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Up-front Matched Unrelated Donor Transplantation in Pediatric Patients With Idiopathic Aplastic Anemia (UPFRONT-MUD)

Primary Purpose

Idiopathic Aplastic Anemia, Severe Aplastic Anemia, Moderate Aplastic Anemia Requiring Transfusions

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

HSCT Arm group

About this trial

This is an interventional other trial for Idiopathic Aplastic Anemia

Eligibility Criteria

undefined - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

age<18years old
Pediatric patients aged less than 18 years with idiopathic aplastic anemia and an indication for treatment (severe aplastic anemia or moderate aplastic anemia requiring transfusions)
With a good probability to have a HLA-10/10 matched unrelated donor available (the patient needs to have at least 3 MUD identified within the book BMDW (Bone Marrow Donors Worldwide) or using the easy match software to be included)
With usual criteria for allo-SCT:
Lansky >70% for those below 16 years and Karnofsky > 70% for those above 16 years
No severe and uncontrolled infection
Adequate organ function: ASAT and ALAT ≤ 5N*, total bilirubin ≤ 2N, creatinine clearance > 70% of higher normal values for age.
With health insurance coverage
Contraception methods** for young girl and men of childbearing age must be prescribed during all the duration of the research.
Parents having read and understand the information note and signed a written informed consent (the patient's agreement depending on his age will be sought)
*because typical presentation of aplastic anemia post-hepatitis
** NB : The authorized contraceptive methods are:
For women of childbearing age and in absence of permanent sterilization: oral, intravaginal or transdermal combined hormonal contraception, oral, injectable or transdermal progestogen-only hormonal contraception, intrauterine hormonal-releasing system (IUS).
For man in absence of permanent sterilization: condoms

Exclusion Criteria:

Patients :

With a matched related donor available
With uncontrolled infection
With seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive PCR HBV or HCV and associated hepatic cytolysis
Renal failure with creatinine clearance below 70% of higher normal values for age
Pregnant (βHCG positive) or breast-feeding
With Heart failure according to NYHA (II or more)
Preexisting acute hemorrhagic cystitis
Urinary tract obstruction
Yellow fever vaccine within 2 months before transplantation
Who have any debilitating medical or psychiatric illness, which preclude understanding the inform consent as well as optimal treatment and follow-up (depending of his age and understanding).
With Contraindication to treatments used during the research

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HSCT arm group

Arm Description

Conditioning regimen Stem cell source Only Bone Marrow With a minimal target dose of 4x108 nucleated cells/kg recipient ideal body weight. If the graft is less rich than the minimum target dose, it can be administered at the discretion to the physician. GVHD Prophylaxis Prevention of EBV reactivation : Rituximab 150mg/m2 IV at Day+5 post HSCT.

Outcomes

Primary Outcome Measures

Proportion of patients with upfront matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) effectively performed

Proportion of patients with upfront matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) effectively performed in the first two months after unrelated donor search.

Secondary Outcome Measures

Graft failure incidence

Neutrophils engraftment

Neutrophils engraftment will be defined as first day of 3 consecutive days with neutrophils >0.5 G/L

Platelets engraftment

Platelets engraftment will be defined as first day of 7 consecutive days with platelets >20 G/L

Absolute number of neutrophils

Absolute numbers of platelets

Acute GvHD incidence

Chronic GvHD incidence

Relapse incidence

Progression free survival

Incidence of CMV infection

Incidence of EBV infection

Incidence of severe infections

Severe infections will be defined as CTACE grade 3-4

Incidence of severe infections

Severe infections will be defined as CTACE grade 3-4

Incidence of severe infections

Severe infections will be defined as CTACE grade 3-4

Incidence of severe infections

Severe infections will be defined as CTACE grade 3-4

Non-relapse mortality

Overall survival

Quality of life questionnaires PedsQL

Quality of life will be evaluated using PedsQL questionnaire. Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Quality of life questionnaires PedsQL

Quality of life will be evaluated using PedQQL questionnaire.Higher scores associated with better health-related quality of life. Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Quality of life questionnaires PedsQL

Quality of life will be evaluated using PedsQL questionnaire. Higher scores associated with better health-related quality of life. Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Quality of life questionnaires PedsQL

Quality of life will be evaluated using PedsQL questionnaire.Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Quality of life questionnaires PedsQL

Quality of life will be evaluated using PedsQL questionnaire.Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Proportion of patients with a donor chimerism of 90% or more

Immune reconstitution

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL

Immune reconstitution

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL

Immune reconstitution

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL.

Immune reconstitution

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL.

Ferritin levels

Full Information

NCT ID

NCT05419843

First Posted

May 23, 2022

Last Updated

June 10, 2022

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT05419843

Brief Title

Up-front Matched Unrelated Donor Transplantation in Pediatric Patients With Idiopathic Aplastic Anemia

Acronym

UPFRONT-MUD

Official Title

Up-front Matched Unrelated Donor Transplantation in Pediatric Patients With Idiopathic Aplastic Anemia: a Phase II Feasibility Study

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Not yet recruiting

Study Start Date

June 2022 (Anticipated)

Primary Completion Date

August 2025 (Anticipated)

Study Completion Date

June 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Pediatric patients with idiopathic aplastic anemia (AA) respond better than adults to immunosuppressive therapy (IST) but the long-term risks of relapse, ciclosporine dependence, and clonal evolution are high. UK investigators reported a 5-year estimated failure-free survival (FFS) after IST of 13.3%. In contrast, in 44 successive children who received a matched unrelated donor (MUD), hematopoietic stem cell transplantation (HSCT), there was an excellent estimated 5-year FFS of 95%. Forty of these children had previously failed IST. Because of those excellent results, up-front fully matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) became an attractive first-line option. In 2005 to 2014, a UK cohort of 29 children with idiopathic AA thus received MUD HSCTs as first-line therapy (they did not receive IST prior to HSCT). Results were excellent, with low Graft versus Host Disease rates and only 1 death (idiopathic pneumonia). This cohort was then compared with historical matched controls, transplanted or not. Outcomes for the up-front unrelated cohort HSCT were similar to Matched Related Donor HSCT and superior to IST and unrelated HSCT post-IST failure. Since then, many investigators are offering up-front MUD HSCT in pediatric patients worldwide. However, those results should be treated with extreme caution: 1) the design is retrospective; 2) the excellent up-front MUD HSCT may arise from the use of alemtuzumab in the conditioning regimen (alemtuzumab is not easily available worldwide) and 3) there was no formal quality-of-life assessment. Moreover, this strategy is highly dependent on donor identification (Caucasian patients have the highest likelihood of having a MUD) and donor not eventually receive HSCT because of the risk of infections/complications caused by unexpected donor delays or cancellation. Prospective trials are thus urgently needed to address the feasibility of such procedure, in term of timing (delay to offer MUD HSCT) and conditioning regimen (nothing is known of the use of other regimens, non alemtuzumab-based, in this setting). The main objective of this Two-Stage Phase 2 multicenter study is to realize up-front HSCT within 2 months once a MUD has been identified.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Idiopathic Aplastic Anemia, Severe Aplastic Anemia, Moderate Aplastic Anemia Requiring Transfusions

7. Study Design

Primary Purpose

Other

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

25 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

HSCT arm group

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

HSCT Arm group

Intervention Description

Primary Outcome Measure Information:

Title

Proportion of patients with upfront matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) effectively performed

Description

Proportion of patients with upfront matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) effectively performed in the first two months after unrelated donor search.

Time Frame

within 2 months (60 days) after identification of a MUD

Secondary Outcome Measure Information:

Title

Graft failure incidence

Time Frame

up to 24 months

Title

Neutrophils engraftment

Description

Neutrophils engraftment will be defined as first day of 3 consecutive days with neutrophils >0.5 G/L

Time Frame

at day 100

Title

Platelets engraftment

Description

Platelets engraftment will be defined as first day of 7 consecutive days with platelets >20 G/L

Time Frame

at day 100

Title

Absolute number of neutrophils

Time Frame

at 1 month

Title

Absolute number of neutrophils

Time Frame

at 2 months

Title

Absolute number of neutrophils

Time Frame

at 3 months

Title

Absolute number of neutrophils

Time Frame

at 6 months

Title

Absolute number of neutrophils

Time Frame

at 12 months

Title

Absolute number of neutrophils

Time Frame

at day of last platelet and red blood cell transfusions (assessed up to 24 months)

Title

Absolute numbers of platelets

Time Frame

at 1 month

Title

Absolute numbers of platelets

Time Frame

at 2 months

Title

Absolute numbers of platelets

Time Frame

at 3 months

Title

Absolute numbers of platelets

Time Frame

at 6 months

Title

Absolute numbers of platelets

Time Frame

at 12 months

Title

Absolute numbers of platelets

Time Frame

up to 24 months

Title

Acute GvHD incidence

Time Frame

at month 3

Title

Chronic GvHD incidence

Time Frame

at 24 months

Title

Relapse incidence

Time Frame

at 12 months

Title

Relapse incidence

Time Frame

at 24 months

Title

Progression free survival

Time Frame

at 12 months

Title

Progression free survival

Time Frame

at 24 months

Title

Incidence of CMV infection

Time Frame

at 12 months

Title

Incidence of EBV infection

Time Frame

at 12 months

Title

Incidence of severe infections

Description

Severe infections will be defined as CTACE grade 3-4

Time Frame

at 3 months

Title

Incidence of severe infections

Description

Severe infections will be defined as CTACE grade 3-4

Time Frame

at 6 months

Title

Incidence of severe infections

Description

Severe infections will be defined as CTACE grade 3-4

Time Frame

at 12 months

Title

Incidence of severe infections

Description

Severe infections will be defined as CTACE grade 3-4

Time Frame

at 24 months

Title

Non-relapse mortality

Time Frame

at 24 months

Title

Overall survival

Time Frame

at 24 months

Title

Quality of life questionnaires PedsQL

Description

Quality of life will be evaluated using PedsQL questionnaire. Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Time Frame

at inclusion

Title

Quality of life questionnaires PedsQL

Description

Time Frame

at 1 month

Title

Quality of life questionnaires PedsQL

Description

Time Frame

at 3 months

Title

Quality of life questionnaires PedsQL

Description

Time Frame

at 6 months

Title

Quality of life questionnaires PedsQL

Description

Quality of life will be evaluated using PedsQL questionnaire.Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Time Frame

at 12 months

Title

Quality of life questionnaires PedsQL

Description

Quality of life will be evaluated using PedsQL questionnaire.Scores varies from 0 to100, with higher scores associated with better health-related quality of life.

Time Frame

at 24 months

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 1 month

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 3 months

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 6 months

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 12 months

Title

Immune reconstitution

Description

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL

Time Frame

at 3 months

Title

Immune reconstitution

Description

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL

Time Frame

at 6 months

Title

Immune reconstitution

Description

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL.

Time Frame

at 12 months

Title

Immune reconstitution

Description

Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL.

Time Frame

at 24 months

Title

Ferritin levels

Time Frame

at 3 months

Title

Ferritin levels

Time Frame

at 6 months

Title

Ferritin levels

Time Frame

at 12 months

Title

Ferritin levels

Time Frame

at 24 months

10. Eligibility

Sex

All

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: age<18years old Pediatric patients aged less than 18 years with idiopathic aplastic anemia and an indication for treatment (severe aplastic anemia or moderate aplastic anemia requiring transfusions) With a good probability to have a HLA-10/10 matched unrelated donor available (the patient needs to have at least 3 MUD identified within the book BMDW (Bone Marrow Donors Worldwide) or using the easy match software to be included) With usual criteria for allo-SCT: Lansky >70% for those below 16 years and Karnofsky > 70% for those above 16 years No severe and uncontrolled infection Adequate organ function: ASAT and ALAT ≤ 5N*, total bilirubin ≤ 2N, creatinine clearance > 70% of higher normal values for age. With health insurance coverage Contraception methods** for young girl and men of childbearing age must be prescribed during all the duration of the research. Parents having read and understand the information note and signed a written informed consent (the patient's agreement depending on his age will be sought) *because typical presentation of aplastic anemia post-hepatitis ** NB : The authorized contraceptive methods are: For women of childbearing age and in absence of permanent sterilization: oral, intravaginal or transdermal combined hormonal contraception, oral, injectable or transdermal progestogen-only hormonal contraception, intrauterine hormonal-releasing system (IUS). For man in absence of permanent sterilization: condoms Exclusion Criteria: Patients : With a matched related donor available With uncontrolled infection With seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive PCR HBV or HCV and associated hepatic cytolysis Renal failure with creatinine clearance below 70% of higher normal values for age Pregnant (βHCG positive) or breast-feeding With Heart failure according to NYHA (II or more) Preexisting acute hemorrhagic cystitis Urinary tract obstruction Yellow fever vaccine within 2 months before transplantation Who have any debilitating medical or psychiatric illness, which preclude understanding the inform consent as well as optimal treatment and follow-up (depending of his age and understanding). With Contraindication to treatments used during the research

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jean-Hugues Pr DALLES

Phone

+33140035388

jean-hugues.dalle@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Matthieu RESCHE-RIGON

Phone

+33142499742

mathieu.resche-rigon@u-paris.fr

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Learn more about this trial

Up-front Matched Unrelated Donor Transplantation in Pediatric Patients With Idiopathic Aplastic Anemia

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