Preventing of GVHD with Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Ruxolitinib At Children and Young Adults with Hemoblastosis

Prospective Pilot Study of the Clinical Efficacy and Safety of the Method for Preventing a Graft-versus-host Disease Through the Agency of Using the Combination of Post-transplantation Cyclophosphamide with Abatacept, Vedolizumab and Ruxolitinib At Children and Young Adults with Hemoblastosis After Hematopoietic Stem Cell Transplantation from an Unrelated or Haploidentic Donor

GVHD prevention using a combination of post-transplantation cyclophosphamide in combination with abatacept, vedolizumab and Ruxolitinib in children and young adults with hematoloblastosis after myeloablative conditioning regimen with treosulfan/TBI, etoposide, fludarabine after HSCT from matched unrelated and haploidentical donors

Study Overview

• Status: Recruiting
• Conditions: Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Myeloblastic Leukemia; Biphenotypic Acute Leukemia; Malignant Lymphoma, Non-Hodgkin; Bilinear Leukemia
• Intervention / Treatment: Drug: Conditioning regimen: Treosulfan 42 g/m2/course or total body irradiation 12 Gray/course, Etoposide 60 mg/kg , Fludarabine 150

Detailed Description

Conditioning regimen:

Treosulfan 42 g/m2/course on the days -5, -4, -3 or total body irradiation 12 Gray/course on the days -8, -7, -6 Etoposide 60 mg/kg on the days -6, -5. or Thiotepa 10 mg/kg -6,-5 Fludarabine 150 mg/m2/course on the days -6, -5, -4, -3, -2

Prevention of GVHD:

Cyclophosphamide 80 mg/kg/course on the days +3, +4 Abatacept 10 mg/kg/day on the days +5, +14, +28, +60, +90 Vedolizumab 10 mg/kg/day, max. 300 mg on the days 0, +14, +28, +60

Ruxolitinib 10 mg/m2 per os, from day -3 to day +90 (after HSCT), orally, twice a day.

Donor selection criteria

In case of detection of two or more suitable donors, the choice is made in favor of:

• CMV Compliance
• Sex of donor and recipient
• medical and psychological suitability and desire of the donor
• Compatibility by blood type

Duration of therapy

• 120 days (for patients with high risk of recurrence: positive minimal residual disease before HSCT, non-remission status after HSCT, patients diagnosed with juvenile myelomonocytic leukemia)
• 180 days (for the rest) Time of observation
• follow up during 3 years after HSCT

Criteria for premature stopping of the study

1. The probability of developing acute GVHD II-IV is above 40%, of which III-IV - above 15%
2. The probability of 100-day transplant-associated mortality is higher than 20%. Goal Evaluation Date Intermediate analysis after 1 year from the beginning. The final analysis is scheduled to take place 100 days after the last patient is included.

Data Monitoring and Management

1. Plan of initial examination of the patient

After signing the informed consent and registration, the patient undergoes an examination in accordance with the standard plan of pre-transplantation examination and additional examinations, including:

• Confirmation of remission status, determination of MRD, chimerism according to the protocol 1. Monitoring of donor chimerism in patients with acute leukemia Point Days Lines

  1 +30 day general, CD34

• Only if a relapse of the disease is suspected, cm can be sent to study chimerism:

  • General

  • Chimerism in the sorted MRD fraction 2. Minimal residual disease (MRD) monitoring in patients with ALL +30, +100 days after HSCT - for all patients: MRD (immunophenotyping), Cytogenetics (if it presence)

    + 60, +180 days after HSCT - for patients with MRD + or refractory before HSCT: MRD (immunophenotyping), Cytogenetics (if it presence) 3. Minimal residual disease (MRD) monitoring in patients with AML

    +100 days after HSCT - for all patients: MRD (immunophenotyping), Cytogenetics (if it presence)

    + 30, +180 days after HSCT - for patients with MRD + or refractory before HSCT: MRD (immunophenotyping), Cytogenetics (if it presence)

    4. Biobanking (KM, blood)

In this protocol, in addition to routine post-transplantation monitoring, the following studies are carried out:

• Study of the subpopulation composition of peripheral blood lymphocytes: B-cells: CD19

T-cells:

CD3/4/8/ TCR/gd CD3/4/8/45RA/CCR7 (CD197) CD3/4/31/45RA CD4/25/127

NK-compartment:

CD3/CD56

TCR repertoire:

Analysis multiplicity: +30, +60, +100, +180, +360 day The amount of blood for analysis is 5 ml in a test tube with EDTA.

• Pathogen-specific immunoreconstitution research - ELISPOT method for evaluating the production of gamma-interferon by peripheral blood mononuclears after incubation with microbial antigens. The main antigens studied are (CMV pp65, EBV, Adenovirus (AdvHexon), BK virus) Multiplicity of analysis of recipients: +30, +60, +100, +180, +360. The amount of blood for analysis on +30 days is 10 ml, subsequently - 5 ml in a test tube with EDTA.
• Virological monitoring by PCR weekly:

Blood: CMV, EBV, ADV by PCR method Chair: ADV MONITORING by PCR is carried out up to 100 days after CGSC. The exception is patients with viremia, or receiving immunosuppressive therapy on day 100.

in case of suspected visceral lesion: cerebrospinal fluid / bal / stool / urine / biopsy / other material

• Biobanking Multiplicity: + 30, +60, +100, +180, +360 Blood in a test tube with EDTA, used 2. Toxicity monitoring:
• Diagnosis and therapy of acute GVHD Clinical diagnosis and staging of acute GVHD is carried out in accordance with standard criteria (Appendix No. 3).

When an isolated rash appears, a skin biopsy is mandatory. When a clinic of acute GVHD appears with damage to the upper and lower gastrointestinal tract (nausea, vomiting, enterocolitis), gastroscopy with a biopsy of the gastric mucosa and colonoscopy with a floor biopsy is reokended.

The biopsy material should also be sent for virological examination. Before starting therapy, a consultation is held with the head of the protocol / appointed expert.

• Criteria for prescribing systemic immunosuppressive therapy: Acute GVHD stage I - therapy is not carried out Acute GVHF stage II-IV - methylprednisolone 1-2 mg / kg / day IV The period for assessing the response to first-line therapy: 72 hours, 7 days, 14 days from the start of therapy.

• Criteria for prescribing second-line therapy: progression of manifestations of O.RTPH after 72 hours or no improvement after 7 days or incomplete resolution of clinical and laboratory manifestations after 14 days

• Diagnosis and therapy of chronic GVHD: Diagnosis and staging of chronic GVHD are performed in accordance with THE NIH criteria (Appendix No. 4). Due to the fact that the development of chronic GVHD is one of the main parameters for the evaluation of the study, the diagnosis and staging of chronic GVHD are performed prospectively, monthly from the day +100, using a structured examination in accordance with Appendix No. 2.

Therapy of chronic GVHD is carried out in accordance with the standard adopted in the clinic

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Maschan Michael,, MD, PhD; Phone Number: +79166512145; Email: mmaschan@yandex.ru

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 117198
    • Recruiting
    • National medical research center of pediatric haematology, oncology and immulogy named after Dmytriy Rogachyov
    • Contact: Maschan Michael; Phone Number: +79166512145; Email: mmaschan@yandex.ru

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients under the age of 21 years with following diseases:

• acute lymphoblastic,
• myeloblastic,
• biphenotypic,
• bilinear leukemia,
• malignant lymphoma,
• myelodysplastic syndrome,

Exclusion Criteria:

Age over 21 years

• Patients with ALL outside clinical and hematological remission

• Clinical status:

  • Lansky/Karnowski index <70% (supplement No.1)
  • Heart function: left ventricular ejection fraction <40% according to ultrasound of the heart1
  • Kidney function: clearance of endogenous creatinine < 70 ml / min
  • Liver function: total bilirubin, ALT, AST, ALP > 2 norms
  • Lung function: lung capacity <50%, for children who cannot carry out of respiratory function - oxygen saturation during pulse oximetry <92%
• Uncontrolled viral, fungal or bacterial infection.
• Mental illness of the patient or caregivers, making it impossible to realize the essence of the study and compromising compliance with medical appointments and sanitary and hygienic regime 1 These patients may receive treatment according to the protocol, but the results will be evaluated separately

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Prevention of GVHD: Cyclophosphamide, Abatacept, Vedolizumab, Ruxolitinib; GVHD prevention using a combination of post-transplantation cyclophosphamide in combination with abatacept, vedolizumab and Ruxolitinib in children and young adults with hematoloblastosis after myeloablative conditioning regimen

Drug: Conditioning regimen: Treosulfan 42 g/m2/course or total body irradiation 12 Gray/course, Etoposide 60 mg/kg , Fludarabine 150; The most significant adverse events limiting the use of HSCT from an unrelated donor are graft-versus-host disease (GVHD) and prolonged immunodeficiency associated with the development of severe infectious complications. The use of post-transplant cyclophosphamide for the prevention of GVHD during allogeneic HSCT from unrelated and haploidentical donors has reduced the incidence of acute clinically significant GVHD in children to 25%, chronic GVHD to 12-30%, but the issue of GVHD control still remains extremely relevant. Emerging data on the use of abatacept, a selective blocker of the costimulatory signal from an antigen-presenting cell, in the prevention of intestinal GVHD and data on the effectiveness of Janus-kinase type 1/2 inhibitors (JAK-1/2) in the treatment and prevention of acute GVHD allow us to justify the use of these drugs in combination with post-transplant cyclophosphamide as a promising pharmacological platform for the prevention of GVHD.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1. Cumulative Incidence stage II-IV after HSCT	Estimate the probability of developing acute GVHD stage II-IV after HSCT-	up to 100 days
Kaplan Meier overal survival	Explore the safety based on an assessment of the frequency of occurrence severe (3-5 degrees) side effects of conditioning- 100-day transplant-associated mortality	up to 100 days
1. Cumulative Incidence stage II-IV after HSCT	Estimate the probability of developing acute GVHD stage II-IV after HSCT	up to 100-day
Kaplan Meier event free survival	Explore the safety based on an assessment of the frequency of occurrence severe (3-5 degrees) side effects of conditioning	during 1 month
Kaplan Meier event free survival	Explore the safety based on an assessment of the frequency of occurrence severe (3-5 degrees) side effects of conditioning- 100-day transplant-associated mortality	up to 100 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
event-free survival	Probability of developing a relapse of the primary disease, transplantation-associated mortality on the horizon of 100 days, general and event-free survival	up to 100 days
Cumulative Incidence of leukocyte engraftment	Probability and kinetics of engraftment of leukocyte and platelet sprouts of donor origin	up to 30 days
Cumulative Incidence of platelet engraftment	Probability and kinetics of engraftment of leukocyte and platelet sprouts of donor origin	up to 30 days
Cumulative Incidence reactivation of CMV	Probability of reactivation of CMV, EBV, AdV, HHV6 infection	up to 6 mouth or up to immunreconstitution
box plot	Kinetics of general and pathogen-specific immunoreconstitution	up to 1 year
Cumulative Incidence of chronic GVHD	Probability of the development of chronic GVHD, its severity and the nature of the involvement of organs and tissues.	up to 1 year
Cumulative Incidence reactivation of EBV	Probability of reactivation of CMV, EBV, AdV, HHV6 infection	up to 6 mouth or up to immunreconstitution
Cumulative Incidence reactivation of AdV	Probability of reactivation of CMV, EBV, AdV, HHV6 infection	up to 6 mouth or up to immunreconstitution
Cumulative Incidence reactivation of HHV6	Probability of reactivation of CMV, EBV, AdV, HHV6 infection	up to 6 mouth or up to immunreconstitution

Collaborators and Investigators

• Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2024
• Primary Completion (Estimated): July 10, 2026
• Study Completion (Estimated): October 10, 2026

Study Registration Dates

• First Submitted: December 13, 2024
• First Submitted That Met QC Criteria: December 24, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 24, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: AML; ALL; vedolizumab; Hematopoetic stem cell transplantation; posttransplant cyclophosphamide; hematoblastosis
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Bone Marrow Diseases; Leukemia, Lymphoid; Leukemia; Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Non-Hodgkin; Myelodysplastic Syndromes; Leukemia, Biphenotypic, Acute; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Fludarabine; Etoposide; Treosulfan
• Other Study ID Numbers: NCHPOI-2024-10

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No