90Y-labelled Anti-CD66 ab in Childhood High Risk Leukaemia

In our Phase 1 trial which concluded in 2019, 9 children affected by refractory or relapsed leukaemia were enrolled at Great Ormond Street Hospital or UCLH. Participants received infusion of a tumour cell targeting antibody to deliver irradiation to the bone marrow and sites containing leukemic blasts prior to BMT. The aim of the Phase 1 study was to identify the dose limiting toxicity and maximum tolerated dose of targeted radiotherapy, and it was found that this treatment was well tolerated with minimal infusion-related side effects.

The current study will enrol a larger cohort of children (aged 0.5 - 18 years) who will receive 90Yttrium administered at an infused activity to target the optimal absorbed dose to the bone marrow. Patients will be treated at GOSH and UCLH and followed up for 12 months post-BMT to evaluate safety and efficacy of targeted radiotherapy with a reduced toxicity conditioning regimen prior to BMT.

PURPOSE AND DESIGN OF THE STUDY Children with high risk or relapsed leukaemia have a poor prognosis with an increased risk of relapse after standard bone marrow transplant. There is an urgent need to offer a different therapeutic strategy for children with such poor risk diseases.

There is evidence that targeted radioimmunotherapy prior to a stem cell transplantation is a feasible and effective treatment that delivers high dose radiation to the bone marrow and spleen (where leukaemia resides),while sparing other tissues and organs from its toxicity. Since leukaemic cells are generally radiosensitive, this approach might increase leukaemia-free survival, while reducing transplant-related morbidity and mortality.

Our previous phase 1 radio-immunotherapy study demonstrated that radio-immunotherapy is non-toxic, but can elicit myelosuppression, with potential for better disease eradication.

This protocol offers a novel and non-toxic therapeutic strategy to children with poor risk leukaemia and aims at reducing the risk of disease relapse after transplant.

RECRUITMENT and CONSENT Children with poor risk leukaemia who fulfill the inclusion and exclusion criteria of this study might be recruited in this trial. Patients and/or their parents will receive appropriate information from one of the investigators regarding the rationale of this study, the possible risks and benefits and the alternatives to taking part. Patients and/or their parents will be given an age appropriate information sheet and consent form and they will be given the time to think about this.

INCLUSION/EXCLUSION CRITERIA Children enrolled in this study must be affected by high risk or relapsed/refractory leukaemia, with a high risk of disease relapse after conventional transplant. Children eligible for this treatment must also be clinically fit for an allogeneic haematopoietic stem cell transplantation, according to clinical and laboratory parameters, which have been specified in details in the protocol.

RISKS, BURDENS AND BENEFITS Patients eligible for this trial are affected by high risk or relapsed/refractory leukaemia and have an indication to an allogeneic stem cell transplantation. Stem cell transplantation carries a significant risk of morbidity/mortality, due to: a)the toxicity of the preparative regimen, b) the posttransplant immunodeficiency with high risk of opportunistic infections, and c) the possible occurrence of graft versus host disease. The use of radioimmunotherapy in the context of a reduced toxicity conditioning regimen prior to the transplantation has proved to be feasible and safe in adult and paediatric studies, without a significant increase of the treatment related toxicity when compared to standard conditioning regimen.

Moreover, higher doses of radiation delivered to patients with leukaemia generate a better leukaemia response and this approach in children with poor risk leukaemia is promising.

Children undergoing this treatment will be carefully followed up and haematological (prolonged cytopaenia, stromal damage) and nonhaematological (mucositis, liver and kidney damage)toxicity will be monitored and recorded.