Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis

Abstract

Objective: Accelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as 'pseudoatrophy', related to reduced inflammation. Treatment-related neurotoxicity may be contributory. We sought objective evidence of post-IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage. Methods: Sera were collected from 22 MS patients pre-and post-IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single-molecule assay. Results: Pre-IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12-month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL). Interpretation: There is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.

Dynamics of pseudo‐atrophy in RRMS reveals predominant gray matter compartmentalization

“…While data on pseudo-atrophy remain discordant and further research is warranted to clarify the contribution of GM atrophy to this interesting phenomenon, evidence suggests that it cannot be interpreted as a simple resolution of inflammatory edema. 9,12,16,35 Findings reported here add new insights into the complex mechanisms of pseudo-atrophy and its relation to the compartmentalized inflammation occurring in the GM of MS patients. Whether this is an expression of a beneficial anti-inflammatory effect (i.e., decrease in soluble neurotoxic factors) of the drug or, as recently shown in MS patients after immunoablative autologous hematopoietic stem cell transplantation, 35 of a transient neurotoxicity following the intense chemotherapy, needs to be demonstrated.…”

“…While data on pseudo‐atrophy remain discordant and further research is warranted to clarify the contribution of GM atrophy to this interesting phenomenon, evidence suggests that it cannot be interpreted as a simple resolution of inflammatory edema 9,12,16,35 . Findings reported here add new insights into the complex mechanisms of pseudo‐atrophy and its relation to the compartmentalized inflammation occurring in the GM of MS patients.…”

“…Findings reported here add new insights into the complex mechanisms of pseudo‐atrophy and its relation to the compartmentalized inflammation occurring in the GM of MS patients. Whether this is an expression of a beneficial anti‐inflammatory effect (i.e., decrease in soluble neurotoxic factors) of the drug or, as recently shown in MS patients after immunoablative autologous hematopoietic stem cell transplantation, 35 of a transient neurotoxicity following the intense chemotherapy, needs to be demonstrated. In either case, ongoing and forthcoming clinical trials including MRI‐derived GM volume loss as an outcome measure need to account for potentially significant GM volume changes as part of the initial treatment effect.…”

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

“…A 4 fold greater reduction of NfL than of NfH SMI 35 suggests differential sensitivity to therapeutic changes using different subunits as the biomarker ( Kuhle et al, 2013 ) although NfH SMI 35 antibodies detect NfH phosphorylation rather than the protein itself and may reflect different aspects of a given disease. Caution should be taken when MS patient are at risk for other treatment-induced neurological complications that can cause serum NfL levels to rise, such as natalizumab-induced progressive multifocal leukoencephalopathy ( Dalla Costa et al, 2019 ) and ablative hemopoietic stem cell transplantation ( Thebault et al, 2020b ).…”

Serum Neurofilament Light Chain Measurement in MS: Hurdles to Clinical Translation

“…For instance, a 10-fold increase was noted at the time of onset of natalizumab-induced progressive multifocal leukoencephalopathy ( Dalla Costa et al, 2019 ). In a cohort of patients undergoing ablative hemopoietic stem cell transplantation for aggressive MS, transient increases in the first year after the treatment reflected chemotherapeutic toxicity ( Thebault et al, 2020c ). Nonetheless, we feel that the identification of a rapidly rising NfL in these situations could be a useful warning signal to trigger a reassessment and additional investigations to identify the cause, or switch therapy.…”