Clinical trial NCT02013375
Conditions: Sickle Cell Disease
Sponsor: Damiano Rondelli, MD
Start date: 2014-04-10; Completion date: 2018-09-07
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Related donor stem cell transplantation using the alemtuzumab/ TBI platform has been shown to be a safe strategy to cure severe sickle cell disease. However, due to a lack of suitable donors, many patients cannot benefit from this strategy. Alternative donor sources are desperately needed to fill this gap. Nearly all patients will have a haploidentical family member who would be able to donate. The use of post transplantation cyclophosphamide has greatly improved the outcome of haploidentical stem cell transplantation. The investigators propose to combine this with alemtuzumab/TBI conditioning.

Detailed description:
Sickle cell anemia is an inherited form of anemia, a condition in which there aren't enough healthy red blood cells to carry adequate oxygen throughout the body. These patients are at increased risk of death, stroke, frequent pain crises, acute chest syndrome as well as chronic conditions including: lung damage, retinopathy, kidney damage, leg ulcers, and pulmonary hypertension.

There's no cure for most people with sickle cell anemia. However, treatments can relieve pain and help prevent co-morbid conditions associated with sickle cell anemia. Hydroxyurea is the only FDA approved drug to help alleviate symptoms associated with sickle cell disease. The mortality rate is still high in patients using hydroxyurea and a significant percentage of patients still have aggressive disease despite the hydroxyurea treatment. Hydroxyurea therapy also does not seem to prevent the development of many of the complications of sickle cell disease such as pulmonary hypertension.

Historically, stem cell transplantation in sickle cell disease was mainly done in the pediatric population. The options were more limited for adults with sickle cell disease with aggressive disease despite hydroxyurea. Most rely on chronic red blood cell transfusions which carry significant risks of infection, iron overload, and alloimmunization. Alloimmunization refers to the production of antibodies which occurs in up to 50% of patients with sickle cell disease who are on chronic transfusion therapy making further transfusions difficult with a high potential for hemolytic transfusion reactions.

Recently the use of a non-myeloablative stem cell transplantation regimen (relying on immunotherapy instead of chemotherapy) for sickle cell disease in adults showed 88% engraftment rates (30 out of 34 patients) with no GVHD and 0% mortality. However, these transplants used only fully HLA-matched siblings, which are unavailable to all but approximately 14-28% of patients who could benefit from such a transplant at UIC.

A recent study at Johns Hopkins carried out a similar haploidentical (half matched) transplant with 14 sickle cell patients who lacked fully HLA-matched donors. Approximately two years following transplant, 57% of patients successfully engrafted (8 or 14 patients). There were no deaths and only one episode of acute GVHD of the skin which resolved without therapy.

The investigators plan to offer stem cell transplantation to sickle cell patients with aggressive disease who only have a partially matched HLA sibling donor. Haploidentical transplants are considered only for patients with no other standard options available who would normally be treated with supportive (palliative) care or given the option to participate in a clinical trial. Donors who are HLA-haploidentical will be the source of hematopoietic stem cells. Potential donors can include any relative (e.g. parents, offspring, siblings, cousins, aunts/uncles, grandparents).

The related donor stem cell transplantation using the alemtuzumab/TBI platform has been shown to be a safe strategy to cure severe sickle cell disease. However, due to a lack of suitable donors, many patients cannot benefit from this strategy. Alternative donor sources are desperately needed to fill this gap. Nearly all patients will have a haploidentical family member who would be able to donate. The use of post transplantation cyclophosphamide has greatly improved the outcome of haploidentical stem cell transplantation. The investigators propose to combine this with alemtuzumab/TBI conditioning.

The investigational component of this study is the combination of the Alemtuzumab (immunotherapy) and Total Body Irradiation conditioning regimen and the HLA Haploidentical Transplant with post-transplant Cyclophosphamide. Investigators plan to study the engraftment rates (transplant success rates) at Day 60 in sickle cell patients undergoing an HLA haploidentical stem cell transplant with post transplant high dose cyclophosphamide.

Arms: arm 1: All subjects will undergo pre-conditioning treatment with alemtuzumab (0.3 mg/kg Day -5, Day -4, Day -3) and total body irradiation (300cGy), followed by stem cell transplant, and post-transplant treatment with cyclophosphamide (50mg/kg/day) and sirolimus (target trough level of 10-15ng/mL).
Interventions: intervention 1: Haploidentical Transplant intervention 2: Alemtuzumab intervention 3: Total Body Irradiation intervention 4: Cyclophosphamide intervention 5: Sirolimus
Intervention descriptions: intervention 1: All subjects will undergo pre-conditioning treatment with alemtuzumab (0.3 mg/kg Day -5, Day -4, Day -3) and total body irradiation (300cGy), followed by stem cell transplant, and post-transplant treatment with cyclophosphamide (50mg/kg/day) and sirolimus (target trough level of 10-15ng/mL). intervention 2: On Day -7, the first test dose of alemtuzumab (0.03 mg/kg) will be administered and on Day -6, the second test dose of alemtuzumab (0.1 mg/kg) will be administered. Alemtuzumab (0.3 mg/kg) will be infused daily on Day -5, -4, and -3. intervention 3: A 300cGy dose of TBI will be administered in a single fraction on Day -2. intervention 4: Cyclophosphamide (50 mg/kg IBW) IV, over approximately 1-2 hours, is given on Day 3 post-transplantation (ideally between 60 and 72 hours after marrow infusion) and on Day 4 (approximately 24 hours after Day 3 cyclophosphamide). intervention 5: Sirolimus will be started on Day +5 (at least 24 hours after the completion of the cyclophosphamide infusion). The starting dose will be 12mg followed by 4mg PO daily. Doses will be adjusted to achieve a whole blood trough level of 4 - 12ng/mL.

Protocol documents: