Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor

GVHD Clinical Trial

— OPTISAGE  

Official title:

Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor Following a Reduced Intensity Conditioning Regimen by Fludarabine-treosulfan

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06083129
• Other study ID #: APHP230276
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: November 1, 2023
• Est. completion date: November 1, 2028

Study information

• Verified date: July 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Régis Peffault de Latour, Pr
• Phone: +33142385073
• Email: regis.peffaultdelatour[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Most of the patients requiring an allo-HSCT are above 50 years of age and are transplanted with a reduced intensity conditioning (RIC) regimen. The optimal RIC and Graft Versus Host Disease (GVHD) prophylaxis regimen allowing a good control of the disease while preventing GVHD remains to be determined for elderly patients. A phase III trial comparing the conventional RIC fludarabine-busulfan 2 days to fludarabine-treosulfan demonstrated an advantage for the flu-treosulfan arm in terms of event free survival (EFS), that should therefore be considered as the new standard of RIC regimen for AML and MDS. GVHD prevention has a crucial role in post-transplant outcomes by potentially interfering with the graft-versus-leukemia (GVL) effect and immune reconstitution. Anti-thymocyte globulins (ATG) are recommended to reduce the risk of acute and chronic GVHD in transplants performed with matched unrelated donors. However, the optimal type of ATG between the 2 approved brands (ATG-thymoglobulin and ATLG-grafalon) displaying distinct characteristics and the optimal dose of ATG are still unknown. In a retrospective study of patients transplanted mainly with RIC with matched related and unrelated donors for haematological malignancies, we observed that Anti-T lymphocyte globulin (ATLG) was associated with a reduction of grade II-IV acute GVHD in comparison to ATG without increasing the incidence of relapse.

In this phase III randomised study, we propose to compare GVHD prevention with ATG versus ATLG in AML and MDS patients above 50 years of age transplanted with a matched unrelated donor following a fludarabine-treosulfan RIC, with the hypothesis that ATLG would better control GVHD in this population of patients thus limiting the risk of morbidity and mortality of the procedure.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 324
• Est. completion date: November 1, 2028
• Est. primary completion date: February 15, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Age = 50 and = 70 years

2. Patient between 50 and 55 years should be unfit for a myeloblative conditioning (SORROR score =2)

3. AML requiring allogeneic stem cell transplantation (intermediate or high-risk AML) in complete cytologic response (CR1 or above) or MDS requiring allogeneic stem cell transplantation (IPSS= 1.5 or IPSS-R > 4.5 or IPSS-R > 3-4.5 with risk features [rapide blast increase, life-threatening neutropenia (<0.3 G/L) or thrombopenia (<30G/L) or high transfusion needs (>2/month for 6 months)]

4. Without an HLA matched related donor

5. Having an identified matched HLA 10/10 unrelated donor

6. With usual criteria for HSCT:

1. ECOG performans status = 2

2. No severe and uncontrolled infection

3. Cardiac left ventricular ejection fraction =50%

4. Lung DLCO > 40%

5. Adequate organ function: ASAT and ALAT = 3N, total bilirubin = 2N, creatinine clearance = 50 mL/min (except if those abnormalities are linked to the hematological disease)

7. With health insurance coverage

8. Having signed a written informed consent

9. Contraception methods must be prescribed during all the duration of the research

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), sexual abstinence (only if this the preferred and usual lifestyle of the participants).

• For man in absence of permanent sterilization: sexual abstinence, condoms

Exclusion Criteria:

1. Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)

2. Uncontrolled infection

3. Seropositivity for HIV or HTLV-1 or active hepatitis B or C

4. Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation

5. Heart failure according to NYHA (II or more) or Left ventricular ejection fraction < 50%.

6. Lung DLCO = 40%

7. Preexisting acute hemorrhagic cystitis

8. Renal failure with creatinine clearance < 50ml / min

9. Pregnancy (ß-HCG positive) or breast-feeding

10. Patients with any debilitating medical or psychiatric illness, which would preclude the realization of the SCT or the understanding of the protocol

11. Patient under state medical aid

12. Patient under legal protection (protection of the court, or in curatorship or guardianship).

13. For Grafalon: Hypersensitivity to the active substance or to any of the excipients

14. For Thymoglobulin: Hypersensitivity to rabbit proteins or to any of the excipients

15. Participation in other interventional clinical trials

16. Any contraindication mentioned in the SmPC of all auxiliary medicinal products planned to be used in the trial: cyclosporine, mycophenolate mofetil, fludarabine, treosulfan

Related Conditions & MeSH terms

• GVHD
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Grafalon
10 mg/Kg/day IV for 3 consecutive days (day-3 to -1 before transplantation)
• Thymoglobulin
2.5 mg/Kg/day IV for 2 consecutive days (day-3 and -2 before transplantation)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of grade II-IV acute Graft Versus Host Disease (GVHD) according to the Mount Sinai Acute GVHD International Consortium (MAGIC) classification	Acute GVHD MAGIC classification permit to diagnose and score the severity of acute GVHD.; MAGIC score varies from Grade 0 to Grade 4. The higher the score the more severe the damage.	At day 100 post-transplantation
Secondary	Number of patients with at least 3 consecutive days with neutrophils > 0.5 G/L and platelets > 20 G/L	Hematopoietic recoveries	Up to 24 months
Secondary	T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood	Immune reconstitution	1 month after transplantation
Secondary	T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood	Immune reconstitution	100 days after transplantation
Secondary	T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood	Immune reconstitution	6 months after transplantation
Secondary	T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood	Immune reconstitution	12 months after transplantation
Secondary	T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood	Immune reconstitution	24 months after transplantation
Secondary	Percentage of chimerism		1 month after transplantation
Secondary	Percentage of chimerism		100 days after transplantation
Secondary	Percentage of chimerism		6 months after transplantation
Secondary	Percentage of chimerism		12 months after transplantation
Secondary	Incidence of grade I acute GVHD	Treatments for acute GVHD will be described : first line treatment, response to steroids, treatment courses for refractory acute GVHD	Up to 24 months
Secondary	Incidence of chronic GVHD	Incidence of chronic GVHD according to National Institutes of Health (NIH) classification. The gradation of chronic GvHD is defined by the number and score of affected organ. The higher the score of each organ and the higher the number of organs affected, the more severe the damage.	12 months after transplantation
Secondary	Incidence of chronic GVHD	Incidence of chronic GVHD according to National Institutes of Health (NIH) classification. The gradation of chronic GvHD is defined by the number and score of affected organ. The higher the score of each organ and the higher the number of organs affected, the more severe the damage.	24 months after transplantation
Secondary	Incidence of relapse	Relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).	12 months after transplantation
Secondary	Incidence of relapse	Relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).	24 months after transplantation
Secondary	Progression free survival		12 months after transplantation
Secondary	Progression free survival		24 months after transplantation
Secondary	Number of severe infections	Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events	100 days after transplantation
Secondary	Number of severe infections	Severe infections correspond to grade 3-4 according to Common Terminology Criteria for Adverse Events	12 months after transplantation
Secondary	Incidence of CytoMegaloVirus (CMV) reactivation		100 days after transplantation
Secondary	Incidence of CytoMegaloVirus (CMV) reactivation		6 months after transplantation
Secondary	Incidence of CytoMegaloVirus (CMV) reactivation		12 months after transplantation
Secondary	Incidence of Ebstein Barr Virus (EBV) reactivation		100 days after transplantation
Secondary	Incidence of Ebstein Barr Virus (EBV) reactivation		6 months after transplantation
Secondary	Incidence of Ebstein Barr Virus (EBV) reactivation		12 months after transplantation
Secondary	Non-relapse mortality		6 months after transplantation
Secondary	Non-relapse mortality		12 months after transplantation
Secondary	Non-relapse mortality		24 months after transplantation
Secondary	Overall survival		12 months after transplantation
Secondary	Overall survival		24 months after transplantation
Secondary	GVHD and relapse free survival (GRFS)	Defined by being alive without disease relapse and without having developed acute grade III-IV or severe chronic GVHD	Up to 24 months after transplantation
Secondary	Health-related Quality of life	Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.	At inclusion
Secondary	Health-related Quality of life	Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.	100 days after transplantation
Secondary	Health-related Quality of life	Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.	6 months after transplantation
Secondary	Health-related Quality of life	Assessed by using the FACT-BMT-v4 questionnaire. It is a 50 items score. The score varies between 0 to 200. The higher the score the lower the quality of life.	12 months after transplantation
Secondary	Number of days of hospitalization for the transplant and after the hospitalization for transplantation related complications		Up to 12 months after transplantation
Secondary	Incidence and severity of veino-occlusive disease (VOD)		100 days after transplantation
Secondary	Lymphocyte counts on standard blood counts before conditioning		7 days before transplantation
Secondary	Number of late acute GvHD, overlap syndromes and chronic GvHD		from day 100 to day 120 after transplantation