% patients who had day 33 MRD-positivity without significant treatment-related toxicity, and encouraging event-free survival in this patient population.