Granulocyte Transfusions After Umbilical Cord Blood Transplant

June 17, 2022 updated by: University of Manchester

The Use of Granulocyte Transfusions After Umbilical Cord Blood Transplant for Leukaemia: A Prospective, Non-randomised, Single-centre Study to Evaluate Safety and Immune Reconstitution

Although most children with leukaemia are cured using drugs (chemotherapy) alone, for some children additional treatments are needed. Stem cell transplant can cure children where chemotherapy and other drugs have failed. In this case, the immune cells of the donor attack the leukaemia cells of the patient. Cord blood collected from the placenta of unrelated babies is often used as a donor cell source and appears to work well at controlling leukaemia and less likely to cause complications such as when the immune cells also mistakenly attack healthy tissues (called graft versus host disease, GVHD).

The investigators have noticed that during cord blood transplant, the donor immune system appears to recover more quickly and not be associated with GVHD, when a type of blood transfusion containing white cells are also given to the patient. The infused white cells appear to stimulate the donor immune cells to expand much more than usually seen.

During this research, the investigators will study this immune cell expansion during cord blood transplant in children with difficult-to-cure leukaemia who also receive a transfusion of white cells, termed granulocytes. The investigators will assess the safety of the effects of the white cell transfusions and the immune cell expansion on the child, and look at the outcomes on the patient's leukaemia, and whether there is GVHD or not.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Most children with acute leukaemia are cured with chemotherapy alone but a few children are either refractory to such therapy, or relapse after it has been administered.

Some of these relapsed or refractory children are given HCT (hematopoietic cell transplantation), and some will be cured with HCT. HCT acts to cure children with leukaemia in two ways:

  • There is chemotherapy given before the transplant, to get rid of recipient marrow and the recipient immune system. This chemotherapy is of higher dose than is given in standard chemotherapy protocols, and this dose escalation might overcome the resistance to chemotherapy that is inherent in children with relapsed or refractory disease.
  • The engrafting immune system - derived from the HCT donor - recognises the residual leukaemia and rejects it. This is known as graft-versus-leukaemia, and this Is the main way that transplant cures refractory diseases.

Most children with refractory and / or relapsed leukaemia will die of their leukaemia. Transplant offers a chance of cure where conventional therapies will fail. Transplant works through this graft-versus leukaemia effect. This is related to graft-versus-disease (GVHD) and involves a recognition by donor derived T-cells of differences in the host leukaemia cells, and more generally in the recipient.

In general, the risk of relapse after transplant is:

  • Reduced where there is graft versus host disease
  • Reduced where the T-cells are left in the graft, a T-cell replete transplant. Often T-cells are removed from the graft - bone marrow, blood, or cord blood - to reduce the risk of GVHD
  • Reduced where there is mismatch between the donor and recipient. The investigators and others have shown that it is possible to do T-cell replete, mismatched unrelated donor transplant in umbilical cord transplant.
  • The risk of relapse is less in cord blood transplant compared to other cell sources, and this is particularly evident where there is residual disease present, and the risk of treatment failure is highest.
  • The risk of chronic GVHD is reduced after cord blood transplant, even where the transplant is T-cell replete and there is mismatch between donor and recipient. Using adult donor-derived, mismatched donor transplant in a T-cell replete setting is associated with a risk of severe acute GVHD and chronic, extensive GVHD which limits quality of life.
  • The most meaningful endpoint for children undergoing transplantation for any indication is disease-free and chronic GVHD-free survival. In malignancy this is best achieved using cord blood in a T-cell replete setting.

One of the investigators groups have published data from a xenograft model demonstrating that cord blood T-cells are better at controlling a human leukaemia than adult T-cells, and that the actual cord T-cells infiltrating the xenografted tumour are Cluster of Differentiation 810 (CD810). However, after T-cell replete transplant most of the recovering T-cells are Cluster of Differentiation 4 (CD4) and not Cluster of Differentiation (CD812). Childhood leukaemia is a rapidly proliferative disease, and experience tells us that relapse can happen early, within the first weeks and months. A graft versus tumour effect must be established quickly therefore, to prevent disease recurrence, and death from disease.

In this research, the investigators seek to replicate results that have been described and published prior. Here the investigators demonstrated early, transient, massive Cluster of Differentiation (CD8) T-cell reconstitution after cord blood transplantation without any chronic GVHD, despite early cessation of post-transplant immune suppression.

This observation is important since it incorporates the important components of a clinically meaningful graft-versus-leukaemia, from previous work:

  • CD8 biased
  • Cord blood
  • T-cell replete setting
  • Mismatched donors
  • No chronic GVHD

This has been recognized by leaders in the field, and as part of the peer review of this work. Milano, an expert in Cord Blood transplant in refractory leukaemia has written that "this is not only economically beneficial but may also result in a paradigm shift for the treatment of patients with high-risk leukaemia's. "

The trial is funded by bone marrow transplant local funds and by funds generated specifically for this research by families, including families with difficult-to-cure, including multiple relapsed and refractory leukaemia. The rationale and patient summaries have been shared with those families, in support of their fundraising efforts. Families of children with such leukaemia understand how transplant works, the risk it generates and the implications when cell therapies also fail where conventional therapy has already failed. They are the best placed of all of us to understand this balance of risk of therapy with risk of treatment failure, and the best placed therefore to understand the rationale and scope of this research.

It is important to replicate the data that the investigators have published. It is important that in a trial setting that the investigators better define the safety of the immune cell expansion, and the nature of the T-cells that are derived. It is important research, for the reasons explained above, and recognised by Milano and other commentators.

There is a control group for T-cell expansion numbers, and for safety evaluations including cytokine release syndrome and engraftment kinetics. This is not an efficacy trial, and the relapsed, refractory leukaemia is rare in children, and so randomisation is not appropriate. The granulocyte doses are standard for children, and what the investigators reported in their preliminary experience.

Study Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 16 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Children, aged <16 years, undergoing a first allogeneic, unrelated donor, T-cell replete, umbilical cord blood HSCT for high risk acute leukaemia.
  2. Availability of at least a 6/8 allelic matched cord blood, of adequate cell dose, after allele-level matching at HLA (Human Leukocyte Antigen)-A, -B, -C, and -DRB1
  3. Informed consent by parent or guardian. Age appropriate Assent will also be collected in those Children age 16 and under.

Exclusion Criteria:

  1. Patients participating in other HSCT clinical trial
  2. The transplant not indicated according to National Health Service England (NHSE) and British Society of Bone Marrow Transplant (BSBMT) Paediatric Transplant Group.
  3. Pooled Granulocyte Transfusion contraindicated for any reason
  4. Previous T cell replete unrelated donor cord blood transplant
  5. Patients with a previous history of sensitivity to granulocyte transfusion will be excluded from the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Granulocytes
Patient to receive pooled granulocytes for 7 days concurrently. 10 participants will be approached for this arm.
Biological: Granulocytes
Receive granulocytes for 7 consecutive days after engraftment post transplant
No Intervention: Control
Non-randomised control arm, where patients who are receiving a stem cell transplant, as described in the eligibility criteria, are asked for a blood sample. This is to establish a baseline versus the experimental arm. 10 participants will be approached for this arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
What is the number of patients with grade 1-4 cytokine release syndrome, related to the granulocytes infusions?
Time Frame: 2 years
This is to access safety of the granulocyte infusions.
2 years
What is the number of patients with allo-immunisation after the granulocyte infusions?
Time Frame: 2 years
This is to access safety of the granulocyte infusions.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
What is the median day to neutrophil and to platelet engraftment, and compared with a control group of cord blood transplant recipients not receiving granulocytes?
Time Frame: 2 years
This is to measure the effect that the granulocyte infusion course have on engraftment and on the disease
2 years
How many patients experience grade II-IV GvHD?
Time Frame: 2 years
This is to measure the effect that the granulocyte infusion course have on engraftment and on the disease
2 years
What is the median disease-free and overall survival in this patient cohort?
Time Frame: 2 years
This is to measure the effect that the granulocyte infusion course have on engraftment and on the disease
2 years
How many patients enter flow and molecular remission after the transplant?
Time Frame: 2 years
This is to measure the effect that the granulocyte infusion course have on engraftment and on the disease
2 years
What is the median date of cessation of immune suppression after the transplant, and compared with a control group of cord blood transplant recipients not receiving granulocytes?
Time Frame: 2 years
This is to measure the effect that the granulocyte infusion course have on engraftment and on the disease
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Manchester

Collaborators

Children's Cancer and Leukaemia Group

Investigators

  • Study Chair: Robert Wynn, MD FRCPath, Royal Manchester Children's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 14, 2021

Primary Completion (Anticipated)

June 1, 2023

Study Completion (Anticipated)

June 1, 2023

Study Registration Dates

First Submitted

December 17, 2021

First Submitted That Met QC Criteria

June 17, 2022

First Posted (Actual)

June 21, 2022

Study Record Updates

Last Update Posted (Actual)

June 21, 2022

Last Update Submitted That Met QC Criteria

June 17, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 295998

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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