Time to Transplant in X-linked Adrenoleukodystrophy

Abstract

Objectives

Cerebral X-linked Adrenoleukodystrophy (cALD) is an inflammatory demyelination of the brain which can lead to death unless treated by hematopoietic stem cell transplantation (HSCT). Survival and improved outcomes for cALD are associated with HSCT at earliest evidence of disease on MRI. Our goal was to determine average duration between diagnosis of cALD and HSCT.

Methods

This was a retrospective review of data of patients age 18 years or younger, using a nationwide administrative healthcare database (Pediatric Health Information System), with an ICD-10 diagnosis of ALD. Time range was October 1, 2015, through June 30, 2021. We determined time to HSCT by duration between index brain MRI, and a code for HSCT.

Results

We identified 27 patients with cALD. Total charges for the cohort was $53 million. Time to transplant averaged 97 days. For Hispanic patients, time to transplant was 117 days, compared to 80 days for White, non-Hispanic patients. Comparison of different hospitals showed significant variability in time to HSCT.

Discussion

We found that time to HSCT was over 3 months for patients with cALD in the hospitals we evaluated. We noted differences in average time by race/ethnicity and by hospital. Our findings suggest opportunity to reduce time to transplant in cALD.

Introduction

X-linked Adrenoleukodystrophy (ALD) is a progressive nervous system disease caused by mutations in the peroxisomal gene ABCD1.¹ Nearly forty percent of boys with ALD will develop an inflammatory demyelination of the brain termed cerebral ALD (cALD), which results in death within a few years of onset. Hematopoietic stem cell transplant can treat cALD if initiated in early stages.^2,3 In contrast, later use of HSCT is associated with poor outcomes and lack of efficacy. Given the known association between performing HSCT at earliest stages of cALD and improved outcomes and higher survival, our goal was to evaluate national trends for the time duration between abnormal brain MRI indicating cALD, and HSCT. We sought to understand whether there was a delay in HSCT, which has importance for cALD because of its progressive course.

Methods

This study was approved by the Institutional Review Board of the Child Health Corporation.

We conducted a retrospective review of all patients age 18 years or younger admitted to a Pediatric Health Information System (PHIS)-participating hospital with an ICD-10 diagnosis of X-linked adrenoleukodystrophy (E71.52x). Time range for the study was October 1, 2015, through June 30, 2021.

The PHIS administrative database has demographic information, diagnosis, and procedure codes from inpatient and emergency room encounters at 51 tertiary care children’s hospitals in the U.S.^4,5 Data from all PHIS sites was included for analysis, including hospitals which joined PHIS during the study time period. The ICD coding were used to create variables for brain MRI and for transplant (bone marrow transplant, umbilical cord blood transplant, hematopoietic stem cell transplant). Time to transplant was determined by time duration between the most recent preceding brain MRI, and a code for a transplant. Results were only included if the time duration was more than 2 weeks and less than 6 months. These time limits were based on assumptions that any transplant done in a less than 2 week time period would likely reflect that an outside (non-PHIS) MRI had been already performed so that a time duration could not be determined. Similarly, that a time duration longer than 6 months was unlikely to be an accurate report on time between concern for cALD and transplant (again, that an outside MRI had been performed that precipitated the transplant).

All analyses were two-sided, and p < 0.05 was considered statistically significant.

Results

We identified 27 patients with cALD; 13 (48%) were Hispanic (Table 1). 21 (78%) of patients had been diagnosed with ALD prior to their index MRI. Average age at ALD diagnosis was 6.2 years; and average age at HSCT was 6.8 years. Total charges for the cohort was $53 million, nearly $2 million per patient.

Table 1.

Selected demographic characteristics. N is 27 individuals. Abbreviations, HSCT, hematopoietic stem cell transplantation.

Group	N (%)
Male	27 (100%)
Race
White	11 (41%)
Hispanic	13 (48%)
Black	2 (7%)
Multiracial	1 (4%)
Private Insurance	9 (33%)
Government Insurance	17 (63%)
Other insurance	1 (4%)
Preceding diagnosis of ALD	21 (78%)
Age at ALD diagnosis, years (range)	6.2 (0.3 – 13.9)
Age at HSCT, years (range)	6.8 (0.3 – 15.7)
Charges, total	$53,943,561
Charges, average	$1,997,910

Time to HSCT averaged 97 days following index MRI (Table 2). Time to transplant was similar for patients who had or had not been diagnosed prior to their index MRI with ALD. For Hispanic patients, time to transplant was 117 days, compared to 80 days for White patients. Comparison of different PHIS hospitals showed significant variability in time to HSCT (Figure 1).

Table 2.

Outcomes. N is 27 individuals. Unpaired t-test calculated for two-tailed p value. Abbreviations: dx, diagnosis; HSCT, hematopoietic stem cell transplantation.

Characteristic	days (mean, median)
Days between MRI and HSCT (Overall)	97, 88
Days between MRI and HSCT (Preceding dx of ALD)	98, 90
Days between MRI and HSCT (NO preceding dx of ALD)	95, 82
Days for Hispanic patient	117, 127
Days for White patient	80, 76	p 0.076

Figure 1.

Hospital and time to HSCT. Y-axis, time to transplant (days); x-axis, PHIS hospital (coded). Dashed line indicates overall average time.

Conclusions

Our work shows that average time to HSCT was over 3 months for cALD. In addition, although not reaching statistical significance, we noted longer times to HSCT in Hispanic boys. We also found a wide variability in time to HSCT at different hospitals, ranging from a month to 6 months. A single-center study from Germany showed a similar duration between diagnosis and transplant of 3 months for cALD.⁶

The American Society for Blood and Marrow Transplantation (ASBMT) suggests autologous and allogeneic HSCT for treatment of cALD.⁷ In general, time to HSCT for all conditions is dependent upon the matching process and finding a donor, and has been estimated at ~ 3 months.⁸

A strength of this study was the use of nation-wide data from PHIS for evaluation of cALD, including from the most recent 6 years. Interestingly, most of the hospitals only did HSCT for one or two patients. For the hospital with the most volume, the time range showed the greatest variability. Another interesting point is that we observed a larger proportion of Hispanic patients (48%), whereas the PHIS hospital patient population coverage is approximately 28%.⁹ There are several possible explanations for this observation which warrant further study.

Limitations for this work are its use of retrospective data. PHIS does not have results including radiology results, thus limiting certainty that the MRI selected as the index was the abnormal MRI prompting HSCT. However, if another outside MRI was the index, then the time lag would be even greater. Thus if anything our time duration is an underestimate of the total time. Outcomes data, such as mortality or degree of neurological impairment post-HSCT, were not available. Future studies to evaluate outcomes and correlation to duration to transplant would be of interest. Because of inherent limitations of the PHIS database, it was also not possible to determine which patients were already followed prospectively with a known ALD diagnosis, versus patients with a new diagnosis. This difference (known patient versus new diagnosis) could impact timing between MRI and HSCT.

Since data from some centers is not included in the PHIS database, our findings represent only a portion of HSCT performed for cALD. For example, in a two year time period (2018–2019), 12 transplants for ALD were reported at the University of Minnesota, which is not part of PHIS.¹⁰ National tracking, reporting, and metrics of details for HSCT in cALD (and other leukodystrophies) would be helpful for assessing opportunities to improve outcomes or reduce potential disparities.

In conclusion, we found that the time to HSCT for cALD was over 3 months. Our findings suggest an opportunity to reduce time to HSCT in cALD, which could help with improving outcomes. We recommend considerations for shortening the time to HSCT: typing known ALD patients at time of first diagnosis; facilitating communication between the transplant team and the leukodystrophy specialist, to ensure that urgency of transplant is considered in timing of admission for transplant; improving efficiency in the process leading to HSCT such as shortening the time of HLA typing; and tracking time to HSCT to permit opportunities for on-going quality improvement. These recommendations could be utilized at all centers and would not be unduly burdensome to providers or to patients and family, could help reduce time to transplant, and could serve as a model for other leukodystrophies in which expeditious HSCT or genetic therapies are indicated.