Benefits of Newborn Screening and Hematopoietic Cell Transplant in Infantile Krabbe Disease

Page KM, Ream MA, Rangarajan HG, et al. Benefits of Newborn Screening and Hematopoietic Cell Transplant in Infantile Krabbe Disease [published online ahead of print, 2022 Jan 18]. Blood Adv. 2022. Read the full article. The following publication highlights the benefits and unique challenges associated with newborn screening (NBS) for early-onset Krabbe disease (also known as infantile Krabbe disease (IKD)) and hematopoietic cell transplantation (HCT). As of this writing (March 2022), NBS for Krabbe disease is now available in 10 states. An application to add Krabbe disease to the Recommended NBS Panel (RUSP) is currently under review.

BACKGROUND

IKD can be treated with hematopoietic cell transplantation (HCT) if done during the first weeks of life before symptoms develop. As a parent of a newborn, hearing this news that your baby is affected by Krabbe disease and for HCT to be effective, life-altering decision making must occur immediately may be seen as a challenge, a burden and a blessing. In this report, the outcomes of those newborns with IKD diagnosed through NBS and treated with HCT are presented. The unique challenges associated with NBS for Krabbe disease are discussed including opportunities for earlier diagnosis and streamlining treatment referrals.  

METHODS

• This is a retrospective review (meaning the authors looked back at the data) of six (6) infants with IKD detected by expanded NBS and referred for HCT before 6 weeks of age.
• All infants, initially identified by low GALCA specific enzyme that receives its instructions from the GALC gene. When the GALC gene isn’t working properly, the enzyme, galactocerebrosidase, is unable to break down certain fats called galactol enzymeA protein needed by the body to break down certain substances by causing a biochemical reaction within the cells. In Krabbe disease, galactocerebrosidase is the deficient enzyme.  Words that end in levels, had extremely elevated psychosineDue to the enzyme deficiency in Krabbe disease, psychosine accumulates in the nervous system of affected individuals. Psychosine, a galactolipid, is a cytotoxic type of lipid, that has destructive pr levels (range, 24-73 nmol/L, normal <2 nmol/L) confirming the IKD diagnosis.
• Neurologic testing before HCT revealed evidence of active IKD in all infants. The newborns appeared healthy, yet all infants showed evidence of active IKD on neurodiagnostic and neuroimaging studies performed before transplant (at 1-3 weeks of age), highlighting the rapid disease course.
• Infants met state-specific criteria and were referred for emergent HCT evaluation at a participating center. Five infants were evaluated as inpatients to expedite the process.
• Cord blood donors were selected from the Be the Match® registry using standard criteria.

RESULTS

• Families were notified of the abnormal NBS results at a median of 6 days of age (range, 5-16). One infant needed an additional blood drawn for confirmatory testing at postnatal day 9 which resulted 7 days later.
• Chemotherapy started at a median of 27 days old (range, 14-32).
• All infants engrafted and survived HCT. The children, now 30-58 months old, are all alive. All but one patient are off immunosuppressive therapy.
• All are gaining developmental milestones but at a slower pace than unaffected age-matched peers. Gross motor function is most notably affected.

CHALLENGES

• Testing newborns for IKD presents unique challenges compared to other diseases diagnosed by NBS.
• For infants to access HCT (or other future treatments), complex care coordination is emergently needed and, for 2 of 6 infants, this included a referral to an out-of-state transplant center.
• Prior reports established HCT before 30 days old as a benchmark among presymptomatic Infants. Only one infant achieved that goal here. The family was integrally involved in hastening the referral, thereby allowing early evaluation (7-days old) and transplant (24-days old). Due to the small numbers, we cannot comment on whether this timing impacted the outcomes.
• Taken together, our experience reflects real-world practice. NBS programs in this series encountered reflex testing delays (e.g., need for extra blood draw), difficulties contacting the family, and delays communicating results.
• Possible remedies to expedite referrals and getting HCT within the first 30 days of life include:
  • Rapid reflex testing using psychosine per recent consensus recommendations
  • Established referral pathways triggered by reflex testing
  • Concurrent pathways to rapidly inform the pediatrician and initiate the referral. When NBS is implemented, relationships with transplant centers should be firmly established.

CONCLUSIONS

• All children undergoing HCT are alive and have shown developmental and neurologic benefits from timely HCT. Long-term follow up is ongoing.
• Clearly, opportunities for improvement still exist for both NBS programs and treating centers to maximize efficiency.
• Optimization of HCT and further development of emerging therapies, all of which must be delivered early in life, are expected to further improve outcomes of infants with IKD.