Regarding our knowledge to date on malignancies. So sickle cell disease is associated with significant morbidity. So patients experience horrible pain, organ damage, and we know who’s more likely to die early. So patients who have heart, lung and kidney disease are more likely to die early. We can offer curative therapies to patients with sickle cell disease. The type that we do with the National Institutes of Health is non-myeloablative conditioning...
Regarding our knowledge to date on malignancies. So sickle cell disease is associated with significant morbidity. So patients experience horrible pain, organ damage, and we know who’s more likely to die early. So patients who have heart, lung and kidney disease are more likely to die early. We can offer curative therapies to patients with sickle cell disease. The type that we do with the National Institutes of Health is non-myeloablative conditioning. So we don’t give high-dose chemotherapy. We give drugs to suppress the immune system to try to decrease the incidence of graft rejection and graft-versus-host disease. And we really have tried to have a goal of mixed chimerism, so a mixture of donor and recipient cells, and that approach in the HLA siblings setting has been efficacious with 85% of patients being free of sickle cell disease with no significant graft-versus-host disease in the haploidentical setting it’s been more challenging.
We initially had a high graft failure rate. More recently with more upfront and immunosuppression, the graft rejection rate has decreased. But with this approach, we have seen an unexpectedly high incidence of myeloid malignancies. Of 120 patients that we transplanted, eight have developed some type of hematologic malignancy. Five of them developed a more aggressive AML or myelodysplastic syndrome and have died. And then other three have developed T-cell ALL, CML, and mantle cell lymphoma, with mixed chimerism, and are still living. So we want to figure out why that is, why we’re seeing it at a higher rate. We have reported three patients who developed myeloid malignancies after our approach. Two of them had sequencing done and were found to have pathogenic TP53 mutations. We found those same mutations were present at baseline. There are investigators at outside institutions who have also shown that clonal hematopoiesis is higher – the prevalence is higher in patients with sickle cell disease.
So we’re hypothesizing that adults, especially those with severe disease comorbidities, older age, may have clonal hematopoiesis at baseline that can expand – those clones can expand potentially after curative therapies, especially in the setting of graft failure with the proliferative stress associated with having to repopulate those cells in the bone marrow. We have seen a higher incidence of myeloid malignancies after gene therapy for sickle cell disease as well. So we want to change our approach from mixed chimerism to full donor chimerism. We expect, our donor being so young, that they’re not going to have clonal hematopoiesis. And the risk of donor drive leukemia report in the literature is very low. So we’re shifting our approach from the goal of mixed chimerism to full donor chimerism.