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Cyclophosphamide

Calcineurin Inhibitors

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Alkylating Agents

Matched sibling transplants will receive PTCy + ATG2.5 ± ATG1.5

Unrelated transplants will receive PTCy + ATG5.0

ATG 5.0

Cyclophosphamide 50 mg/kg on days +3 and +4

Cyclophosphamide injection

ATG 2.5 mg/kg on day -1 ± 1.5 mg/kg on day -2

ATG 2.5±1.5

Leonardo J Arcuri, MD, PhD

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.

Patients with a matched sibling donor will be assigned to the PTCy+ATG2.5±1.5 arm, while patients with an matched unrelated donor will be assigned to the PTCy+ATG5.0 arm

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

Upon finalization of the study, data will be shared on reasonable requests.

Cumulative incidence of acute graft-versus-host disease, grades III-IV by the MAGIC criteria

Cumulative incidence of acute graft-versus-host disease, grades II-IV by the MAGIC criteria

Cumulative incidence of steroid-refractory graft-versus-host disease

Cumulative incidence of chronic graft-versus-host disease

Cumulative incidence of steroid-requiring chronic graft versus host disease

Cumulative incidence of death not caused by primary malignant disease or following relapse

Cumulative incidence of relapse of primary malignant disease

Composite outcome of death or primary disease relapse

Incidence of cytomegalovirus reactivation

Incidence of posttransplant lymphoproliferative disorder

Cumulative incidence of cytomegalovirus disease

Instituto Nacional de Cancer, Brazil

Leukemia, Myelomonocytic, Juvenile

Leukemia, Biphenotypic, Acute

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Acute Leukemia of Ambiguous Lineage

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Gastrointestinal Agents

Abatacept

Vedolizumab

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Enzyme Inhibitors

Cyclophosphamide 100 mg/kg/course on the days +3, +4 Abatacept 10 mg/kg/day on the days +5, +14, +28, +45, +60, +90, +120 Vedolizumab 10 mg/kg/day, max. 300 mg on the days -1, +14, +28

GVHD prevention: post-transplantation cyclophosphamide, abatacept, vedolizumab, calcineurin inhibitor

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

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 Cyclophosphamide 50 mg/kg/course on the days -3, -2 or Etoposide 60 mg/kg on the days -6, -5 Fludarabine 150 mg/m2/course on the days -6, -5, -4, -3, -2

Prevention of GVHD:

Cyclophosphamide 100 mg/kg/course on the days +3, +4 Abatacept 10 mg/kg/day on the days +5, +14, +28, +45, +60, +90, +120 Vedolizumab 10 mg/kg/day, max. 300 mg on the days -1, +14, +28 Cyclosporine A or Tacrolimus 3 mg/kg/day from -1 to 120 (in case of high risk of relapse: patients with JMML, without of remission o positive MRD after HSCT)/180 days or Ruxolitinib (in case of intolerance to calcineurin inhibitors) 5m/day for patients \<12 years old and 10 mg/day for patients \>12 years old by scheme of CNI.

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

Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients 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 Calcineurin Inhibitor at Children and Young Adults With Hemoblastosis After Hematopoietic Stem Cell Transplantation From an Unrelated or Haploidentic Donor

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PTCy and ATG for MSD and MUD Transplants	NCT06299462	Acute Myeloid L... Acute Lymphobla... Myelodysplastic... Hodgkin Lymphom... Non-hodgkin Lym...	ATG 5.0 Cyclophosphamid... ATG 2.5±1.5	18 Years - 60 Years	Instituto Nacional de Cancer, Brazil
Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis	NCT05515029	Acute Lymphobla... Myeloblastic Le... Biphenotypic Ac... Malignant Lymph... Myelodysplastic... Juvenile Myelom...	GVHD prevention...	1 Day - 21 Years	Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis	NCT05515029	Acute Lymphobla... Myeloblastic Le... Biphenotypic Ac... Malignant Lymph... Myelodysplastic... Juvenile Myelom...	GVHD prevention...	1 Day - 21 Years	Federal Research Institute of Pediatric Hematology, Oncology and Immunology
PTCy and ATG for MSD and MUD Transplants	NCT06299462	Acute Myeloid L... Acute Lymphobla... Myelodysplastic... Hodgkin Lymphom... Non-hodgkin Lym...	ATG 5.0 Cyclophosphamid... ATG 2.5±1.5	18 Years - 60 Years	Instituto Nacional de Cancer, Brazil

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