Sickle cell disease [SCD] is a very common genetic disease characterized by the presence of an abnormal hemoglobin that can give rise to the requirement of life long transfusions or recurrent painful crises due to veno-occlusion by the sickle cells. There is significant morbidity and mortality associated with the disease. Complications include recurrent vaso-occlusive pain crises, stroke, renal, and pulmonary dysfunction. Affected patients have a poor quality of life, frequent hospital admissions and reduced life expectancy. Effective treatments including stem cell transplantation is associated with reduced complications include recurrent pain crises, chronic red blood cell transfusions and the need for hydroxyurea therapy. Stroke is the most devastating complication and despite chronic blood transfusions almost half of the patients will suffer a recurrent stroke or new silent cerebral infarcts. The only curative therapy is an allogeneic hematopoietic stem cell transplant (HSCT). Toxicities related to preparative regimen and lack of HLA identical siblings are the major limitations of transplant for patients with SCD. We have been using haplo-identical transplants for the past 9 years in more than 200 patients suffering from leukemia, aplastic anemia and primary immune deficiencies with overall survival of 50-60% and survival of >70% if taken up early for transplant. In this study, we would like to establish a protocol for haploidentical transplant for Sickle cell disease which would ensure a 1 year survival rate of 70%.  

In the department of Haematology, we have been performing transplants for sickle cell anemia for the past 10 years and have performed about 20 transplants. We have also performed 4 haplo-identical transplants for sickle cell anemia including 2 with T cell αβ depletion and 2 with post transplant cyclophosphamide without T cell depletion. We have also been performing haplo-identical transplants for other hematological disorders for the past 9 years and have completed more than 200 haplo-identical transplants.  

Introduction: The wide spread use of stem cell transplantation as a curative therapy in sickle cell disease (SCD) is limited by the availability of matched sibling donors. The use of Haplo-identical donors could be a potential way forward to overcome this limitation.

Aim: In this phase II study, we would like to establish a protocol for haplo-identical transplant for SCD using a Fludarabine/Treosulfan/Thiotepa based conditioning along with either αβ T cell and B cell depletion of the graft or using post-transplant cyclophosphamide (PTCy) as primary graft versus host disease (GVHD) prophylaxis.

Methods: Patients with SCD who are eligible to take part in this study will receive conditioning with a Fludarabine/Treosulfan/Thiotepa protocol commonly used in SCD followed by infusion of either αβ depleted CD34 positive stem cell graft or a standard T cell replete graft from a haplo-identical donor. The haplo-identical donor will be identified from within the family based on standard eligibility criteria that are used within the department. Patients who receive a non-T cell depleted graft will receive post transplant cyclophosphamide along with Cyclosporine (CSA) and Mycophenolate Mofetil (MMF) as GVHD prophylaxis. Following the infusion, patient will be monitored for acute infusional toxicity, for engraftment and for development of graft versus host disease. Patients will also be routinely monitored for infections as is done for all haplo-identical transplants. Patients will be followed up for 1 year to look for evidence of chronic graft versus host disease and for overall survival.

Conclusion: We aim to find out if this protocol will help in ensuring a 1 year overall survival rate of 70% when using a haplo-identical donor.