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Cited by 26

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Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy

Matsukawa, Takashi, Yamamoto, Tomotaka, Honda, Akira, Toya, Takashi, Ishiura, Hiroyuki, Mitsui, Jun, Tanaka, Masaki, Hao, Akihito, Shinohara, Akihito, Ogura, Mizuki, Kataoka, Keisuke, Seo, Sachiko, Kumano, Keiki, Hosoi, Masataka, Narukawa, Kensuke, Yasunaga, Megumi, Maki, Hiroaki, Ichikawa, Motoshi, Nannya, Yasuhito, Imai, Yoichi, Takahashi, Tsuyoshi, Takahashi, Yuji, Nagasako, Yuki, Yasaka, Kyoko, Mano, Kagari Koshi, Matsukawa, Miho Kawabe, Miyagawa, Toji, Hamada, Masashi, Sakuishi, Kaori, Hayashi, Toshihiro, Iwata, Atsushi, Terao, Yasuo, Shimizu, Jun, Goto, Jun, Mori, Harushi, Kunimatsu, Akira, Aoki, Shigeki, Hayashi, Shin, Nakamura, Fumihiko, Arai, Syunya, Momma, Kazunari, Ogata, Katsuhisa, Yoshida, Toshikazu, Abe, Osamu, Inazawa, Johji, Toda, Tatsushi, Kurokawa, Mineo, Tsuji, Shoji·2020·Brain Communications
DOI 10.1093/braincomms/fcz048PMC PMC7425345
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Abstract

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2–125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0–104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

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Graphical Abstract CC BY-NC · PubMed Central
Figure 1 Prospective follow-up of 45 patients with adolescent/adult ALD and enrolment for HSCT. Forty-five male patients with ALD were enrolled in this study in a prospective manner from September 29, 2003, to October 31, 2018. Among them, 25 patients were considered for HSCT on the basis of detection of MRI lesions in the cerebrum, cerebellum or brainstem. HSCT was conducted on 12 patients. We did not conduct HSCT on eight patients because five patients were in advanced stages (Patients 13, 14, 16, 17 and 19) and three declined to undergo HSCT (Patients 15, 18 and 20). CB = cerebello-brainstem form of ALD; AMN-CB = AMN with later development of cerebello-brainstem form of ALD. aOne patient with AMN died of a brain haemorrhage.
Figure 1 Prospective follow-up of 45 patients with adolescent/adult ALD and enrolment for HSCT. Forty-five male patients with ALD were enrolled in this study in a prospective manner from September 29, 2003, to October 31, 2018. Among them, 25 patients were considered for HSCT on the basis of detection of MRI lesions in the cerebrum, cerebellum or brainstem. HSCT was conducted on 12 patients. We did not conduct HSCT on eight patients because five patients were in advanced stages (Patients 13, 14, 16, 17 and 19) and three declined to undergo HSCT (Patients 15, 18 and 20). CB = cerebello-brainstem form of ALD; AMN-CB = AMN with later development of cerebello-brainstem form of ALD. aOne patient with AMN died of a brain haemorrhage.CC BY-NC · PubMed Central
Figure 2 Survival probability of HSCT-treated and non-HSCT-treated ALD patients. We performed Kaplan–Meier analysis and the log-rank test for patients with ALD who underwent HSCT and for those who did not. The horizontal axis shows months after the onset of cerebral/cerebellar/brainstem lesions. The vertical axis shows the survival probability of patients with ALD. The solid line shows the survival probability of patients with ALD who underwent HSCT, and the dotted line shows the survival probability of those who did not. Survival probability was significantly different between patients with ALD who underwent HSCT and those who did not (P = 0.0089). The numbers of Patients 0, 50, 100, 150, 200 and 250 months after the onset of cerebral/cerebellar/brainstem lesions were 12, 7, 2, 0, 0 and 0 among those who underwent HSCT and 8, 5, 2, 1, 1 and 1 among those who did not undergo HSCT, respectively.
Figure 2 Survival probability of HSCT-treated and non-HSCT-treated ALD patients. We performed Kaplan–Meier analysis and the log-rank test for patients with ALD who underwent HSCT and for those who did not. The horizontal axis shows months after the onset of cerebral/cerebellar/brainstem lesions. The vertical axis shows the survival probability of patients with ALD. The solid line shows the survival probability of patients with ALD who underwent HSCT, and the dotted line shows the survival probability of those who did not. Survival probability was significantly different between patients with ALD who underwent HSCT and those who did not (P = 0.0089). The numbers of Patients 0, 50, 100, 150, 200 and 250 months after the onset of cerebral/cerebellar/brainstem lesions were 12, 7, 2, 0, 0 and 0 among those who underwent HSCT and 8, 5, 2, 1, 1 and 1 among those who did not undergo HSCT, respectively.CC BY-NC · PubMed Central
Figure 3 Changes in brain MRI findings. (A) Representative coronal or axial images obtained by FLAIR imaging (upper panels) and T1W imaging with Gd enhancement (lower panels) on brain MRI before and after HSCT in Patients 2, 4 and 7. In Patient 2, the white matter lesions enlarged and were Gd-enhanced before HSCT. The white matter lesions became small (upper panels) and the Gd-enhanced lesions became gradually obscure (lower panels) after HSCT. In Patient 4, the white matter lesions in the pyramidal tracts enlarged until 1.4 months after HSCT but subsequently became small (upper panels). The white matter lesions in the pyramidal tracts were Gd-enhanced before HSCT but disappeared after HSCT (lower panels). In Patient 7, the white matter lesions in the frontal, parietal, temporal and occipital lobes enlarged until 1.3 months after HSCT, but the white matter lesions subsequently became small (upper panels). The white matter lesion in the splenium of the corpus callosum was Gd-enhanced before HSCT but disappeared after HSCT (lower panels). (B) Axial FLAIR images of Patient 18 who declined to undergo HSCT. When we considered HSCT for the patient, brain MRI showed limited white matter lesions in the pyramidal tracts and mild white matter lesions in the optic radiations, the brachia of the inferior colliculus and the cerebellum (Loes score, 3.5). These white matter lesions showed progressive enlargement, and brain MRI taken 57.5 months later showed massive cerebral, cerebellar and brainstem white matter lesions accompanied with marked atrophy (Loes score, 34). FLAIR = fluid-attenuated inversion recovery; T1W = T1 weighted.
Figure 3 Changes in brain MRI findings. (A) Representative coronal or axial images obtained by FLAIR imaging (upper panels) and T1W imaging with Gd enhancement (lower panels) on brain MRI before and after HSCT in Patients 2, 4 and 7. In Patient 2, the white matter lesions enlarged and were Gd-enhanced before HSCT. The white matter lesions became small (upper panels) and the Gd-enhanced lesions became gradually obscure (lower panels) after HSCT. In Patient 4, the white matter lesions in the pyramidal tracts enlarged until 1.4 months after HSCT but subsequently became small (upper panels). The white matter lesions in the pyramidal tracts were Gd-enhanced before HSCT but disappeared after HSCT (lower panels). In Patient 7, the white matter lesions in the frontal, parietal, temporal and occipital lobes enlarged until 1.3 months after HSCT, but the white matter lesions subsequently became small (upper panels). The white matter lesion in the splenium of the corpus callosum was Gd-enhanced before HSCT but disappeared after HSCT (lower panels). (B) Axial FLAIR images of Patient 18 who declined to undergo HSCT. When we considered HSCT for the patient, brain MRI showed limited white matter lesions in the pyramidal tracts and mild white matter lesions in the optic radiations, the brachia of the inferior colliculus and the cerebellum (Loes score, 3.5). These white matter lesions showed progressive enlargement, and brain MRI taken 57.5 months later showed massive cerebral, cerebellar and brainstem white matter lesions accompanied with marked atrophy (Loes score, 34). FLAIR = fluid-attenuated inversion recovery; T1W = T1 weighted.CC BY-NC · PubMed Central

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Authors
Matsukawa, T., Yamamoto, T., Honda, A., Toya, T., Ishiura, H., Mitsui, J., Tanaka, M., Hao, A., Shinohara, A., Ogura, M., Kataoka, K., Seo, S., Kumano, K., Hosoi, M., Narukawa, K., Yasunaga, M., Maki, H., Ichikawa, M., Nannya, Y., Imai, Y., Takahashi, T., Takahashi, Y., Nagasako, Y., Yasaka, K., Mano, K. K., Matsukawa, M. K., Miyagawa, T., Hamada, M., Sakuishi, K., Hayashi, T., Iwata, A., Terao, Y., Shimizu, J., Goto, J., Mori, H., Kunimatsu, A., Aoki, S., Hayashi, S., Nakamura, F., Arai, S., Momma, K., Ogata, K., Yoshida, T., Abe, O., Inazawa, J., Toda, T., Kurokawa, M., & Tsuji, S.
Affiliations
  • Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
  • Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
  • Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
  • Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
  • Department of Neurology, National Hospital Organization Higashisaitama National Hospital, Saitama 349-0196, Japan
  • Department of Neurology, Fujimi Kogen Hospital, Nagano 399-0214, Japan
ORCID
Venue
Brain Communications
Publisher
Oxford University Press (OUP)
Published
2020-01-01
Volume
2
Issue
1
ISSN
2632-1297
DOI
10.1093/braincomms/fcz048
PMC
PMC7425345
Cited by
26
References
27
Language
en
Licence
creativecommons.org/licenses/by-nc/4.0/ (vor, 13 d)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology of Japan
  • Ministry of Health, Labour and Welfare, Japan
  • Japan Agency for Medical Research and Development

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