GRanulocyte Augmented Cord Blood Transplantation for Poor Risk leukaEmia (GRACE)

A Multi-centre Phase I/II Trial of Granulocyte-augmented Cord Blood Transplantation for Young Adults With Very Poor Risk Acute Myeloid Leukaemia.

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia; Stem Cell Transplantation; Stem Cell Transplantation, Hematopoietic; Cord Blood Stem Cell Transplantation; Cellular Therapy
• Intervention / Treatment: Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Johnna Ward GRACE Trial Manager; Phone Number: 02032999000; Email: kch-tr.gracestudy@nhs.net

Study Locations

• United Kingdom
  • London, United Kingdom
    • Kings College Hospital NHS Trust
    • Principal Investigator: Mili N Shah, BSc MBBS MRCP FRCPath
    • Contact: Johnna Ward Trial Manager/Research Nurse; Phone Number: +44 (0) 20 3299 9000; Email: kch-tr.gracestudy@nhs.net
  • London, United Kingdom
    • The Royal Marsden Hospital NHS Foundation Trust
    • Contact: Francesca Temple-Brown Senior Trials Manager- Transplant; Phone Number: 0044 20 3186 5004; Email: francesca.temple-brown@rmh.nhs.uk
    • Principal Investigator: Chloe Anthias
  • Manchester, United Kingdom
    • The Christie NHS Foundation Trust
    • Principal Investigator: John Chadwick, MBBS, MRes, PhD
    • Contact: Jake Healey Senior Trial Coordinator; Email: jake.healey@nhs.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA:

1. Availability of a suitable cord blood unit
2. Age between 16 and 55 years

3. Primary diagnosis of Acute Myeloid Leukaemia (AML) or MDS/AML (as defined by ICC 2022) fitting one or more of the following criteria:

   • TP53 mutation (single- or multi-hit)
   • Presence of inv(3) (q21.3q26.2) or t(3;3)(q21.3;q26.2)
   • Adverse risk (as per ICC 2022) and >0.1% MRD by flow cytometry after 2 cycles of induction
   • AML (any risk) with partial remission (<10% blasts) after 2 cycles induction
   • Early relapse (<6 months) after chemotherapy alone (excluding t(16;16), inv(16) or t(8;21))

4. Bone marrow performed within 28 days of starting conditioning chemotherapy demonstrates either:

   • <10% blasts
   • >10% blasts with a hypocellular background (must be discussed with the trial team)

5. Suitable fitness and organ function as per the following criteria:

   • Glomerular filtration rate >50 mL/min/1.73m2
   • Ejection fraction >50%
   • FEV1 >65% without dyspnoea on mild activity
   • AST/ALT <3 x ULN
   • Bilirubin <1.5 x ULN (excluding Gilbert's syndrome)
   • Performance Status (ECOG) of 0 or 1
6. Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must agree to use appropriate, highly effective, contraception from the point of commencing therapy until 12 months after transplant

EXCLUSION CRITERIA:

1. AML Secondary to a myeloproliferative neoplasm
2. Active CNS disease
3. Prior allogeneic stem cell transplant
4. 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)
5. History of cardiac arrhythmia
6. Ischaemic heart disease, valvular heart disease or congestive cardiac failure
7. Transient ischaemic attack or cerebrovascular accident
8. Rheumatologic disease (SLE, RA, polymyositis, mixed CTD or polymyalgia rheumatica)
9. Ulcerative colitis or Crohn's disease
10. Liver cirrhosis
11. Presence of an active second malignancy
12. Uncontrolled infection, including viral reactivation (CMV, EBV)
13. HIV positive
14. Hepatitis B/C active infection with measurable viral load (patients with chronic hepatitis B or C infection require clear documentation of absence of cirrhosis by either fibroscan or biopsy, regardless of viral load)
15. Pregnancy, breastfeeding, unwilling to use contraception
16. Contraindications to administration of pooled granulocytes
17. Previous history of sensitivity to granulocytes
18. Inability of patient to give informed consent
19. Any other organ dysfunction or co-morbidity that precludes transplant in the opinion of the investigator
20. Any concern by PI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Phase I: T replete cord blood transplant + conditioning + 1 day Granulocytes; All 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 to participants for 1 day starting on the day of transplant.	Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design; All 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.
Active Comparator: Phase I: T replete cord blood transplant + conditioning + 3 day Granulocytes; All 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 participants for 3 days starting on the day of transplant.	Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design; All 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.
Active Comparator: Active Comparator: Phase I: T replete cord blood transplant + conditioning + 5 day Granulocytes; All 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 participants for 5 days starting on the day of transplant.	Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design; All 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.
Active Comparator: Active Comparator: Phase I: T replete cord blood transplant + conditioning + 7 day Granulocytes; All 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 participants for 7 days starting on the day of transplant.	Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design; All 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.
Experimental: Phase II: T replete cord blood transplant + conditioning + Granulocytes at Recommended Phase II Dose; All 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- at the Recommended Phase II Dose (RP2D)	Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design; All 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and Severity of Cytokine Release Syndrome (CRS)	Frequency and Severity of Cytokine Release Syndrome (CRS) assessed via ASTCT Consensus Grading for CRS	Day 0 (day of allograft) to Day 28 post allograft
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)	Day 0 (day of allograft) to Day 100 post allograft
Frequency and Severity of Chronic Graft vs Host Disease	Frequency and Severity of Chronic Graft vs Host Disease assessed by NIH criteria	Day 100 post allograft to Day 360 post allograft
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	Day 0 (day of allograft) to Day 100 post allograft
Frequency of Primary Graft Failure	Frequency of Primary Graft Failure	Day 0 (day of allograft) to Day 28 post allograft
Rate of Relapse-Free Survival (RFS)	Relapse-free survival (RFS) rate: number of patients who remain relapse-free and alive within 1 year from transplant	Day 0 (day of allograft) to Day 360 post allograft

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Non-Relapse Mortality (NRM)	Non-relapse mortality (NRM): number of patients who die from aetiology not related to disease relapse.	Day 0 (day of allograft) to Day 360 post allograft
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.	Day 0 (day of allograft) to Day 360 post allograft
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.	Day 0 (day of allograft) to Day 360 post allograft

Collaborators and Investigators

• Sponsor: University of Manchester
• Collaborators: King's College Hospital NHS Trust; Royal Marsden NHS Foundation Trust; Institute of Cancer Research, United Kingdom; The Christie NHS Foundation Trust
• Investigators: Principal Investigator: Mark Williams, BA MB BChir PhD MRCP FRCPath, University of Manchester; Principal Investigator: Mili N Shah, BSc MBBS MRCP FRCPath, Kings College Hospital NHS Trust

Study record dates

Study Major Dates

• Study Start (Estimated): February 9, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: November 20, 2025
• First Submitted That Met QC Criteria: January 19, 2026
• First Posted (Actual): January 28, 2026

Study Record Updates

• Last Update Posted (Actual): March 11, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: TP53; Myelodysplastic Syndrome; Cord Blood Transplantation; Grace; granulocyte-augmented cord blood transplantation; poor risk acute myeloid leukaemia; MECOM
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
• Other Study ID Numbers: 357519

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No