Treosulfan-Based Conditioning for Bone Marrow Failure
Recruiting in Palo Alto (17 mi)
+27 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: Fred Hutchinson Cancer Research Center
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This trial tests if a combination of three drugs can reduce complications for patients with bone marrow failure diseases. The drugs work by killing harmful cells, stopping their growth, and reducing immune reactions.
Do I need to stop my current medications for this trial?
The trial protocol does not specify if you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.
What data supports the idea that Treosulfan-Based Conditioning for Bone Marrow Failure is an effective treatment?
The available research shows that Treosulfan-Based Conditioning is effective for treating bone marrow failure disorders. In a study with 14 patients who had various marrow failure disorders, all patients successfully received donor cells, and 13 out of 14 were alive with their diseases corrected after three years. This suggests that the treatment is effective in establishing donor cell acceptance with low side effects and good long-term outcomes. Compared to other treatments, Treosulfan-Based Conditioning has a lower risk of serious complications and high survival rates, making it a promising option for patients with marrow failure disorders.12345
What safety data is available for Treosulfan-based conditioning in bone marrow failure treatment?
Treosulfan-based conditioning, often combined with fludarabine and thymoglobulin, has been studied for its safety and efficacy in hematopoietic cell transplantation. Studies show promising results with good engraftment and low toxicity. In a multicenter trial, 31 patients with nonmalignant diseases received treosulfan, fludarabine, and thymoglobulin, resulting in a 0% transplant-related mortality at day 100 and a 90% survival rate at 2 years. The combination was effective in establishing donor engraftment with low toxicity, although some patients experienced graft-versus-host disease (GVHD). The use of thymoglobulin was associated with a lower incidence of severe acute GVHD. These findings support the safety and potential of treosulfan-based conditioning for bone marrow failure treatment.12346
Is the drug combination of Fludarabine, Thymoglobulin, and Treosulfan a promising treatment for bone marrow failure?
Yes, the combination of Fludarabine, Thymoglobulin, and Treosulfan is promising for treating bone marrow failure. It has shown to be effective in helping patients recover with low toxicity and high survival rates. This drug combination helps establish donor cells in the patient's body, which is crucial for recovery, and has a good safety profile.14578
Eligibility Criteria
This trial is for people aged 1 to under 50 with bone marrow failure diseases treatable by transplant, who have specific genetic mutations or meet diagnostic criteria. Excluded are those with certain other conditions, previous transplants, severe lung function impairment, liver issues, uncontrolled infections, HIV positive status or unwillingness to use contraception.Inclusion Criteria
I have a SAMD9 or SAMD9L disorder with a confirmed mutation.
My bone marrow failure disorder can be treated with a stem cell transplant from a donor.
I have Shwachman-Diamond syndrome with a confirmed genetic mutation.
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Exclusion Criteria
I am HIV positive.
I have had a solid organ transplant.
My bilirubin levels are not more than twice the normal limit, unless due to Gilbert's syndrome.
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Treatment Details
Interventions
- Fludarabine (Anti-metabolites)
- Thymoglobulin (Rabbit Anti-thymocyte Globulin; rATG) (Immunosuppressant)
- Treosulfan (Alkylating agents)
Trial OverviewThe study tests a pre-transplant conditioning regimen using treosulfan combined with fludarabine and rabbit antithymocyte globulin (rATG) in patients with bone marrow failure diseases. The goal is to see if this combination reduces complications post-transplant.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Treatment (conditioning regimen; transplant; GVHD prophylaxis)Experimental Treatment15 Interventions
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
Fludarabine is already approved in European Union, United States, Canada for the following indications:
🇪🇺 Approved in European Union as Fludara for:
- Chronic lymphocytic leukemia
- Mantle-cell lymphoma
- Non-Hodgkin's lymphoma
🇺🇸 Approved in United States as Fludara for:
- Chronic lymphocytic leukemia
- Non-Hodgkin's lymphoma
- Stem Cell Transplant Conditioning
🇨🇦 Approved in Canada as Fludara for:
- Chronic lymphocytic leukemia
- Non-Hodgkin's lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Emory UniversityAtlanta, GA
Vanderbilt University Medical CenterNashville, TN
Memorial Sloan Kettering Cancer CenterNew York, NY
Medical College of WisconsinWauwatosa, WI
More Trial Locations
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Who Is Running the Clinical Trial?
Fred Hutchinson Cancer Research CenterLead Sponsor
Fred Hutchinson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
National Heart, Lung, and Blood Institute (NHLBI)Collaborator
National Marrow Donor ProgramCollaborator
Blood and Marrow Transplant Clinical Trials NetworkCollaborator
References
A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. [2021]Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin(®)) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/(T)busulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.
Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. [2013]Antithymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as a part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective in preventing GVHD and rejection of organ transplants. As the fludarabine-based conditioning regimens without total body irradiation have been reported to be promising for bone marrow transplantation (BMT) from alternative donors in SAA, thymoglobulin was added to fludarabine and cyclophosphamide conditioning to reduce GVHD and to allow good engraftment in unrelated BMT. Five patients underwent BMT with cyclophosphamide (50 mg/kg once daily i.v. on days -9, -8, -7 and -6), fludarabine (30 mg/m2 once daily i.v. on days -5, -4, -3 and -2) and thymoglobulin (2.5 mg/kg once daily i.v. on days -3, -2 and -1) from HLA-matched unrelated donors. Complete donor type hematologic recovery was achieved in all patients. No serious complication occurred during BMT. Only one patient developed grade I acute GVHD resolved spontaneously. Except for one who had rupture of hepatic adenoma 78 days after BMT, all the other four patients are still alive with median 566 days. Fludarabine, cyclophosphamide plus thymoglobulin conditioning allows for the promising results of good engraftment, tolerable toxicity and minimal GVHD.
Successful engraftment with fludarabine, cyclophosphamide, and thymoglobulin conditioning regimen in unrelated transplantation for severe aplastic anemia: A phase II prospective multicenter study. [2017]Antithymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective for preventing graft-versus-host disease (GVHD) and the rejection of organ transplants. After the promising results of our preliminary study, we conducted a phase II prospective multicenter clinical trial using a fludarabine (Flu), cyclophosphamide (Cy), and thymoglobulin conditioning regimen to allow good engraftment in patients who underwent unrelated transplantation for SAA. Twenty-eight patients underwent bone marrow (N = 15) or mobilized peripheral blood (N = 13) transplantation from HLA-matched unrelated donors with Cy (50 mg/kg once daily intravenously (i.v.) on days -9, -8, -7, and -6), Flu (30 mg/m² once daily i.v. on days -5, -4, -3, and -2), and thymoglobulin (2.5 mg/kg once daily i.v. on days -3, -2, and -1). Donor-type hematologic recovery was achieved in all patients. The estimated survival rate (SR) was 67.9%, and all the events were treatment-related mortality (TRM), which included thrombotic microangiopathy (N = 2), pneumonia (N = 1), myocardiac infarction (N = 1), posttransplantation lymphoprolifarative disease (N = 3), and chronic GVHD-associated complications (N = 2). The SR of patients who received bone marrow (60.0%) was not different from that of patients who received mobilized peripheral blood (76.9%) (P = .351), but the SR of patients who received more than 15 units of red blood cells before transplantation (45.5%) was significantly lower than that of the other patients (82.4%) (P = .048). The Flu, Cy, and thymoglobulin conditioning regimen achieved promising results for successful engraftment, but the TRM was high. This study was registered at www.clinicaltrials.gov (NCT00737685), and now we are performing a new multicenter study (NCT00882323) to decrease the TRM by reducing the dose of Cy.
Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. [2021]Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.
Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders. [2019]Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other nonmalignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant-related mortality, particularly in patients with comorbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome, n = 3; Diamond Blackfan anemia, n = 4; GATA2 deficiency, n = 2; paroxysmal nocturnal hemoglobinuria, n = 4; and an undefined marrow failure disorder, n = 1) who underwent HCT on a prospective, phase II, multicenter clinical trial. Patients were given HLA-matched related (n = 2) or unrelated (n = 12) grafts after conditioning with treosulfan (42 g/m2), fludarabine (150 mg/m2), ± thymoglobulin (n = 11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.
Antithymocyte globulin induction in living donor renal transplant recipients: final report of the TAILOR registry. [2022]The Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry was established to assess clinical experience with rabbit antithymocyte globulin (rATG; Thymoglobulin) in living donor renal transplant recipients.
Treosulfan in combination with fludarabine as part of conditioning treatment prior to allogeneic hematopoietic stem cell transplantation. [2020]The combination of treosulfan with fludarabine (Treo-Flu) is one of the new megatherapies prior to hematopoietic stem cell transplantation. Preclinical studies have documented the myeloablative and myelosuppressive effects of treosulfan, in addition to its immunosuppressive and antimalignant activities. Treosulfan pharmacokinetics involves nonenzymatic activation and generation of epoxides as active compounds. In the clinical studies, the most common adverse effects of Treo-Flu were grade 4 hematologic toxicities with leukopenia, neutropenia and thrombocytopenia. Among the most common nonhematologic toxicities, grade 2 or lower mucositis was usually reported. One of the advantages of treosulfan-based conditioning regimens is their good safety profile, especially the low risk of hepatic venoocclusive disease. Additional drugs reported in combination with the Treo-Flu backbone are thiotepa and melphalan. Treo-Flu alone and in multiple drug combinations can be successfully and safely combined with posttransplant cyclophosphamide immunosuppression for unma¬nipulated haploidentical transplantations. On the basis of chimerism studies, the Treo-Flu megatherapy lacks full myeloablative potential, but the profound myelosuppression with donor cell-mediated alloreactivity can result in full donor chimerism in the majority of transplant recipients. The clinical studies of allogeneic hematopoietic stem cell transplantation show high heterogeneity, but the safety and feasibility of the Treo-Flu regimen are evident and support its place among reduced-intensity protocols.
Determination of Treosulfan and Fludarabine in Plasma by Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry (TFLC-MS/MS). [2023]Treosulfan is a structural analog of the alkylating agent busulfan which has been shown in clinical trials to exhibit comparable myeloablative activity while causing fewer serious side effects. Treosulfan is currently being considered for FDA approval in combination with fludarabine, one of the most commonly used myeloablative agents, as a conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Because plasma concentrations of both treosulfan and fludarabine exhibit significant interindividual variability, therapeutic drug monitoring (TDM) is indicated to ensure dosages are administered that maximize efficacy while minimizing toxicity. In this chapter, we describe a rapid, accurate assay to detect treosulfan and fludarabine simultaneously in human plasma using turbulent flow liquid chromatography coupled to electrospray ionization tandem mass spectrometry (TFLC-ESI-MS/MS). Treosulfan and fludarabine are extracted from only 100 μL of acidified plasma via protein precipitation with methanol containing isotope-labeled internal standards. The extract is injected into the TFLC-ESI-MS/MS system, and the analytes are quantified using multiple reaction monitoring and a six-point calibration curve.