Gene therapy exceeds expectations in β-thalassemia

Lurie Children’s photographer

The gene therapy LentiGlobin can reduce or eliminate transfusion dependence in patients with β-thalassemia, according to a pair of phase 1/2 studies.

Fifteen of the 22 patients in these trials were able to discontinue red blood cell (RBC) transfusions after receiving LentiGlobin.

In the 9 patients with severe transfusion-dependent β-thalassemia (TDT), LentiGlobin reduced the transfusion volume by 73%.

There were 5 adverse events (AEs) considered possibly or probably related to LentiGlobin, all them grade 1.

“These study results exceeded our expectations, with clinical benefit for nearly all patients . . . ,” said Alexis Thompson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“Since we saw such positive results, we are now enrolling patients as young as 5 years old on a phase 3 trial of gene therapy for transfusion-dependent thalassemia.”

Dr Thompson and her colleagues reported results from the phase 1/2 trials—known as HGB-204 and HGB-205—in NEJM. The studies were sponsored by Bluebird Bio, the company developing LentiGlobin.

Patients in HGB-204

HGB-204 (also known as Northstar) is a multicenter study that was recently completed. It included 18 patients with TDT. They had a median age of 20 (range, 12 to 35) at baseline, and 72% were female. Seventy-eight percent were Asian, and 22% were white.

Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 13.6 ml/kg (range, 10.4 to 21.8). The median age at which patients started regular transfusions was 3.5 years (range, 0 to 26.0). Six patients had undergone splenectomy.

Patients in HGB-205

HGB-205 is an ongoing study being conducted at a single site in France. It was designed to evaluate LentiGlobin in patients with TDT or severe sickle cell disease.

The NEJM paper includes 4 patients with TDT from this study. They had a median age of 18 (range, 16 to 19) at baseline, and half were female. Half were Asian, and the other half were white.

Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 15.2 ml/kg (range, 11.6 to 15.7). The median age at which patients started regular transfusions was 1.8 years (range, 0 to 14.0). Three patients had undergone splenectomy.

Treatment

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients.

CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA^T87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced RBC transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 AEs considered possibly or probably related to LentiGlobin. These included abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs, including 2 episodes of grade 3 veno-occlusive liver disease that were attributed to busulfan.

The remaining serious AEs were Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis (all grade 3), as well as device-related thrombosis and infectious diarrhea (both grade 2).

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin.

The 3 serious AEs were tooth infection and major depression (both grade 3), as well as pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

At the last study visit (12 to 36 months post-treatment), the median HbA^T87Q level in these patients was 6.0 g/dL (range, 3.4 to 10.0), and the median total hemoglobin was 11.2 g/dL (range, 8.2 to 13.7).

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin infusion.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

At their most recent study visit (12 months to 30 months), these 3 patients had median HbA^T87Q levels of 8.2 g/dL, 6.8 g/dL, and 6.6 g/dL, respectively. Their median total hemoglobin levels were 9.0 g/dL, 10.2 g/dL, and 8.3 g/dL, respectively.

For the 6 patients with a β0/β0 genotype who continued to receive RBC transfusions, the median HbA^T87Q level was 4.2 g/dL (range, 0.3 to 8.7) at the last study visit.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” said study author Philippe Leboulch, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But there is also hope with protocol modifications we have introduced in our phase 3 trials.”

Lurie Children’s photographer

The gene therapy LentiGlobin can reduce or eliminate transfusion dependence in patients with β-thalassemia, according to a pair of phase 1/2 studies.

Fifteen of the 22 patients in these trials were able to discontinue red blood cell (RBC) transfusions after receiving LentiGlobin.

In the 9 patients with severe transfusion-dependent β-thalassemia (TDT), LentiGlobin reduced the transfusion volume by 73%.

There were 5 adverse events (AEs) considered possibly or probably related to LentiGlobin, all them grade 1.

“These study results exceeded our expectations, with clinical benefit for nearly all patients . . . ,” said Alexis Thompson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“Since we saw such positive results, we are now enrolling patients as young as 5 years old on a phase 3 trial of gene therapy for transfusion-dependent thalassemia.”

Dr Thompson and her colleagues reported results from the phase 1/2 trials—known as HGB-204 and HGB-205—in NEJM. The studies were sponsored by Bluebird Bio, the company developing LentiGlobin.

Patients in HGB-204

HGB-204 (also known as Northstar) is a multicenter study that was recently completed. It included 18 patients with TDT. They had a median age of 20 (range, 12 to 35) at baseline, and 72% were female. Seventy-eight percent were Asian, and 22% were white.

Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 13.6 ml/kg (range, 10.4 to 21.8). The median age at which patients started regular transfusions was 3.5 years (range, 0 to 26.0). Six patients had undergone splenectomy.

Patients in HGB-205

HGB-205 is an ongoing study being conducted at a single site in France. It was designed to evaluate LentiGlobin in patients with TDT or severe sickle cell disease.

The NEJM paper includes 4 patients with TDT from this study. They had a median age of 18 (range, 16 to 19) at baseline, and half were female. Half were Asian, and the other half were white.

Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 15.2 ml/kg (range, 11.6 to 15.7). The median age at which patients started regular transfusions was 1.8 years (range, 0 to 14.0). Three patients had undergone splenectomy.

Treatment

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients.

CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA^T87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced RBC transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 AEs considered possibly or probably related to LentiGlobin. These included abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs, including 2 episodes of grade 3 veno-occlusive liver disease that were attributed to busulfan.

The remaining serious AEs were Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis (all grade 3), as well as device-related thrombosis and infectious diarrhea (both grade 2).

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin.

The 3 serious AEs were tooth infection and major depression (both grade 3), as well as pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

At the last study visit (12 to 36 months post-treatment), the median HbA^T87Q level in these patients was 6.0 g/dL (range, 3.4 to 10.0), and the median total hemoglobin was 11.2 g/dL (range, 8.2 to 13.7).

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin infusion.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

At their most recent study visit (12 months to 30 months), these 3 patients had median HbA^T87Q levels of 8.2 g/dL, 6.8 g/dL, and 6.6 g/dL, respectively. Their median total hemoglobin levels were 9.0 g/dL, 10.2 g/dL, and 8.3 g/dL, respectively.

For the 6 patients with a β0/β0 genotype who continued to receive RBC transfusions, the median HbA^T87Q level was 4.2 g/dL (range, 0.3 to 8.7) at the last study visit.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” said study author Philippe Leboulch, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But there is also hope with protocol modifications we have introduced in our phase 3 trials.”

Lurie Children’s photographer

The gene therapy LentiGlobin can reduce or eliminate transfusion dependence in patients with β-thalassemia, according to a pair of phase 1/2 studies.

Fifteen of the 22 patients in these trials were able to discontinue red blood cell (RBC) transfusions after receiving LentiGlobin.

In the 9 patients with severe transfusion-dependent β-thalassemia (TDT), LentiGlobin reduced the transfusion volume by 73%.

There were 5 adverse events (AEs) considered possibly or probably related to LentiGlobin, all them grade 1.

“These study results exceeded our expectations, with clinical benefit for nearly all patients . . . ,” said Alexis Thompson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“Since we saw such positive results, we are now enrolling patients as young as 5 years old on a phase 3 trial of gene therapy for transfusion-dependent thalassemia.”

Dr Thompson and her colleagues reported results from the phase 1/2 trials—known as HGB-204 and HGB-205—in NEJM. The studies were sponsored by Bluebird Bio, the company developing LentiGlobin.

Patients in HGB-204

HGB-204 (also known as Northstar) is a multicenter study that was recently completed. It included 18 patients with TDT. They had a median age of 20 (range, 12 to 35) at baseline, and 72% were female. Seventy-eight percent were Asian, and 22% were white.

Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 13.6 ml/kg (range, 10.4 to 21.8). The median age at which patients started regular transfusions was 3.5 years (range, 0 to 26.0). Six patients had undergone splenectomy.

Patients in HGB-205

HGB-205 is an ongoing study being conducted at a single site in France. It was designed to evaluate LentiGlobin in patients with TDT or severe sickle cell disease.

The NEJM paper includes 4 patients with TDT from this study. They had a median age of 18 (range, 16 to 19) at baseline, and half were female. Half were Asian, and the other half were white.

Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 15.2 ml/kg (range, 11.6 to 15.7). The median age at which patients started regular transfusions was 1.8 years (range, 0 to 14.0). Three patients had undergone splenectomy.

Treatment

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients.

CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA^T87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced RBC transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 AEs considered possibly or probably related to LentiGlobin. These included abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs, including 2 episodes of grade 3 veno-occlusive liver disease that were attributed to busulfan.

The remaining serious AEs were Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis (all grade 3), as well as device-related thrombosis and infectious diarrhea (both grade 2).

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin.

The 3 serious AEs were tooth infection and major depression (both grade 3), as well as pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

At the last study visit (12 to 36 months post-treatment), the median HbA^T87Q level in these patients was 6.0 g/dL (range, 3.4 to 10.0), and the median total hemoglobin was 11.2 g/dL (range, 8.2 to 13.7).

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin infusion.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

At their most recent study visit (12 months to 30 months), these 3 patients had median HbA^T87Q levels of 8.2 g/dL, 6.8 g/dL, and 6.6 g/dL, respectively. Their median total hemoglobin levels were 9.0 g/dL, 10.2 g/dL, and 8.3 g/dL, respectively.

For the 6 patients with a β0/β0 genotype who continued to receive RBC transfusions, the median HbA^T87Q level was 4.2 g/dL (range, 0.3 to 8.7) at the last study visit.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” said study author Philippe Leboulch, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But there is also hope with protocol modifications we have introduced in our phase 3 trials.”