Gene Therapy for Rare Brain Disease Effective, but Comes With Blood Cancer Risk

While the use of elivaldogene autotemcel (eli-cel; Skysona) gene therapy has demonstrated long-term efficacy in patients with cerebral adrenoleukodystrophy (CALD), that benefit comes with a risk of developing hematologic cancers, according to results from a pair of studies.

In one of the reports, seven of 67 boys with CALD who were treated with eli-cel were diagnosed with a hematologic cancer 14 to 92 months later — six with myelodysplastic syndrome (MDS) and one with acute myeloid leukemia (AML), reported David A. Williams, MD, of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, and colleagues.

These patients were included in the phase II/III ALD-102 and phase III ALD-104 trials, the results of which led to the accelerated approval of eli-cel for early, active CALD in boys ages 4 to 17 years (with a boxed warning for hematologic malignancy).

“Our results suggest that patients who are considering lentiviral vector gene therapy should continue to be educated on the risk of hematologic cancer and, if treated, monitored closely,” Williams and colleagues wrote in the New England Journal of Medicine (NEJM).

Hematologic cancer was diagnosed in one patient treated in the ALD-102 study, with 222 person-years of follow-up (incidence rate 0.5 per 100 person-years), and in six patients in the ALD-104 study, with 116 person-years of follow-up (incidence rate 5.2 per 100 person-years).

Williams and colleagues pointed out that the conditioning agents used in the ALD-102 study (busulfan-cyclophosphamide) could potentially reduce the risk of cancer compared with the agents used in the ALD-104 study (busulfan-fludarabine).

“For patients treated with eli-cel, one intervention to reduce the risk of cancer may be to consider the use of busulfan-cyclophosphamide as the preparative regimen instead of busulfan-fludarabine,” they wrote.

In the second report, also published in NEJM, Williams and colleagues reported that of 32 boys ages 17 and younger who were treated with eli-cel in the ALD-102 study and followed for up to 8.9 years in the ongoing LTF-304 follow-up study, 94% were alive at month 24, 94% had stable neurologic function scores compared with baseline scores, and 81% had no major functional disabilities.

The authors advised that the risk of oncogenesis with eli-cel should be weighed against the severity and natural history of CALD, as well as the availability of other treatments and their risks, including allogeneic hematopoietic stem cell transplant (HSCT).

Since gene therapy is an evolving field, “ongoing follow-up is critical to understanding the longer-term safety and efficacy of novel treatments like eli-cel,” they concluded.

Childhood CALD is a rare, neurologically debilitating form of adrenoleukodystrophy (about one-third of cases) that generally occurs in young boys. It is caused by a mutation in the ABCD1 gene that leads to the overproduction of very-long-chain fatty acids in the white matter of the brain and spinal cord.

Eli-cel uses ex vivo transduction with the Lenti-D lentiviral vector to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells, which allows patients to produce the ALD protein that helps break down those very-long-chain fatty acids.

While HSCT can slow or stop CALD progression and improve survival, and even improve functional outcomes if performed early enough, children with mismatched unrelated donors have high risks of graft failure, graft-versus-host disease, and mortality.

In an accompanying editorial, Cynthia E. Dunbar, MD, of the National Heart, Lung, and Blood Institute, noted that while only about 20% of patients with CALD have an available matched donor, “major advances in the safety and efficacy of haploidentical transplantation since the introduction of post-transplantation cyclophosphamide, including in children, suggest that allogeneic HSCT may be more broadly applicable in cerebral adrenoleukodystrophy.”

However, “autologous gene therapy for cerebral adrenoleukodystrophy has, strikingly, preserved neurologic function and extended life in patients treated early in the disease course, and I hope that vector modifications can make the process less genotoxic in the future,” she added.

Of the patients who developed hematologic cancers, five with MDS underwent allogeneic HSCT, and four remain free of MDS without recurrence of symptoms of CALD, and one died from presumed graft-versus-host disease 20 months after transplant and 49 months after receiving eli-cel. The patient with the most recent case of MDS is awaiting HSCT.

The patient with AML is alive and had full donor chimerism after HSCT.

Williams and colleagues observed that all seven cases of hematologic cancers were probably mediated by Lenti-D lentiviral vector insertion.

“Of the six cases with available data, all were found to be associated with expansion of a clone that contains at least one confirmed insertion site in a known proto-oncogene: MECOM in five cases and PRDM16 in one case,” they wrote. “The seventh case of cancer is undergoing more-detailed investigation.”

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