Conference Coverage

Most patients off transfusions after gene therapy for thalassemia


Key clinical point: Most patients who received lentiviral BB305 gene therapy for thalassemia were able to stop transfusions.Major finding: Eleven of 18 patients became transfusion independent, and transfusions were reduced for the remainder of patients.

Study details: Open label, international, single-arm phase 1/2 study of 20 patients with transfusion-dependent beta thalassemia.

Disclosures: The study was funded by bluebird bio. Dr. Walters also reported consulting agreements with several pharmaceutical companies and laboratories.

Source: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.



– Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.

None of the study participants died, and the majority of patients are now transfusion independent.

The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.

Eight patients had the beta0/beta0 genotype, and had essentially been transfusion dependent from infancy. Six other patients were betaE/beta0, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.

Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.

As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.

The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 106 CD34+ cells/kg (range, 5.2-18.1).

“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.

The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.

The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.

The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).

Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.

However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.

Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.

No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.

The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.

Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.

Of the patients who were able to stop transfusions, just two had the beta0/beta0 genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta0/beta0 genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.

In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.

Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.

“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.

The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.

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