Stem Cell Transplant for Sickle Cell Disease

Overseen By Lani Krauz, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Illinois at Chicago

Must be taking: Immune-suppressive agents

Disqualifiers: HIV, Pregnancy, Cirrhosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

45 Participants Needed

Trial Summary

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 treatment Alemtuzumab, Campath, Lemtrada, MabCampath, Allogeneic Non-Myeloablative Stem Cell Transplantation, Sirolimus, Rapamune for Sickle Cell Disease?

Research shows that using Alemtuzumab with a non-chemotherapy regimen for stem cell transplantation in adults with sickle cell disease led to successful engraftment, no mortality, and improved quality of life, with no cases of graft-versus-host disease. ^{1 2 3 4 5}

Is stem cell transplant using Alemtuzumab (Campath) generally safe for humans?

Alemtuzumab (Campath) is used in stem cell transplants to reduce complications like graft-versus-host disease, but it can cause delayed immune recovery, increasing the risk of infections and viral reactivations. Some patients have experienced serious side effects like acute kidney failure and blood clotting issues, although these are rare. Overall, it helps control transplant-related complications, but careful monitoring is needed due to potential risks. ^{1 2 4 5 6}

How does the treatment for sickle cell disease using Alemtuzumab, Allogeneic Non-Myeloablative Stem Cell Transplantation, and Sirolimus differ from other treatments?

This treatment is unique because it uses a non-chemotherapy approach with low-dose irradiation and alemtuzumab to prepare the body for a stem cell transplant, reducing the risk of graft-versus-host disease (a condition where the donor cells attack the recipient's body) and improving quality of life without the severe side effects of traditional chemotherapy. ^{1 2 3 5 7}

What is the purpose of this trial?

The investigators propose to determine the engraftment and transplant related morbidity and mortality after a non-myeloablative allogeneic hematopoietic stem cell transplant protocol using immune- suppressive agents and low-dose total body irradiation (TBI) without standard chemotherapy in patients with aggressive sickle cell disease who are not candidates for or experienced complications from hydroxyurea therapy. Fully HLA matched siblings will be used as donors for hematopoietic stem cells to reduce the risk of morbidity and mortality in this cohort of patients.

Research Team

Damiano Rondelli, MD

Principal Investigator

University of Illinois at Chicago

Eligibility Criteria

This trial is for individuals aged 16-60 with aggressive sickle cell disease who haven't responded well to or can't take hydroxyurea. Candidates must have a fully matched sibling donor, good heart and lung function, no HIV or chronic hepatitis, and be willing to sign consent. They should have had complications like frequent pain episodes, stroke, vision problems due to retinopathy, kidney issues, or severe anemia requiring transfusions.

Inclusion Criteria

Patients with sickle cell disease, subtype Hgb SS, SC, or SB disease who are on chronic transfusion therapy for a prior stroke or those patients who were intolerant of hydroxyurea therapy or were being treated with hydroxyurea therapy and were complicated by at least one of the following: Stroke or central nervous system event lasting longer than 24 hours, Frequent vaso-occlusive pain episodes, Recurrent episodes of priapism, Acute chest syndrome with recurrent hospitalizations, Red-cell alloimmunization, Bilateral proliferative retinopathy with major visual impairment in at least one eye, Osteonecrosis of 2 or more joints, Sickle cell nephropathy, Stage I or II sickle lung disease, Symptoms of pulmonary hypertension and mean pulmonary artery pressure > 25mmHg, Age 16-60 years, Karnofsky performance status of 70 or higher, Adequate cardiac function, Adequate pulmonary function, Estimated GFR ≥ 30mL/min, ALT ≤ 3x upper limit of normal, No evidence of chronic active hepatitis or cirrhosis, HIV-negative, Patient is not pregnant, History of compliance with medications and medical care, Patient is able and willing to sign informed consent, Patient has an HLA-identical matched related donor

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive alemtuzumab and low-dose total body irradiation (TBI) as part of the conditioning regimen

1 week

5 visits (in-person)

Transplantation

Participants undergo allogeneic hematopoietic stem cell transplantation

1 day

1 visit (in-person)

Post-Transplant Monitoring

Participants are monitored for engraftment and transplant-related morbidity and mortality

365 days

Regular visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alemtuzumab
• Allogeneic Non-Myeloablative Stem Cell Transplantation
• Sirolimus

Trial Overview The study tests a less harsh stem cell transplant from fully matched siblings using immune-suppressing drugs (Alemtuzumab and Sirolimus) and low-dose radiation instead of standard chemo. The goal is to see if this method helps patients accept the new cells with fewer complications.

Participant Groups

Group I: Allogeneic Non-Myeloablative Stem Cell Transplantation Experimental Treatment 3 Interventions

The transplant regimen will consist of alemtuzumab 1mg/kg divided over five days, 300 cGy TBI, followed by sirolimus dosed for a target serum trough level of 10- 15 ng/mL.

Alemtuzumab is already approved in United States, 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

Who Is Running the Clinical Trial?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

Findings from Research

A population pharmacokinetic model for alemtuzumab was developed using data from 206 pediatric patients, revealing that body weight significantly affects the drug's clearance and distribution, which can lead to variable drug exposure.

The study suggests that the current standard dosing method may not be optimal for all children, and individualized dosing based on this model could improve treatment outcomes and reduce toxicity associated with alemtuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. Admiraal, R., Jol-van der Zijde, CM., Furtado Silva, JM., et al.[2023]

Alemtuzumab (CAMPATH-1H) is an effective monoclonal antibody for depleting T-cells in stem cell transplantation, significantly reducing the risk of graft-versus-host disease (GVHD) while maintaining low rates of graft rejection.

Current protocols for using alemtuzumab, either added to stem cell infusions or administered before transplantation, show excellent control of GVHD and have been associated with reduced transplant-related mortality, particularly from infections, although further clinical trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in stem cell transplantation. Hale, G.[2021]

In a study involving 13 high-risk adult patients with sickle cell disease, a chemotherapy-free stem cell transplantation regimen resulted in successful engraftment in all patients, with 92% maintaining stable mixed donor/recipient chimerism after a median follow-up of 22 months.

The treatment showed no mortality or graft-versus-host disease, and patients experienced significant improvements in hemoglobin levels and quality of life, including aspects like bodily pain and vitality, highlighting the efficacy and safety of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease. Saraf, SL., Oh, AL., Patel, PR., et al.[2017]

Alemtuzumab (Campath 1H), a monoclonal antibody targeting CD52 on B and T cells, is increasingly used as a conditioning agent for bone marrow transplantation, but it can have serious side effects.

In a case study of a 37-year-old woman, acute renal failure and disseminated intravascular coagulation (DIC) occurred after receiving Campath, leading to the abortion of her transplant and ongoing dialysis, highlighting the need for caution and further investigation into its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. Osborne, WL., Lennard, AL.[2017]

In a study of 17 pediatric patients undergoing matched unrelated hematopoietic stem cell transplantation (HSCT) with Campath-1H, the incidence of grade I-II acute graft versus host disease (GVHD) was only 29.4%, and no cases of chronic GVHD were observed, suggesting effective reduction of GVHD risk.

Despite a 35.3% relapse rate of primary disease, the overall survival rates were high at 100% at 100 days and 94% at one year, indicating that Campath-1H does not significantly increase the risk of life-threatening infections or relapse compared to conventional regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretransplant conditioning with Campath-1H (alemtuzumab) in pediatric matched unrelated hematopoietic stem cell transplants: an institutional experience. Nageswara Rao, AA., Kumar, R., Altaf, S., et al.[2017]

In a study of 10 kidney transplant recipients treated with alemtuzumab, long-term immunosuppressive therapy was found to influence the balance of T-regulatory and Th17 cells, which are important for immune response regulation.

The research demonstrated that T-regulatory cells can effectively suppress Th17 cell activity, suggesting a potential mechanism for managing immune responses in patients undergoing long-term immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Th17 cells in alemtuzumab-treated patients: the effect of long-term maintenance immunosuppressive therapy. Hester, J., Mills, N., Shankar, S., et al.[2022]

In a study involving 16 children and adolescents with sickle cell disease, a nonmyeloablative hematopoietic cell transplantation regimen showed 100% event-free and overall survival rates after a median follow-up of 19.5 months, with no observed sickling crises or graft-versus-host disease (GVHD).

All patients achieved mixed donor-recipient engraftment, indicating successful integration of donor stem cells, and sirolimus weaning was possible for most patients, suggesting a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease. Guilcher, GMT., Monagel, DA., Nettel-Aguirre, A., et al.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Alemtuzumab in stem cell transplantation. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease. [2017]

4. Italy pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Pretransplant conditioning with Campath-1H (alemtuzumab) in pediatric matched unrelated hematopoietic stem cell transplants: an institutional experience. [2017]

6. United States pubmed.ncbi.nlm.nih.gov

Th17 cells in alemtuzumab-treated patients: the effect of long-term maintenance immunosuppressive therapy. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease. [2020]