Stem Cell Transplantation in Friedreich Ataxia: Cure for Leukemia but No Effect on Neurological Progression

Major Points and Findings:

This single case report has a negative neurological result and is included for that reason. A girl was diagnosed with Friedreich ataxia (FRDA) and acute myeloid leukaemia at the same time, at age 10. Her leukaemia was cured by a donor blood stem cell transplant. Ten years later her blood cells carry the donor’s normal frataxin gene and her blood frataxin level is normal, yet her ataxia has progressed at the same rate as other children with the same genetic severity. She now uses a wheelchair.

The report concerns haematopoietic (blood-forming) stem cell transplantation, which is a different treatment from the mesenchymal or umbilical cord cell infusions offered for ataxia. The case is relevant because of the principle it illustrates. Healthy donor cells in the bloodstream, present permanently and in large numbers, did not protect the nervous system in a genetic ataxia.

Aim:

To describe the 10-year neurological, cardiac and laboratory course of a patient with FRDA after allogeneic haematopoietic stem cell transplantation given for leukaemia, and to consider what it says about blood stem cell approaches to replacing frataxin.

Methods:

Single-patient case report from the Children’s Hospital of Philadelphia and Memorial Sloan Kettering Cancer Center, supported by the Friedreich’s Ataxia Research Alliance.

A girl aged 10 years 3 months was admitted to intensive care with chest pain, a fast heart rate and thyrotoxicosis. Persistently low blood counts led to a bone marrow test, which showed high-risk acute myeloid leukaemia, t(6;9), without spread to the nervous system. At the same admission doctors noted a slightly wide-based gait, ataxia, a fine finger tremor, slightly reduced vibration sense and absent tendon reflexes. Brain MRI was normal. Genetic testing found expanded GAA repeats of 699 and 1066 in both copies of the FXN gene, confirming FRDA. Echocardiography showed moderate thickening of the left ventricle.

Induction chemotherapy with cytarabine, daunorubicin and etoposide did not achieve remission. Two cycles of topotecan, vinorelbine, thiotepa and clofarabine cleared measurable disease. She then received CD34-selected peripheral blood stem cells from an unrelated male donor matched at 11 of 12 HLA markers, after conditioning with rabbit anti-thymocyte globulin, clofarabine, melphalan and thiotepa. Before the transplant, cardiac MRI showed normal heart size and pumping function (left ventricular ejection fraction 74%) with borderline septal thickening of 1.1 cm.

For comparison, her course was plotted against six other FRDA patients seen at the same hospital within five years of her, who presented at age 8 to 10 with similar repeat lengths (shorter repeat 599 to 833, longer repeat 1033 to 1333). All were followed with the same tests over a similar period, although only four of the six had cardiac follow-up. The measures were the modified Friedreich Ataxia Rating Scale (mFARS), the 9-hole peg test of hand function, septal wall thickness and ejection fraction.

Results:

There were no major unexpected complications, no graft-versus-host disease, and no return of leukaemia over 10 years.

Blood: Ten years after transplant, genetic testing on blood showed the donor’s normal GAA repeat lengths of 10 and 16. Blood frataxin was in the normal control range (reported as frataxin M 4.79 ng/mL and frataxin E 9.25 ng/mL).

Nervous system:

• mFARS worsened by 20 points over 10 years.
• 9-hole peg test time doubled over 10 years.
• Speech became mildly affected, walking and arm function worsened, and spasticity increased.
• Reflexes stayed absent and the nerve damage in the limbs showed no reversal.
• She now uses a wheelchair and cannot walk independently, “at roughly the expected time” for her genetic severity.
• Her trajectory was similar to that of the six comparison patients.

Of the other FRDA complications, she developed diabetes and sleep apnoea. She has not needed scoliosis surgery.

Heart: Heart wall thickening did not progress and eventually resolved, and her echocardiogram 10 years after transplant was reported as normal. Ejection fraction stayed stable. The authors interpret this cautiously. The same pattern was seen in some of the comparison patients, wall thickness in FRDA can decrease without any long-term benefit, and falls in ejection fraction usually come late in the disease. They call the cardiac finding “notable but not definitive”.

Conclusions:

The authors conclude that a person with FRDA can come through an allogeneic stem cell transplant safely, which is useful to know if one ever needs it for cancer, but that the transplant “did not have a major effect on neurologic progression”. They offer several reasons why:

• The blood-brain barrier keeps most donor-derived cells out of brain tissue.
• A standard transplant does not deplete the brain’s own microglia and monocytes. The authors suggest that deeper depletion might be required for donor cells to have any effect there.
• Frataxin works inside mitochondria and is not normally secreted, so healthy donor cells do not pass it to neighbouring deficient cells.
• Part of the damage in FRDA happens during development, so replacing frataxin at age 10 may be too late for some structures.
• The chemotherapy itself may have harmed nerves and masked any benefit, and diabetes may have interfered as well.

They state that the differences between this clinical transplant and the purpose-built approaches being designed for FRDA “prohibit the use of the present observations as evidence for potential benefit in the CNS”. They also note that small differences in progression cannot be detected with one patient and six comparators, because progression in FRDA varies from person to person.

Background Information:

Friedreich ataxia is a recessive disease in which expanded GAA repeats in the FXN gene (96% of cases) reduce production of frataxin, a protein needed by mitochondria. It affects the spinal cord and cerebellum, peripheral nerves, heart muscle and the insulin-producing cells of the pancreas, leading to ataxia, spasticity, weakness, scoliosis, optic nerve damage, hypertrophic cardiomyopathy and diabetes. It is not known to raise cancer risk, and the authors consider the leukaemia in this patient a coincidence.

Several experimental strategies aim to restore frataxin: gene therapy delivered by adeno-associated virus to the heart and nervous system, protein replacement, and drugs that switch the silenced gene back on. Another idea under study is to correct a patient’s own blood stem cells and rely on their monocyte descendants entering the brain and handing frataxin to neurons. With an ordinary transplant and unmodified donor cells, normal frataxin in the blood for a decade did not slow the neurological disease. Any cell-based treatment for FRDA has to show that its effect reaches the nervous system, because a normal blood test does not demonstrate that.