Transplant Approach for Sickle Cell Disease
(SUN-RAY Trial)
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Children's National Research Institute
Disqualifiers: HIV, Hepatitis B/C, Uncontrolled infections, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
This multicenter prospective study seeks to determine if daratumumab given, prior to HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus, can prevent pure red blood cell aplasia with an acceptable safety profile in patients with anti-donor red blood cell antibodies, achieving an event-free survival similar to transplanted patients without such antibodies.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug Alemtuzumab in the treatment approach for Sickle Cell Disease?
Alemtuzumab has been shown to effectively reduce graft-versus-host disease (a condition where the transplanted cells attack the recipient's body) and treatment-related mortality in hematopoietic stem cell transplantation, which may suggest potential benefits in similar transplant settings for Sickle Cell Disease.12345
Is the transplant approach for sickle cell disease using treatments like Alemtuzumab and Total Body Irradiation generally safe?
Alemtuzumab has been used in transplant procedures and is associated with some risks, such as neurologic toxicity, especially in older patients. Total Body Irradiation (TBI) can cause treatment-related toxicities, but fractionated doses may reduce these effects. Safety varies based on individual health conditions and treatment specifics.678910
How is the drug combination of Alemtuzumab, Daratumumab, Sirolimus, and Total Body Irradiation unique for treating Sickle Cell Disease?
This drug combination is unique because it uses Alemtuzumab to deplete T-cells, reducing the risk of graft-versus-host disease (a condition where transplanted cells attack the body) in bone marrow transplants, which is not a standard treatment for Sickle Cell Disease. The use of Total Body Irradiation and other drugs like Daratumumab and Sirolimus in this context aims to improve transplant outcomes by minimizing immune reactions and supporting the acceptance of new cells.3451112
Eligibility Criteria
This trial is for individuals with Sickle Cell Anemia or Disease who have antibodies against donor red blood cells. They're looking at whether a new treatment can help them receive transplants from siblings without complications.Inclusion Criteria
I have a sickle cell genotype with significant symptoms or treatments in the past year.
I am between 2 and 24 years old with sickle cell disease and have a sibling donor who is a perfect match but has a different blood type, or I have antibodies against donor blood types.
I have sickle cell disease with complications or treatments as described.
See 2 more
Exclusion Criteria
My lung function is low, and I may have severe asthma.
I have a sibling donor match for a blood or marrow transplant without major blood type issues.
Life expectancy less than 6 months
See 5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Pre-treatment
Participants receive daratumumab intravenously on days -49, -42, -35, and -28 prior to HCT
7 weeks
4 visits (in-person)
Conditioning
Participants undergo conditioning with alemtuzumab and low dose total body irradiation
1 week
5 visits (in-person)
Transplantation
Hematopoietic cell transplant (HCT) is performed
1 day
1 visit (in-person)
Post-transplant Treatment
Sirolimus is given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism
1 year
Follow-up
Participants are monitored for safety and effectiveness after treatment, including immune reconstitution and donor chimerism testing
1 year
Multiple visits (in-person and virtual)
Treatment Details
Interventions
- Alemtuzumab (Monoclonal Antibodies)
- Daratumumab (Monoclonal Antibodies)
- Sirolimus (Immunosuppressants)
- Total Body Irradiation (Radiation)
Trial OverviewThe study tests if daratumumab, along with alemtuzumab, low-dose total body irradiation, and sirolimus before sibling donor transplant, can prevent complications in patients with anti-donor antibodies.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Recipients with red cell alloantibodies (non-ABO) against donor antigensExperimental Treatment4 Interventions
Patients in this cohort are treated pre-HCT with Daratumumab, intravenously, on days -49, -42, -35 and -28. The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY on day -2 with gonadal shielding. Sirolimus will be given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism. G-CSF, at 5 mcg/kg/day, will be given post stem cell infusion until neutrophil engraftment is achieved.
Group II: Recipients with a major ABO incompatible donorExperimental Treatment4 Interventions
Patients in this cohort are treated pre-HCT with Daratumumab, intravenously, on days -49, -42, -35 and -28. The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY on day -2 with gonadal shielding. Sirolimus will be given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism. G-CSF, at 5 mcg/kg/day, will be given post stem cell infusion until neutrophil engraftment is achieved.
Alemtuzumab is already approved in United States, European Union, European Union for the following indications:
🇺🇸 Approved in United States as Campath for:
- Chronic lymphocytic leukemia
- Multiple sclerosis
🇪🇺 Approved in European Union as Lemtrada for:
- Multiple sclerosis
🇪🇺 Approved in European Union as Campath for:
- Chronic lymphocytic leukemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's National HospitalWashington, United States
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Who Is Running the Clinical Trial?
Children's National Research InstituteLead Sponsor
Children's Hospital at MontefioreCollaborator
Alberta Children's HospitalCollaborator
Ann & Robert H Lurie Children's Hospital of ChicagoCollaborator
The Hospital for Sick ChildrenCollaborator
Nationwide Children's HospitalCollaborator
Levine Children's HospitalCollaborator
Doris Duke Charitable FoundationCollaborator
Janssen PharmaceuticalsIndustry Sponsor
References
Use of the ImmuKnow assay to evaluate the effect of alemtuzumab-depleting induction therapy on cell-mediated immune function after renal transplantation. [2021]Good outcomes after renal transplantation are dependent on effective immunosuppression while minimizing infection. Alemtuzumab (Campath or Campath-1H) is an anti-CD52 humanized monoclonal IgG1 antibody which induces rapid and sustained depletion of circulating lymphocytes and has been effectively used as an immunosuppressant in post-transplant induction therapy.
Alemtuzumab induction in deceased donor kidney transplantation. [2017]Alemtuzumab (Campath-1H), a humanized monoclonal antibody directed against CD52, is a lymphocyte-depleting agent currently being evaluated as an induction agent in solid organ transplantation. This study analyzed the clinical outcomes and effects on peripheral blood lymphocyte subset counts in adult deceased donor renal transplant recipients who received an alemtuzumab-based induction protocol.
Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. [2023]Label="BACKGROUND AND OBJECTIVE">Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.
Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. [2017]Alemtuzumab (Campath 1H) is a recombinant DNA derived humanized monoclonal antibody which targets CD52 antigens on B and T cells. It is increasingly used as a conditioning agent for bone marrow transplantation. We describe the case of a 37 year old woman who developed acute renal failure and disseminated intravascular coagulation (DIC) following one dose of Campath and Fludarabine. Campath was thought to be the most likely causal agent although Fludarabine alone or in combination with Campath cannot be excluded. Despite there being many documented side effects of Campath there are currently no reports in the literature of acute renal failure and DIC. The transplant had to be aborted and 9 months on the patient is still requiring dialysis twice a week.
Alemtuzumab in allogeneic hematopoetic stem cell transplantation. [2021]With the use of reduced-intensity conditioning (RIC), early toxicity of allogeneic stem cell transplantation (SCT) has been much reduced. Graft-versus-host disease (GvHD) causes morbidities and mortality. Alemtuzumab is a mAb directed against CD52. When administered prior to transplant, it leads to T-cell depletion. Incorporation of alemtuzumab in RIC results in low rates of GvHD and treatment-related mortality (TRM) in haematological diseases, even in the setting of mismatched-donor transplantation.
Evaluating the Efficacy of Modified BeEAM(Bendamustine, Etoposide, Cytarabine, Melphalan) Regimen as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Lymphoma: An Experience from Two Centers of a Developing Country. [2023]Background: High-dose chemotherapy followed by Autologous SCT (stem cell transplantation) is a treatment of choice for relapsed and refractory lymphoma. Due to cost, toxicity, and shortage of Carmustine, we decided to conduct a phase 2 clinical trial to evaluate the safety and efficacy of Bendamustine instead of Carmustine in a previously used BEAM-like protocol. Materials and Methods:102 patients (median age,37) with Hodgkin(n=54) and non-Hodgkin lymphoma(n=48) were recruited and transplanted in two centers. After stem cell harvesting, a modified BeEAM regimen was administered to all the patients. Overall survival and disease-free survival (DFS) at two years were calculated as the study's primary endpoints. Results: Neutrophil and platelet recovery were observed after a median of 12 and 13 days, and all the patients were engrafted. Fever was observed in 25(24.5%) with only two documented infections. The only grade III toxicities were mucositis (20%) and nausea (15.6%). No transplant-related mortality (TRM) was observed after 100 days. After a median follow-up of 37(range 25-48) months, 68(66.6%) patients were in complete remission while 21 patients were in partial response, and 16 patients (15.6%) developed progressive disease, among which 13 (12.7%) had died. The OS at two years was (89 of 102, 87.3%), and the DFS rate was 68 of 102(66.7%). Conclusion: Our study showed that modified BeEAM is a safe, effective, and feasible conditioning regimen for ASCT in lymphoma instead of the BEAM regimen.
The influence of total dose, fractionation, dose rate, and distribution of total body irradiation on bone marrow transplantation. [2021]Total body irradiation (TBI) is a common component of many preparative regimens used prior to bone marrow transplantation. The biologic effects of TBI are influenced by a number of factors, including total dose, dose fractionation, dose rate, and dose distribution. Higher doses of TBI result in greater antileukemic activity, but this effect may be offset by concomitant increases in treatment-related toxicities. Increased doses of TBI also produce a greater degree of immunosuppression. Fractionated TBI results in decreased late toxicities and immunosuppressive effects when compared with single-dose TBI, yet the extent of marrow ablation seems to be similar. For both single-dose and fractionated TBI, higher dose rates produce increased treatment-related toxicities. Dose rates also may affect marrow ablation and immunosuppression. By targeting radiation to leukemic or immunocompetent cells, alterations in dose distribution have the potential to significantly improve the clinical benefits of TBI. Directed external beam irradiation is one approach to achieving the goal of targeted therapy. Other approaches involve the conjugation of radionuclides to antibodies that recognize specific cell-surface antigens or to aminophosphonic acid compounds that bind to bone. Such specific targeting of radiation could lead to significant increases in the intensity of therapy without resulting in greater treatment-related toxicities.
Radiation-free allogeneic conditioning with fludarabine, carmustine, and thiotepa for acute lymphoblastic leukemia and other hematologic malignancies necessitating enhanced central nervous system activity. [2017]Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days -6 to -4), carmustine (400 mg/m2 on day -6), and thiotepa (5 mg/kg twice daily on days -5 and -4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58-1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system-active conditioning.
Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. [2019]The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.
Thiotepa-Based Regimens Are Valid Alternatives to Total Body Irradiation-Based Reduced-Intensity Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. [2023]Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, in whom reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI-based or a chemotherapy-based approach is better is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The current study aimed to compare transplantation outcomes after RIC with TBI-based or thiotepa-based regimens in patients with ALL. The study cohort comprised patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000 and 2020 who received an RIC regimen containing either TBI (4 to 6 Gy) or thiotepa. We identified a total of 265 patients, including 117 who received a TBI-based RIC regimen and 148 who received a thiotepa-based RIC regimen. Univariate analysis revealed no significant differences in the following transplantation outcomes for TBI versus thiotepa: relapse, 23% versus 28% (P = .24); nonrelapse mortality, 20% versus 26% (P = .61); leukemia-free survival, 57% versus 46% (P = .12); overall survival, 67% versus 56% (P = .18); graft-versus-host disease (GVHD]/relapse-free survival, 45% versus 38% (P = .21); grade II-IV acute GVHD, 30% in both groups (P = .84); grade III-IV acute GVHD, 9% versus 10% (P = .89). The sole exception was the incidence of chronic GVHD, which was higher in the recipients of TBI-based regimens (43% versus 29%; P = .03). However, multivariate analysis revealed no differences in transplantation outcomes between the 2 groups. In patients aged ≥40 years receiving RIC, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens, as no differences were observed in the main transplantation outcomes.
CAMPATH: from concept to clinic. [2018]Lymphocyte depletion has a long history in the area of therapeutic immunosuppression. CAMPATH-1H (alemtuzumab) was generated in an attempt to replace anti-lymphocyte globulins in the transplant arena. Its efficacy in killing lymphocytes has established it as a licensed drug for the management of chronic lymphocyte leukaemia. Short-term therapy with alemtuzumab has demonstrated long-term benefit in a number of autoimmune conditions. This drug has the potential to facilitate recruitment of tolerance processes so enabling drug minimization in transplantation, autoimmune and hypersensitivity diseases.
Alemtuzumab in stem cell transplantation. [2021]Alemtuzumab, otherwise called CAMPATH-1H, is a humanized monoclonal antibody directed against the CD52 antigen of lymphocytes. It is one of a family of CAMPATH-1 antibodies that have been used over the last 20 yr in stem cell transplantation for depletion of donor and recipient T-cells to prevent graft-versus-host disease and graft rejection. Clinical trials have been carried out by a cooperative group of physicians and the protocols have gradually evolved as different problems have been identified and overcome. T-cell depletion carries risks of reducing graft-versus-tumor effects and increasing susceptibility to virus reactivation, but offers significant benefits in terms of reduced mortality and morbidity from graft-versus-host disease (GVHD). Two protocols are currently favored: (1) simple addition of CAMPATH-1H to the stem cell infusion and (2) administration in vivo prior to the transplant--especially in the context of nonmyeloablative conditioning regimens. Both of these give excellent control of GVHD with minimal graft rejection. Contrary to earlier expectations, a short course of posttransplant cyclosporin A (CyA) appears to further reduce transplant-related mortality, mainly by a reduction in late deaths from infection. These results need to be consolidated by means of prospective clinical trials.