Riom-ès-montagnes, France

MT2023-20: Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide for Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure.

Cytokine-Treated Veto Cells in Treating Patients With Hematologic Malignancies Following Stem Cell Transplant

PRIMARY OBJECTIVE: I. To determine the optimal dose of anti-viral veto cells, defined as the dose which achieves engraftment without severe graft-vs-host disease (GVHD) at 42 days after non-myeloablative megadose T cell depleted haploidentical hematopoietic cell transplantation (HCT). SECONDARY OBJECTIVES: I. Toxicity. II. Response rate. III. Time to progression. IV. Infections. V. Immune reconstitution. VI. Overall survival up to 1 year. OUTLINE: This is a dose-escalation study of cytokine-treated veto cells. CONDITIONING REGIMEN: Patients receive anti-thymocyte globulin (ATG) intravenously (IV) over 4 hours on days -9 to -7 and fludarabine IV over 1 hour on days -6 to -3, then undergo total body irradiation (TBI) on day -1. TRANSPLANT: Patients undergo peripheral blood stem cell transplantation (PBSCT) IV over 30-60 minutes on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days +3 and +4 and cytokine-treated veto cells IV over 30-60 minutes on day +7. After completion of stem cell transplant, patients are followed up once a week for 4 weeks, once a month for 3 months, and then periodically for one year.

The EndRAD Trial: Eliminating Total Body Irradiation (TBI) for NGS-MRD Negative Children, Adolescents, and Young Adults With B-ALL

A Phase II pilot trial will estimate survival after a non-TBI based conditioning regimen in patients diagnosed with B-acute lymphoblastic leukemia (ALL) who are pre-allogeneic hematopoietic cell transplantation (HCT) next-generation-sequence (NGS) minimal residual disease (MRD) negative. The relationship of NGS-MRD status to survival in children, adolescents, and young adults with B-ALL undergoing any approach to allogeneic HCT will be explored in a larger cohort (treatment [phase II] and observational arms of the study). The primary objective is to estimate 2-year event free survival (EFS) in pre-HCT NGS-MRD negative patients with B-ALL undergoing a non-TBI based conditioning regimen through a multi-center prospective trial. The accrual period is 3 years. Patients that are NGS-MRD negative with B-ALL may be eligible for the Treatment Arm, which is myeloablative non-TBI conditioning with busulfan, fludarabine, and thiotepa followed -matched related, unrelated, and umbilical cord blood transplants. Patients that are NGS-MRD positive will be followed on the observational arm for outcome. Study sampling will include NGS-MRD bone marrow (BM) aspirate and peripheral blood (PB) samples collected [same day when possible] pre-HCT (within 4 weeks), and post-HCT on days 42 ± 14, 100 ± 20, and 365 ± 60; PB samples only will also be collected day 180± 60 and 270± 60; day +30, day +100, and 1-year post-HCT. NGS-MRD peripheral blood sample only at 6 months and 9 months post-HCT; (Blast specimen at time of diagnosis or relapse is required for NGS-MRD testing).

Cyclophosphamide, Fludarabine, Total-Body Irradiation, and Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer or Other Disease

Siplizumab for Sickle Cell Disease Transplant

Phase I/II label single arm safety assessment study of Siplizumab-based conditioning. It is designed to determine the safety and feasibility of hematopoietic stem cell transplantation for patients with advanced sickle cell disease using in vivo T cell depletion with Siplizumab. It is a three-stage design with a target sample size of at most 18 patients. At the first stage, a total of 6 patients will be recruited, the study will be stopped, if 2 or more of patients experience any of the following events: graft failure/Grade 3-4 acute GVHD/death in the first 100 days. If not, the study will proceed to the second stage and recruit additional 6 patients. The study will be stopped if 4 or more patients experience an event as specified above among the 12 patients. If not, the study will proceed to the third stage and recruit additional 6 patients, the study will be stopped any time if 6 or more patients experience an event among the 18 patients. The study will be stopped at any time if a patient death occurs.

Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity

Background: - With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS) for patients with suspected inborn errors of immunity (IEI), the number of recognized IEI has increased in recent years to over 400 distinct immune defects. - Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially curative therapy for many hematologic diseases. - Hematopoietic stem cell transplant is now an accepted standard or an appropriate experimental approach for treatment of an increasing number of IEI - We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation using selected conditioning regimens and selected donor sources in reconstituting normal hematopoiesis and immune function and reversing the disease phenotype in patients with IEI. Objectives: -To determine whether allogeneic HSCT in patients with IEI results in sustained donor engraftment defined as neutrophil recovery with ANC >= 500/mm^3 for 3 consecutive days associated with > 50% donor T-cell and myeloid cell donor chimerism by day 100 for diseases characterized by loss of function, and >75% donor T-cell and myeloid cell chimerism for diseases characterized by gain-of-function mutations. Eligibility: - Participants ages 4-69 years old with a known IEI, or with clinical evidence of an IEI with a history of recurrent infections requiring prolonged courses of therapy, or evidence of immune dysregulation manifested by autoimmune/autoinflammatory disease, atopy, hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, or impaired response to vaccination. A virally-driven malignancy alone will also constitute a basis for inclusion. - Have an 8/8, 7/8, or 6/8 HLA-matched related or unrelated donor (HLA -A, -B, -C, DRB1, by high resolution typing) or a haploidentical related donor; unrelated donors are identified through the National Marrow Donor Program. Design: For Recipients with Fully Matched Donors - Patients with IEI receiving a high intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m^2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 4 days on days -6, -5, -4, -3 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time pharmacokinetics (PKs) and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 52-72 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0. - Patients with IEI receiving an intermediate intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 3 days on days -6, -5, -and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 39-54 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0. -Patients with IEI receiving a low intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m^2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 2 days on days -6, and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 26-36 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0. In all cohorts, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m^2 subcutaneously divided over 3 days, on days -14, -13 and -12. For Recipients with 7/8 or 6/8 Matched Related or Unrelated Donors and Haploidentical Related Donors - Patients with IEI receiving a high intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m^2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 4 days on days -6, -5, -4, and -3 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (52-72 mg h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0. - Patients with IEI receiving an intermediate intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days - 6, -5, -4, -and 3, busulfan IV once daily for 3 days on days -6, -5, and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (39-54 mg h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0. - Patients with IEI receiving a low intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 2 days on day -6 and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (26-36 mg h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0. In all cohorts, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m2 subcutaneously divided over 3 days, on days -14, -13 and -12. For Post-Transplant GVHD Prophylaxis -Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to approximately day +35 and tacrolimus from day +5 to approximately day +180. If there is no evidence of GVHD, tacrolimus will be stopped or tapered at approximately day +180.

Bendamustine With or Without Cyclophosphamide in Preventing GVHD in Patients Undergoing Stem Cell Transplant

PRIMARY OBJECTIVE: I. Evaluate the safety of substituting the standard post-transplant cyclophosphamide (PT-CY) given on day +3 and +4 with post-transplant bendamustine (PT-BEN) in patients undergoing HLA-mismatched hematopoietic cell transplantation. SECONDARY OBJECTIVES: I. To evaluate treatment-related mortality. II. To assess acute and chronic graft-versus-host disease (GVHD). III. To assess overall survival, progression-free survival and relapse rates. IV. To evaluate the risk of acute cystitis. V. To evaluate immune reconstitution after transplantation. OUTLINE: This is a dose-escalation study of bendamustine. Patients are assigned to 1 of 2 treatment schedules. SCHEDULE I (NON-LYMPHOMA): Patients receive fludarabine intravenously (IV) over 1 hour on days -5 to -2, melphalan IV over 30 minutes on days -5 and -4, and undergo total body irradiation (TBI) on day -1 and stem cell transplantation IV over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by orally (PO) once daily (QD) or twice daily (BID) for 6 months and mycophenolate mofetil PO thrice daily (TID) until day 100. Beginning day 7, patients receive filgrastim-sndz subcutaneously (SC) QD until blood cell levels return to normal. SCHEDULE II (LYMPHOID MALIGNANCIES): Patients receive fludarabine IV over 1 hour, bendamustine IV over 30-60 minutes on days -5 to -3 and undergo TBI on day -1 and stem cell transplantation over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal. CD20+ patients receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8. After completion of study treatment, patients are followed weekly for 3 months, every 3 months in year 1, and every 6 months in year 2.

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

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

Allo HSCT Using RIC and PTCy for Hematological Diseases

A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) Syndrome

Background: - In 2019, investigators at the National Institutes of Health defined a new disease syndrome named VEXAS: Vacuoles in bone marrow cells, E1 enzyme mutations, X-linked, Autoinflammatory, Somatic syndrome. This syndrome is characterized by inflammatory and hematologic features and is frequently accompanied by marrow dysplasia, progressive bone marrow failure, and in some cases, the development of overt myelodysplastic syndrome (MDS) or other myeloid neoplasms. Somatic mutations are present at methionine 41 in UBA1, an X-linked gene encoding the major E1 ubiquitin activating enzyme that initiates the majority of cellular ubiquitylation. - The inflammatory features of VEXAS include fever, pulmonary infiltrates, skin lesions, ear and nose chondritis, musculoskeletal involvement, and elevated inflammatory markers. The hematologic features include cytopenia, characteristic vacuoles in myeloid and erythroid precursors cells, and dysplastic bone marrow. Patients included in the initial description of the syndrome fulfill clinical or classification criteria for both inflammatory diseases (relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant cell arteritis) and hematologic conditions (MDS, myeloid neoplasms or plasma cell dyscrasia). The inflammatory features of VEXAS are refractory to treatment other than high doses of glucocorticoids. Increased mortality and frequent morbidity are common in VEXAS secondary to the disease and treatment-related complications. The clinical manifestations of VEXAS are time-dependent. Systemic inflammation typically precedes progressive bone marrow failure with or without the development of hematologic malignancies leading to death. Escalating doses of glucocorticoids are typically administered to control the refractory, progressive features of systemic inflammation. Worsening cytopenias often require transfusion support. - The discovery of hematologic mosaicism as the genetic driver of rheumatologic/hematologic syndromes defines a novel class of diseases, termed hematoinflammatory diseases (HINDS), and it raises the possibility that therapies aimed at eradicating these clones may be efficacious in this patient population. Objectives: Primary Objectives: - To determine whether allogeneic hematopoietic stem cell transplantation (HSCT) results in sustained donor engraftment at day 100 and one-year post-HSCT. - To determine whether allogeneic HSCT results in reversal of the clinical phenotype of VEXAS at one year and two years post-HSCT without requiring interval prednisone at >= 0.5 mg/kg per day for reasons other than graft-versus-host disease (GVHD). Eligibility: - Recipients ages 18-75 year-old with or without a somatic mutation in UBA1 who have: 1) the clinical phenotype for VEXAS with refractory cutaneous, pulmonary, musculoskeletal, and/or other recurrent acute inflammatory manifestations, and 2) require >= 0.5 mg/kg per day of prednisone for inflammatory manifestations OR have cytopenia (transfusion dependent anemia, transfusion dependent thrombocytopenia/platelets <75,000, neutropenia <1,000/microL) or myeloid neoplasm (by WHO criteria) or being intolerant or refractory to use steroids. - Have an 8/8 or 7/8 HLA-matched related or unrelated donor, or a haploidentical related donor. Design: -For Recipients with 8/8 HLA Matched Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 40 mg/m^2 IV once daily for four days on days -6, -5, -4, -3 and Busulfan IV for three days on days -6, -5, -and -4 followed by HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose and/or real time PKs and will be targeted to AUC of 2500-3500 microMol*min/L (31-43 mg*h/L) (2.5 - 2.8 mg/kg IV may be used on D-6 with real time PK for D-5 and D-4). -For Recipients with 7/8 HLA Matched Donors or Haploidentical Related Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 30 mg/m^2 IV once daily for five days on days -6, -5, -4, -3, and -2, cyclophosphamide 14.5 mg/kg for two days on days -6 and -5, 200 cGy total body irradiation (TBI) on day -1, busulfan IV once daily for two days on days -4 and -3, and HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose and/or real time PKs and will be targeted to an AUC of 2500-3500 microMol*min/L (21-29 mg*h/L) (2.5 -2.8 mg/kg IV per day may be used on D-4 with real time PK for D-3). -For Post-Transplant GVHD Prophylaxis: Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to approximately day +45 and tacrolimus from day +5 to approximately day +180.