Establishing a platform for Haplo-identical transplant in Children with Sickle cell disease (HaChS study)

Sickle cell disease [SCD] is a very commongenetic disease characterized by the presence of an abnormal hemoglobin thatcan give rise to the requirement of life long transfusions or recurrent painfulcrises due to veno-occlusion by the sickle cells. There is significant morbidity and mortality associated with thedisease. Complications include recurrent vaso-occlusive pain crises, stroke,renal, and pulmonary dysfunction. Affected patients have a poor quality oflife, frequent hospital admissions and reduced life expectancy. Effectivetreatments including stem cell transplantation is associated with reducedcomplications include recurrent pain crises, chronic red blood celltransfusions and the need for hydroxyurea therapy. Stroke is the mostdevastating complication and despite chronic blood transfusions almost half ofthe 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 siblingsare the major limitations of transplant for patients with SCD. Wehave been using haplo-identical transplants for the past 9 years in more than200 patients suffering from leukemia, aplastic anemia and primary immunedeficiencies with overall survival of 50-60% and survival of >70% if takenup early for transplant. In this study, we would like to establish a protocolfor haploidentical transplant for Sickle cell disease which would ensure a 1year survival rate of 70%.

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

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

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

Methods: Patients with SCD who are eligible to takepart in this study will receive conditioning with a Fludarabine/Treosulfan/Thiotepaprotocol commonly used in SCD followed by infusion of either αβ depleted CD34positive stem cell graft or a standard T cell replete graft from ahaplo-identical donor. The haplo-identical donor will be identified from withinthe family based on standard eligibility criteria that are used within thedepartment. Patients who receive a non-T cell depleted graft will receive posttransplant cyclophosphamide along with Cyclosporine (CSA) and MycophenolateMofetil (MMF) as GVHD prophylaxis. Following the infusion, patient will bemonitored for acute infusional toxicity, for engraftment and for development ofgraft versus host disease. Patients will also be routinely monitored forinfections as is done for all haplo-identical transplants. Patients will befollowed up for 1 year to look for evidence of chronic graft versus hostdisease and for overall survival.

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