Safety and Efficacy of Reduced dose chemotherapy in children and adolescents with high grade mature B Non-Hodgkin Lymphoma – A Prospective Multicenter Phase II Single Arm Study

Review of literature:

Mature B-cell non-Hodgkin lymphoma (NHL) is a highly curable malignancy in children, with survival rates exceeding 90% in high-income countries (HICs) using short-course, multi-agent, dose-intense chemotherapy. This is in contrast to the reported event-free survival (EFS) in pediatric B-NHL from LMICs, which ranges from 20-72%. The striking difference in outcomes of children with Mature B-cell non-Hodgkin lymphoma (NHL) getting treated in HIC and LMIC, despite using the same treatment protocol, are attributed to the treatment-related mortality (TRM) due to chemotherapy related toxicities and increased relapses resulting from the inability to deliver intense chemotherapy on time.  TRMs reported in LMICs are 10-25%, compared to less than 2% in HICs. This highlights the importance of development of a treatment protocol for Pediatric B-NHL adapted for problems unique to LMIC settings, rather than directly adopting a protocol developed in resource replete setting.

We recently published the results of the prospective pilot study study among 25 children in which we attempted to reduce TRM by pre-emptively reducing the doses of chemotherapeutic agents by 25% across all cycles. We counter-balanced the reduced dose intensity with the addition of Rituximab, to the reduce the risk of relapse. This approach resulted in a significant improvement in the outcomes with a 4-year EFS of 88%, OS of 92%, and TRM of 4%, compared to previous reports from India.

There is scarcity of prospective data from LMIC setting regarding the safety of adding Rituximab to multiagent chemotherapy regimen in the management of Pediatric high-grade B-NHL.

Since direct adoption of standard chemotherapeutic regimens developed in resource replete setting results in higher TRM, we propose to study whether pre-emptive reduction of doses of chemotherapeutic agents will reduce the treatment related mortality while counterbalancing the reduced dose intensity with the addition of rituximab to reduce the risk of relapse.

Rationale for the study:

·       This study will help in developing a uniform standard resource-adapted treatment protocol for Pediatric high-grade mature B-NHL across the country as well as other resource limited settings.

·       This study will help in prospectively assessing the impact of the addition of Rituximab to the chemotherapy backbone to improve the outcomes and reduce the toxicity.

·       This study attempts to bridge the survival gap between HIC and LMICs, by improving the outcomes of Pediatric high-grade mature B-NHL. This will be in line with the aim of WHO-GICC initiative to achieve a survival rate of at least 60% of children with cancer globally by 2030.

Research question:

Among children aged 1-18 years of age with high grade mature B Non-Hodgkin lymphoma, does 25% and beyond dose reduction of chemotherapy compensated with the addition of Rituximab lead to 25% improvement of the 1 – year event free survival (from 60% to 85%) in Group B and 20% improvement of the 1 – year event free survival (from 45% to 65%) in Group C, compared with historical controls receiving standard dose chemotherapy, without any increased toxicity?

Hypothesis:

Null hypothesis (H0):

Among children aged 1-18 years of age with high grade mature B Non-Hodgkin lymphoma, 25% and beyond dose reduction of chemotherapy compensated with the addition of Rituximab does not lead to 25% improvement of the 1 – year event free survival (from 60% to 85%) in Group B and does not lead to 20% improvement of the 1 – year event free survival (from 45% to 65%) in Group C, compared with historical controls receiving standard dose chemotherapy, without any increased toxicity.

Alternate hypothesis (H1):

Among children aged 1-18 years of age with high grade mature B Non-Hodgkin lymphoma, 25% and beyond dose reduction of chemotherapy compensated with the addition of Rituximab leads to 25% improvement of the 1 – year event free survival (from 60% to 85%) in Group B and leads to 20% improvement of the 1 – year event free survival (from 45% to 65%) in Group C, compared with historical controls receiving standard dose chemotherapy, without any increased toxicity.