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Optimization of bendamustine-containg graft-versus-host disease (GVHD) prophylaxis to reduce the incidence of secondary haemophagocytic lymphohistiocytosis and GVHD
Prognosis of patients undergoing allogeneic stem cell transplantation (HCT) for high-risk myeloid malignancies, including refractory acute myeloid leukemia, with standard HCT technologies have relatively poor prognosis with 10-30% long-term disease-free survival. One of the approaches to augment graft-versus-leukemia effect the use of post-transplantation bendamustine in graft-versus-host disease prophylaxis. Despite high frequency of responses and durable remissions after this approach majority of patients develop a serious complication - cytokine release syndrome, which can be life-threatening in some patients. The combination bendamustine (PTB) and post-transplantation cyclophosphamide (PTCY) facilitates comparable graft-versus leukemia effect to PTB, but with better safety profile and reduced incidence of severe cytokine release syndrome.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental: Test cohort 1 - ruxolitinib | Experimental | Days +3 through +4: Bendamustine 50 mg/m2 iv x 2 days; Days +3 through +4: Cyclophosphamide 25 mg/kg iv x 2 days; Days -1 through +21: ruxolitinib 10 mg/kg/day p.o.; mycophenolate mofetil Days +5 through +35 30 mg/kg/day p.o.; Days +5 through +100: Tacrolimus 0.03 mg/kg/day with further correction by concentration |
|
| Test cohort 2 - abatacept | Experimental | Days +3 through +4: Bendamustine 50 mg/m2 iv x 2 days; Days +3 through +4: Cyclophosphamide 25 mg/kg iv x 2 days; Days -1 through +21: ruxolitinib 10 mg/kg/day p.o.; mycophenolate mofetil Days +5 through +35 30 mg/kg/day p.o.; Days +5 through +100: Tacrolimus 0.03 mg/kg/day with further correction by concentration |
|
| Experimental: Expansion cohort | Experimental | Days +3 through +4: Bendamustine 50 mg/m2 iv x 2 days; Days +3 through +4: Cyclophosphamide 25 mg/kg iv x 2 days; Days -1,+5, +14, +21 abatacept 10 mg/kg/day i.v.; Days +5 through +100: Tacrolimus 0.03 mg/kg/day with further correction by concentration |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ruxolitinib | Drug | ; Days -1 through +21: ruxolitinib 10 mg/kg/day p.o. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Overall survival analysis | Measure: Kaplan-Meier estimate of death from all causes | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of secondary hemophagocytic lymphohistiocytosis | Based on H-score diagnostic criteria. | 100 days |
| Incidence of HSCT-associated adverse events (safety and toxicity) | Toxicity assessment is based on NCI CTC AE 6.0 grades. Veno-occlusive disease incidence and severity assessment is based on EBMT criteria 2016. Transplant-associated microangiopathy incidence assessment is based on Schoettler et al. criteria. All toxicity measurements will be aggregated as severity scores. |
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Inclusion Criteria:
Acute myeloid leukemia Chronic myeloid leukemia, Ph+ Myelodysplastic Syndromes Myeloprolipherative neoplasms - High-risk disease defined as: Acute myeloid leukemia: >5% of clonal blasts in bone marrow despite adequate previous induction therapy or allogeneic stem cell transplantation Myelodysplastic Syndrome: >5% of blasts despite previous therapy Myeloid malignancy with with -7 or complex karyotype, or p53 mutation regardless of blast count in bone marrow Treatment-related myelodysplastic syndrome Second or subsequent allogeneic HCT after relapse of a myeloid malignancy Chronic myelomonocytic leukemia Myeloprolipherative neoplasms, unclassifiable
- No severe concurrent illness
Exclusion Criteria:
Acute myeloid leukemia Chronic myeloid leukemia, Ph+ Myelodysplastic Syndromes Myeloprolipherative neoplasms - High-risk disease defined as: Acute myeloid leukemia: >5% of clonal blasts in bone marrow despite adequate previous induction therapy or allogeneic stem cell transplantation Myelodysplastic Syndrome: >5% of blasts despite previous therapy Myeloid malignancy with with -7 or complex karyotype, or p53 mutation regardless of blast count in bone marrow Treatment-related myelodysplastic syndrome Second or subsequent allogeneic HCT after relapse of a myeloid malignancy Chronic myelomonocytic leukemia Myeloprolipherative neoplasms, unclassifiable
- No severe concurrent illness
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Alexandr D Kulagin, MD, Prof | Contact | +78123386265 | bmt-director@1spbgmu.ru | |
| Ivan S Moiseev, MD, Prof. | Contact | +78123386201 | moisiv@mail.ru |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pavlov University | Recruiting | Saint Petersburg | 197022 | Russia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40372957 | Background | Moiseev I, Bondarenko S, Vlasova Y, Morozova E, Smirnova A, Epifanovskaya O, Zhogolev D, Chernishova D, Meliboev A, Khudayberdiev J, Mazing A, Lapin S, Kholopova I, Botina A, Baykov V, Popova M, Kosarev O, Kulagin A. Allogeneic hematopoietic cell transplantation with a combination of posttransplantation bendamustine and cyclophosphamide in refractory myeloid neoplasms. Cancer. 2025 May 15;131(10):e35893. doi: 10.1002/cncr.35893. |
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10 years
Submit a study proposal and request to use the data to Pavlov University Clinical Trial department: spbgmutrials@yandex.ru
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| Abatacept (Orencia) | Drug | Days -1,+5, +14, +21 abatacept 10 mg/kg/day i.v. |
|
| 100 days |
| Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence | Proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease | 100 days |
| Incidence of acute GVHD grade II-IV | Cumulative incidence of patients with acute GVHD II-IV grade | 180 days |
| Incidence of moderate and severe chronic GVHD | Cumulative incidence of patients with moderate and severe chronic GVHD according to MAGIC 2018 criteria | 2 years |
| Non-relapse mortality analysis | Cumulative incidence of patients with mortality without hematological relapse of malignancy | 2 years |
| Relapse rate analysis | Cumulative incidence of patients with relapse | 2 years |
| Event-free survival analysis | Kaplan-Meier estimate of death or relapse | 2 years |
| GVHD-event-free survival analysis | Kaplan-Meier estimate of death, grade III-IV acute GVHD, severe chronic GVHD or relapse | 2 years |
| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| D015464 | Leukemia, Myelogenous, Chronic, BCR-ABL Positive |
| D009190 | Myelodysplastic Syndromes |
| D054438 | Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative |
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D009196 | Myeloproliferative Disorders |
| D001855 | Bone Marrow Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D054437 | Myelodysplastic-Myeloproliferative Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| C540383 | ruxolitinib |
| D000069594 | Abatacept |
| ID | Term |
|---|---|
| D018796 | Immunoconjugates |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D012712 | Serum Globulins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D005916 | Globulins |
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