Bone Marrow Transplantation In Sickle Cell Disease

A bone marrow transplant is a complicated process that involves several tests and personnel. Routine labs including CBC, CMP, and 24-hour urine creatinine are performed.  A brain MRI/MRA inspects for the extension of brain infarcts and vascular abnormalities.  An echocardiogram is performed to estimate pulmonary pressures. Dental clearance and pulmonary function tests are also a part of pre-transplant testing. Most importantly,  HLA- typing is performed to find a donor for the transplant.  Red cell phenotype of both the recipients and the donor is obtained. Screening for donor-directed antibodies is also undertaken because of the risk of pure red cell aplasia post-transplant.[6][7]

Researchers have developed and improved the bone marrow transplant technique since the first transplant done in 1984. The technique entails using chemotherapy for conditioning to remove the recipient's cells and later replacing it with the donor cells free of sickling. The first transplantation in 1984 used cyclophosphamide at 120mg/kg and fractionated total body irradiation to destroy the patient's bone marrow and replaced it with matched donor stem cells. The patient then received GVHD prophylaxis consisting of a short course of methotrexate and methylprednisolone for 28 days.

There has been an improvement in the chemotherapy including the use of busulfan which was found to sustain engraftment in patients who receive the bone marrow transplant.[4] Various conditioning regimens, as well as post-transplant cyclophosphamide, have improved outcomes in bone marrow transplant.[8][9]

Since the first transplant in 1984, over 1200 cases have been reported. Major problems limiting the transplant to all patients include finding a matched donor, the risk associated with the procedure including graft vs. host disease and cost. If there is transplant mismatch, there is a high risk of morbidity and mortality. HSCT is safest when a matched donor is available, but unfortunately, only a few transplant candidates have such donors. Even with this, there is still a 9 percent risk of graft rejection and a 15 percent risk of chronic graft-versus-host disease. As a result, scientists are looking for various ways to reduce these complications including the use of less toxic medications and finding other stem cell sources like related and unrelated cord blood, haploidentical transplant and myeloablative allogeneic transplant. The unrelated cord blood stem cell transplant and haploidentical stem cell have been found to be less successful due to an increase in graft vs. host disease.

Many of the medications used as immunosuppressives are toxic and can cause infertility. These agents can also induce secondary malignancy in these patients. A good example is a case study on a patient who developed a Sertoli-Leydig tumor reported after stem cell transplantation.

Bone marrow donors are unlikely to get severe complications from donating their marrow cells. However, there has been a report of chronic pain in these patients. In a prospective study by Shaw et al., they found that 11% of teenage females around the age of 13-17-years-old reported Grade 2-4 pain compared to 3% in males in the same age group. Therefore, these patients should also be followed carefully to address pain-crisis syndrome.[10][11][12][13]

Sickle cell anemia is a persistent chronic disorder with no cure. Patients develop recurrent vaso-occlusive crisis because of the clogging of tiny capillary vessels most especially in the bones. Apart from the sickling of the cells, other cells interact to cause more adhesion of the red blood cells including inflammatory cells, and platelets. This phenomenon also occurs in multiple organs in the body including the chest, heart, lungs, abdomen, kidneys, and extremities. Because of the repeated attacks, organ damage can occur due to the ischemia. The first presentation of sickle cell crisis in an infant is usually dactylitis with swelling of both the hand and foot, hence the name hand-foot syndrome. The dorsum of the hands and foot are very painful and swollen. Infants may also show signs of anemia such as conjunctiva pallor, jaundice, and poor capillary bed refill.

The only cure for this disorder is a hematopoietic stem cell transplant. This curative therapy, unfortunately, can lead to some complications and sometimes death, so it is only available for severe sickle cell patients who have complications including stroke, recurrent vaso-occlusive crisis, recurrent transfusion, renal damage, and other complications. To reduce these complications and increase the availability of stem cell transplant to sickle cell patients, researchers are now working on gene therapy. Bone marrow transplant in sickle cell patients has been around for over two decades, and it has helped improve the quality of life of patients. Although this intervention is not yet perfect because of the post-transplant complications, it should still be offered to patients to cure this debilitating disease.

Sickle cell disease was discovered more than a century ago as a genetic disorder. Approximately 8% of the population has this disease. There have been advances in how we screen and treat these patients, but there is still more to do regarding management. Apart from helping to improve patients’ quality of life, finding a definitive cure can help reduce the costs spent annually on the management of patients with sickle cell disease. An estimated $900,000,000 is spent annually on healthcare expenditure.[9] Finding a cure would also help reduce the opioid epidemic caused by the over-prescription of opioid medications for pain control. Bone marrow transplantation is an excellent start to finding this cure. The newer gene therapy studies in pre-clinical and clinical trials have shown favorable outcomes in sickle cell patients. Although bone marrow transplantation is not yet perfect because of complications involved, it still serves as a hope for patients with severe sickle cell disease as the benefit outweighs the risks.