In this issue of Blood, Miller et al describe the efficacy of hematopoietic cell transplantation (HCT) in 60 patients with childhood cerebral adreno-leucodystrophy (ALD).1  To further improve the outcomes of cellular treatment options in this very rare disease, there is need for coordination of care and a well-functioning international clinical and research network.

After the first report from Aubourg in 19902  and a 2004 international report from Peters et al (n = 126 of whom only 94 with complete dataset were analyzed),3  the data from Miller et al once again demonstrate efficacy of transplantation for otherwise rapidly fatal childhood neurodegenerative disease. The outcomes from this recent (2003-2009) single-center cohort are encouraging, with an overall survival rate of ∼ 80%, with ∼ 90% survival for those who receive a transplant when minimally affected (absent neurologic disease or Loes score < 10). In line with previous reports,2-4  predictors for poor survival/disease progression after HCT were high Loes scores (> 10) or having neurologic dysfunction before HCT. Miller and colleagues speculate that better supportive care in the past decade and better patient selection are the main causes of improved survival rates in this recent cohort. Several centers, most notably the University of Minnesota, have been leaders in advancing the care of patients with inherited metabolic diseases (IMDs). In addition, Miller et al present the long-term (neurologic) outcomes of HCT and the impact of adjuvant treatment with NAC (N-acetyl-L-cysteine) on survival, and they speculate on how to improve outcomes further. These are all very important issues to move the field forward.

Further improvement of the outcomes (survival and neurologic) of this very rare, devastating disease (which should also apply for other rare IMDs) can only happen when we as a transplant community: (1) centralize and coordinate the cellular therapies (such as HCT and gene-therapy) for these rare diseases and (2) tighten the international collaboration through a well-functioning international network.

The most important argument for these recommendations is the rarity of the disease. With the exception of the University of Minnesota, there are no other centers in the world transplanting these numbers of X-linked ALD (X-ALD) patients (60 in 6 years). In the study by Peters et al, only 126s patients were included from 43 centers between 1989 and 1999.3  This demonstrates that it is very difficult to perform single-center studies (for studying novel therapies), gain experience in clinical care, provide multidisciplinary follow-up (because most patients continue to have residual disease burden), and recognize typical disease-specific, post-HCT complications. For X-ALD, future topics of interest include:

  1. How can we improve survival rates and neurologic outcome?

  2. Can toxicity be further reduced using nonmyeloablative conditioning regimens, which may result in better survival and neurologic outcome?

  3. Does mixed-chimerism, which may be a result from reduced-intensity conditioning, influence the long-term results as it does in other IMDs (eg, Hurler disease)?5  If it does, it may have implications for gene-therapy trials as well.

  4. Can we optimize the outcomes with adjuvant therapies, such as NAC, which was shown by Miller et al in a previous report to impact the survival in neurologically affected patients before HCT?1,6  As previously mentioned, there is need for further study of the effect of adjuvant therapies, such as NAC, to further improve outcomes.

  5. Patients (and parents) may profit from well-organized, dedicated, disease-specific, multidisciplinary teams. As early diagnosis and early transplantation influence outcome, early recognition of certain problems, which may be part of residual disease burden, is of importance to prevent more severe morbidities. This can be done best by experienced teams in specialized centers.

For X-ALD (which may also apply to other IMDs), nationwide, regional, or state-centralized care may improve outcomes after HCT. It would substantially increase the experience of the multidisciplinary teams caring for these rare diseases, increase data collection for international studies, and promote uniform treatment protocols or guidelines. These centers should be organized as clinical and research networks. In The Netherlands there has been 1 national referral center (UMC Utrecht) for HCT in IMDs since 2004. Within a multidisciplinary team the indication for HCT is made and after transplantation there is a standardized, multidisciplinary follow-up program for these patients. This has definitely impacted the process of care for this vulnerable patient group. In the past decade, international collaboration, such as the introduction of transplantation guidelines for IMD within the European Group for Blood and Marrow Transplantation, has resulted in better outcomes (higher survival and lower morbidity rates). For example, the survival rate of HCT in Hurler syndrome increased from 50% to > 90%.7  And currently, an international long-term follow-up study, including the majority of the European- and North American–transplanted Hurler syndrome patients, is in its analyses phase.

We have to build on these collaborations to continue to improve treatment in X-ALD and other IMDs. Greater international collaboration will lead to better outcomes in this interesting and challenging field.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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