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NCT Number: NCT05419843

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

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.

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Key information

Conditions

Idiopathic Aplastic Anemia Anemia Anemia, Aplastic Bone Marrow Diseases Bone Marrow Failure Disorders Hematologic Diseases Hemic and Lymphatic Diseases Moderate Aplastic Anemia Requiring Transfusions Severe Aplastic Anemia

Age range

Up to 18 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

HSCT Arm group

Other

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.

Primary outcomes

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

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

    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 outcomes

  1. Graft failure incidence

    Time frame: up to 24 months

  2. Neutrophils engraftment

    Time frame: at day 100

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

  3. Platelets engraftment

    Time frame: at day 100

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

  4. Absolute number of neutrophils

    Time frame: at 1 month

  5. Absolute number of neutrophils

    Time frame: at 2 months

  6. Absolute number of neutrophils

    Time frame: at 3 months

  7. Absolute number of neutrophils

    Time frame: at 6 months

  8. Absolute number of neutrophils

    Time frame: at 12 months

  9. Absolute number of neutrophils

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

  10. Absolute numbers of platelets

    Time frame: at 1 month

  11. Absolute numbers of platelets

    Time frame: at 2 months

  12. Absolute numbers of platelets

    Time frame: at 3 months

  13. Absolute numbers of platelets

    Time frame: at 6 months

  14. Absolute numbers of platelets

    Time frame: at 12 months

  15. Absolute numbers of platelets

    Time frame: up to 24 months

  16. Acute GvHD incidence

    Time frame: at month 3

  17. Chronic GvHD incidence

    Time frame: at 24 months

  18. Relapse incidence

    Time frame: at 12 months

  19. Relapse incidence

    Time frame: at 24 months

  20. Progression free survival

    Time frame: at 12 months

  21. Progression free survival

    Time frame: at 24 months

  22. Incidence of CMV infection

    Time frame: at 12 months

  23. Incidence of EBV infection

    Time frame: at 12 months

  24. Incidence of severe infections

    Time frame: at 3 months

    Severe infections will be defined as CTACE grade 3-4

  25. Incidence of severe infections

    Time frame: at 6 months

    Severe infections will be defined as CTACE grade 3-4

  26. Incidence of severe infections

    Time frame: at 12 months

    Severe infections will be defined as CTACE grade 3-4

  27. Incidence of severe infections

    Time frame: at 24 months

    Severe infections will be defined as CTACE grade 3-4

  28. Non-relapse mortality

    Time frame: at 24 months

  29. Overall survival

    Time frame: at 24 months

  30. Quality of life questionnaires PedsQL

    Time frame: at inclusion

    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.

  31. Quality of life questionnaires PedsQL

    Time frame: at 1 month

    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.

  32. Quality of life questionnaires PedsQL

    Time frame: at 3 months

    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.

  33. Quality of life questionnaires PedsQL

    Time frame: at 6 months

    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.

  34. Quality of life questionnaires PedsQL

    Time frame: at 12 months

    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.

  35. Quality of life questionnaires PedsQL

    Time frame: at 24 months

    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.

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

    Time frame: at 1 month

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

    Time frame: at 3 months

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

    Time frame: at 6 months

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

    Time frame: at 12 months

  40. Immune reconstitution

    Time frame: at 3 months

    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

  41. Immune reconstitution

    Time frame: at 6 months

    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

  42. Immune reconstitution

    Time frame: at 12 months

    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.

  43. Immune reconstitution

    Time frame: at 24 months

    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.

  44. Ferritin levels

    Time frame: at 3 months

  45. Ferritin levels

    Time frame: at 6 months

  46. Ferritin levels

    Time frame: at 12 months

  47. Ferritin levels

    Time frame: at 24 months

Study contacts

Contact information is provided by the study sponsor or research team.

Jean-Hugues Pr DALLES

CONTACT

[email protected]

+33140035388

Matthieu RESCHE-RIGON

CONTACT

[email protected]

+33142499742

Sponsors and collaborators

Lead sponsor

Assistance Publique - Hôpitaux de Paris

Other

Registry information

Official study title

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

Acronym: UPFRONT-MUD

Important dates

Study start
2022
Primary completion
2025
Study completion
2027
First posted
Jun 15, 2022
Registry last updated
Jun 15, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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