Anand Padmanabhan, MD
Sickle cell disease (SCD) and thalassemia affect millions of people around the globe. Patients with SCD can have debilitating complications such as strokes, vaso-occlusive (VOC) disease, and chronic pain, and while red blood cell (RBC) transfusion and novel therapeutics have improved outcomes, such complications remain a significant cause of both morbidity and mortality. Patients with thalassemia are managed on lifelong blood transfusions and chelation therapy. In this context, recent efforts have been aimed at developing curative therapies for these diseases.
BCL11A is a transcription factor that suppresses the production of fetal hemoglobin (HbF) in RBCs, leading to the production of adult Hb (HbA). It has been proposed that in diseases characterized by defects in hemoglobin production, such as SCD and thalassemia, HbF upregulation could ameliorate anemia, reduce transfusion requirements, and decrease clinical complications. As readers may be aware, a recent seismic advance in genome editing technology, CRISPR-Cas 9, received significant attention when its inventors received the Nobel Prize in Chemistry earlier this year. These advances, in the context of SCD and thalassemia, were discussed in the Plenary Scientific Session abstract “Safety and Efficacy of CTX001 in Patients With Transfusion-Dependent β-Thalassemia and Sickle Cell Disease: Early Results From the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9-Modified CD34+ Hematopoietic Stem and Progenitor Cells,” by Dr. Haydar Frangoul and colleagues. To induce potentially curative levels of HbF in erythrocytes, the investigators used an ex vivo CRISPR-Cas9–based gene-editing platform to edit the erythroid enhancer region of BCL11A in hematopoietic stem and progenitor cells (HSPCs), producing a “living cellular drug,” CTX001. Dr. Frangoul, from The Children’s Hospital at TriStar Centennial and Sarah Cannon Research Institute, detailed results from two multicenter first-in-human clinical studies of these “CRISPRed” HPSCs for the treatment of patients with transfusion-dependent thalassemia (CLIMB THAL-111) and SCD (CLIMB SCD-121).
The studies enrolled adult patients between the ages of 18 and 35 years. Enrollment criteria included patients with transfusion-dependent thalassemia receiving a high volume of RBC transfusions every year (> 10/year) during a recent two-year period and those with severe SCD, defined as patients with more than two VOC crises per year, requiring medical care, also in the prior two years. Peripheral blood HPSCs were mobilized and collected by apheresis. Given risks for precipitating sickle crises, plerixafor alone (as opposed to in combination with granulocyte-colony stimulating factor) was used to mobilize HPSCs from patients with SCD. The erythroid enhancer region of BCL11A was edited in CD34+ cells from the collected apheresate. Prior to infusion of CTX001, patients received myeloablation with busulfan and were monitored for stem cell engraftment and hematopoietic recovery, adverse events, total Hb and HbF production, and several clinical outcomes such as transfusion requirement and VOC.
Dr. Frangoul presented data on outcomes in seven patients with transfusion-dependent thalassemia and three with SCD. In the thalassemia group, follow-up ranged from three to 20 months, and from three to 16 months in the SCD group. All patients engrafted neutrophils and platelets successfully, and all treated patients demonstrated increases in total Hb and HbF over time. Remarkably, patients with thalassemia ceased receiving RBC transfusions, with the last occurring between 0.9 and 1.9 months after CTX001 infusion. The first thalassemia patient treated with CTX001 continues to remain transfusion-free for more than 15 months. Patients with SCD had no VOCs since CTX001 infusion; the first patient with SCD who received CTX001 was observed to be free of VOCs for more than 15 months, a stark contrast to frequent VOCs that occurred in the pretreatment period.
The safety profile after CTX001 infusion was generally consistent with busulfan myeloablation. Serious adverse events related or possibly related to CTX001 were reported in one patient with thalassemia; they included headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome. All four of these serious adverse events occurred in the context of HLH and were either resolved or clinically improved.
This exciting study demonstrates that gene-edited HSPCs that upregulate HbF production can result in significant improvement in patients with transfusion-dependent thalassemia and severe SCD. These results support the excitement in the field that gene editing offers a potential cure for these debilitating diseases. Evaluation of this therapy in a larger number of patients and with longer periods of follow-up is critically needed to confirm these very promising early results.
Dr. Padmanabhan indicated no relevant conflicts of interest.