PTCy and ATG for MSD and MUD Transplants

Efficacy Evaluation of Post-transplant Cyclophosphamide-based Graft-versus-host Disease Prophylaxis With ATG, Calcineurin Inhibitor-free, for Matched-sibling or Matched-unrelated Transplantation

Hematopoietic stem cell transplantation is a curative treatment for a number of benign and malignant hematologic diseases. One of the key parts of hematopoietic stem cell transplantation is the prophylaxis of graft-versus-host disease. Since the end of the 1970s, with the introduction of cyclosporine, calcineurin inhibitors (cyclosporine and tacrolimus) have become part of almost all prophylactic regimens, even though they are a group of drugs with a poor toxicity profile that requires monitoring. constant serum level. Since 2008, post-transplant cyclophosphamide has been introduced with great success, associated with a calcineurin inhibitor and mycophenolate, in the prophylaxis of graft-versus-host disease in haploidentical transplantation (50% matched).

Since then, in view of this enormous success, efforts have been made to incorporate post-transplant cyclophosphamide in matched related and unrelated transplants, or with a mismatch.

This is a prospective, 2-arm, non-randomized study. Arm 1, with related donors, and arm 2, with unrelated donors. Patients will be allocated in these arms according to donor availability (patients with a matched-sibling donor will receive a matched-sibling transplant; patients with no related donors but with unrelated donors, an unrelated transplant).

Patients who are ready for transplantation with matched-sibling or unrelated donors will be recruited to participate in the study.

The stem cell collection target will be 5E6 CD34/kg recipient weight for peripheral source. If a quantity greater than this is collected, the remainder will be cryopreserved according to the institutional protocol.

Graft-versus-host disease prophylaxis will be performed on D+3 and D+4 with cyclophosphamide and with ATG on D-1 or on D-2 and D-1, depending on ATG de-escalation, for matched-sibling transplants, according to prespecified criteria based on the 3+3 approach; and on D+3 and D+4 with cyclophosphamide and with ATG on D-2 and D-1, for unrelated donors.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Hodgkin Lymphoma; Acute Lymphoblastic Leukemia; Non-hodgkin Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide injection; Drug: ATG 2.5±1.5; Drug: ATG 5.0

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

Contacts and Locations

• Study Contact: Name: Leonardo J Arcuri, MD, PhD; Phone Number: +5521981334715; Email: leonardojavier@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patient with (1) acute leukemia in first or second remission; (2) myelodysplasia with less than 20% blasts; (3) Hodgkin's or non-Hodgkin's lymphoma, in partial remission after salvage therapy
• Who will receive a related or unrelated, HLA-compatible transplant;
• Who is a transplant candidate with FluMel, FluTBI, CyTBI, BuCy or BuFlu conditioning;
• Peripheral blood source;
• Age between 18 and 60 years.

Exclusion Criteria:

• Renal dysfunction (Cr > 1.5 mg/dL)
• Hepatic dysfunction (transaminases x2 the normal value)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Matched-sibling donor transplants; Matched sibling transplants will receive PTCy + ATG2.5 ± ATG1.5	Drug: Cyclophosphamide injection; Cyclophosphamide 50 mg/kg on days +3 and +4; Drug: ATG 2.5±1.5; ATG 2.5 mg/kg on day -1 ± 1.5 mg/kg on day -2
Experimental: Matched unrelated donor transplants; Unrelated transplants will receive PTCy + ATG5.0	Drug: Cyclophosphamide injection; Cyclophosphamide 50 mg/kg on days +3 and +4; Drug: ATG 5.0; ATG 2.5 mg/kg on days -2 and -1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of grades III-IV acute GVHD by the MAGIC criteria	Cumulative incidence of acute graft-versus-host disease, grades III-IV by the MAGIC criteria	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of grades II-IV acute GVHD by the MAGIC criteria	Cumulative incidence of acute graft-versus-host disease, grades II-IV by the MAGIC criteria	6 months
Cumulative incidence of steroid-refractory acute GVHD as defined by Mohty et al PMID 32756949	Cumulative incidence of steroid-refractory graft-versus-host disease	6 months
Cumulative incidence of chronic GVHD as defined by the NIH criteria	Cumulative incidence of chronic graft-versus-host disease	3 years
Cumulative incidence of steroid-requiring chronic GVHD as defined by the NIH criteria	Cumulative incidence of steroid-requiring chronic graft versus host disease	3 years
Cumulative incidence of non-relapse mortality, i.e., death not following disease relapse	Cumulative incidence of death not caused by primary malignant disease or following relapse	3 years
Cumulative incidence of relapse, defined as > 5% blasts in bone marrow or 1% blasts in peripheral blood (acute leukemias/myelodysplasia) or biopsy proven relapse or positve PET-CT (lymphoma)	Cumulative incidence of relapse of primary malignant disease	3 years
Rate of overall survival	Death by any cause	3 years
Rate of disease-free survival (death or relapse)	Composite outcome of death or primary disease relapse	3 years
Cumulative incidence of clinically significant CMV reactivation (which led to antiviral treatment)	Incidence of cytomegalovirus reactivation	3 year
Cumulative incidence of posttransplant lymphoproliferative disorder (biopsy-proven or positive EBV PCR combined with clinical symptoms)	Incidence of posttransplant lymphoproliferative disorder	3 years
Cumulative incidence CMV disease (biopsy-proven CMV disease OR suggestive CMV+ BAL)	Cumulative incidence of cytomegalovirus disease	3 years
Measuremnt of quality of life using the FACT-BMT scale	Measurement quality of life	2 years

Collaborators and Investigators

• Sponsor: Instituto Nacional de Cancer, Brazil
• Investigators: Principal Investigator: Leonardo J Arcuri, MD, PhD, Instituto Nacional de Câncer

Study record dates

Study Major Dates

• Study Start (Estimated): May 21, 2024
• Primary Completion (Estimated): June 1, 2031
• Study Completion (Estimated): June 1, 2031

Study Registration Dates

• First Submitted: March 13, 2023
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 7, 2024

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: graft-versus-host disease; ATG; posttransplant cyclophosphamide; calcineurin-free GVHD prophylaxis
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Lymphoma; Myelodysplastic Syndromes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: PTCy-ATG-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Upon finalization of the study, data will be shared on reasonable requests.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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