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Two key methods of GVHD prevention in allogeneic HSCT have a number of limitations: ex vivo T depletion is associated with an excess of infectious complications, and pharmacological immunosuppression with insufficient efficacy of GVHD prevention. Modern graft engineering technologies make it possible to create a graft with a balanced cell composition, reducing the risk of adverse events, in particular, severe forms of acute and chronic GVHD, while preserving the immunological function of the graft. In the proposed concept, enrichment of the T graft with regulatory cells will reduce the risk of GVHD and preserve a sufficient number of T lymphocytes in the graft for the formation of protective anti-infective immunity in the early stages after HSCT. The combination of partial T depletion and pharmacological immunosuppression minimized in volume and duration will combine the advantages of T depletion (early engraftment, low risk of GVHD, low risk of organ complications) and pharmacological prophylaxis (restoration of anti-infective immunity).
Infusion of ex-vivo T-depleted peripheral blood hematopoietic stem cells (CD3 depletion product)
Infusion of donor lymphocytes enriched with T regulatory lymphocytes (CD25 selective product)
Drug therapy (pharmacological prophylaxis of GVHD)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cyclosporine A | Active Comparator | Four groups corresponding to the pharmacological prophylaxis of GVHD: 1) Cyclosporine A |
|
| Sirolimus | Active Comparator | Drug therapy (pharmacological prophylaxis of GVHD) 2) Sirolimus |
|
| Ruxolitinib | Active Comparator | Drug therapy (pharmacological prophylaxis of GVHD) Ruxolitinib |
|
| Abatacept | Active Comparator | Drug therapy (pharmacological prophylaxis of GVHD) Abatacept |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cyclosporine A (CsA) | Drug | The combination of partial T depletion and pharmacological immunosuppression minimized in volume and duration will combine the advantages of T depletion (early engraftment, low risk of GVHD, low risk of organ complications) and pharmacological prophylaxis (restoration of anti-infective immunity). |
| Measure | Description | Time Frame |
|---|---|---|
| Feasibility- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | proportion of patients who received an infusion of the planned dose of regulatory T lymphocytes (at least 80%) | day 30 |
| Safety- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Cumulative risk of GVHD Grade III-IV (target < 5%) | 120 days after HSCT |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative probability of engraftment | up to 100 day | |
| Time to engraftment of neutrophils and platelets | 100 day after HSCT | |
| Cumulative risk of acute GVHD Grade II-IV |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Michael Maschan, Prof | Contact | +79166512145 | mmaschan@yandex.ru |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National medical research center of pediatric haematology, oncology and immulogy named after Dmytriy Rogachyov, Moscow, 117198 | Recruiting | Moscow | Russia |
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|
| Sirolimus | Drug | Pharmacological prophylaxis of GVHD is one of the key subjects of evaluation in the current study. Since the optimal pharmacological approach is not known, the allocation of the patients to study groups will be by randomization procedure, although not for the purpose of direct comparison, but for unbiased descriptive analysis. There will be four main groups and an additional group to be open for allocation based on the main group closing for fitting the stopping rules. The details of pharmacological GVHD prevention are Sirolimus 1 mg -3 till +30 4-8 ng/ml |
|
| Ruxolitinib (JAKAVI®) | Drug | Pharmacological prophylaxis of GVHD is one of the key subjects of evaluation in the current study. Since the optimal pharmacological approach is not known, the allocation of the patients to study groups will be by randomization procedure, although not for the purpose of direct comparison, but for unbiased descriptive analysis. There will be four main groups and an additional group to be open for allocation based on the main group closing for fitting the stopping rules. The details of pharmacological GVHD prevention regimens are Ruxolitinib 5 mg -2 till +30 |
|
| Abatacept | Drug | Pharmacological prophylaxis of GVHD is one of the key subjects of evaluation in the current study. Since the optimal pharmacological approach is not known, the allocation of the patients to study groups will be by randomization procedure, although not for the purpose of direct comparison, but for unbiased descriptive analysis. There will be four main groups and an additional group to be open for allocation based on the main group closing for fitting the stopping rules. Abatacept 10 mg/kg -1, +7, +14, +28 |
|
| up to 100 days after HSCT |
| Cumulative risk of viral | (CMV, ADV, EBV, HHV-6) DNA detection in blood, peak viral DNA load and the duration of detectable viral DNA (each virus separately) | at 120 day after HSCT |
| cumulative risk of developing severe chronic GVHD | Severity of chronic GVHD | at 2 years |
| Cumulative risk of leukemia relapse | at 2 years |
| Cumulative risk of non-relapse mortality | at 100 days and 2 years |
| Overall survival | at 3 years |
| Event-free survival | at 3 years |
| GVHD- and relapse-free survival | at 3 years |
| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| D012008 | Recurrence |
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007945 | Leukemia, Lymphoid |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D016572 | Cyclosporine |
| D020123 | Sirolimus |
| C540383 | ruxolitinib |
| D000069594 | Abatacept |
| ID | Term |
|---|---|
| D003524 | Cyclosporins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D018796 | Immunoconjugates |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D012712 | Serum Globulins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D005916 | Globulins |
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