Allogeneic stem cell transplantation is the only potentially curative therapy for patients with high-risk Acute Myeloid Leukaemia, but relapse is common and remains the leading cause of death. Patients with certain mutations and those transplanted without first clearing their disease have very poor outcomes with most relapsing soon after transplant, and then surviving only a few months. A recent trial at the Royal Manchester Children's Hospital used cord blood stem cells alongside a type of white blood cell called 'granulocytes' and produced surprisingly good outcomes for children with very resistant leukaemia.
GRACE is a clinical trial for adults (\<55 years) with Acute Myeloid Leukaemia that has not responded to chemotherapy or harbours mutations that predict a very poor response to conventional transplant. Participants will receive a transplant using umbilical cord blood and be given additional infusions of white blood cells, called granulocytes. The trial will be split into two parts:-The first will study the safety of this new approach. The experience of the investigators in children is that granulocyte infusions cause a fever, rash and expansion of another type of white blood cell called lymphocytes. Children that did not have this reaction did not respond to treatment. The investigators therefore believe that the reaction is necessary for the treatment to work, but the investigators must ensure that it is safe in adult patients. The trial design allows the investigators to determine the dose of granulocytes that is best tolerated and most likely to be effective.
The aim of the second part is to demonstrate that the new treatment is more effective than conventional transplantation.
The study will be conducted in three NHS transplant centres. Patients will be recruited over 36 months and followed up for a minimum of 1 year. The study is funded by Blood Cancer UK.
Availability of a suitable cord blood unit
Age between 16 and 55 years
TP53 mutation (single- or multi-hit)
Presence of inv(3) (q21.3q26.2) or t(3;3)(q21.3;q26.2)
AML Secondary to a myeloproliferative neoplasm
Active CNS disease
Prior allogeneic stem cell transplant
Participation in another clinical trial that would alter any aspect of the transplant protocol or that aims to reduce the subsequent risk of relapse (discuss with trial team if unsure)
Sequential
Cord blood transplantation + conditioning + granulocytes of variable days according to study design
Biological/VaccineAll participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to all participants- but for a variable number of days starting on the day of transplant according to study design (1,3,5 or 7 days). The study consists of two phases- Phase 1 has two components (dose escalation and dose optimisation) to identify the Recommended Phase II Dose (RP2D) of granulocytes. Phase 2 will assess preliminary efficacy based Relapse Free Survival at 1 year.
Frequency and Severity of Cytokine Release Syndrome (CRS)
Frequency and Severity of Cytokine Release Syndrome (CRS) assessed via ASTCT Consensus Grading for CRS
Frequency and Severity of Acute Graft vs Host Disease
Frequency and Severity of Acute Graft vs Host Disease assessed by modified Glucksberg criteria (revised by MAGIC)
Frequency and Severity of Chronic Graft vs Host Disease
Frequency and Severity of Chronic Graft vs Host Disease assessed by NIH criteria
Frequency of Transplant Related Mortality (TRM)
Frequency of Transplant Related Mortality (TRM) defined as death due to any transplantation-related cause other than disease relapse
Frequency of Non-Relapse Mortality (NRM)
Non-relapse mortality (NRM): number of patients who die from aetiology not related to disease relapse.
Duration of Overall Survival
Overall survival: time from Day 0 to date of death from any cause. Patients who are alive will be censored at the date of last follow-up.
Duration of GvHD Free Relapse Free Survival (GRFS)
GvHD-free, relapse-free survival (GRFS): time from day to the first occurrence of any of the following events: acute grade III-IV and/or chronic GvHD requiring systemic immune suppressive treatment, disease relapse or progression, or death from any cause. Patients who are alive and free of any of these event will be censored at the date of last follow-up.
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University of Manchester
Lead sponsor
King's College Hospital NHS Trust
Collaborator
Institute of Cancer Research, United Kingdom
Collaborator
The Christie NHS Foundation Trust
Collaborator
Royal Marsden NHS Foundation Trust
Collaborator
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