https://orcid.org/0000-0002-1273-7566
TO THE EDITOR:
We read with interest the article by Heyman et al1 that described a subanalysis of the ASPEN trial with specific focus on patients with Waldenström macroglobulinemia (WM) with peripheral neuropathy (PN) symptoms who received Bruton tyrosine kinase inhibitors (BTKis). Although we want to congratulate the authors for bringing attention to a severe WM complication,2 we would like to raise some concerns.
First, the definitions for PN lack clarity, because formal objective assessments were not required per protocol.1 Were proper questionnaires or PN neurologic scales3-5 used? Without neurophysiological data, the diagnosis of PN was merely presumed from symptoms; a validated clinical scale should have been used to confirm the diagnosis in the context of a standardized initial assessment.6 In addition, it remains unclear how many patients had immunoglobulin M (IgM)–associated PN and not coincidental PN. Only 10 of 49 patients presented with anti-myelin associated glycoprotein antibodies (4 at high titer), and it is known that low titers may not be specific.7,8 Moreover, because most of the patients received previous therapy for WM, an iatrogenic PN should also be considered. In addition, it is not clear how many patients suffered from pain, because it is uncommon in IgM paraproteinemic neuropathies.2 Finally, because patients were primarily treated for WM symptoms other than PN, the quality-of-life improvements measured by patient-reported outcomes might be biased by overall disease response rather than reflecting specific improvements in PN symptoms. However, it is important to note that this subgroup of patients commenced BTKi treatment for reasons other than neuropathy, which may not reflect the typical IgM-associated PN cases usually characterized by isolated neuropathy.
The authors acknowledged several study limitations. However, in our opinion, this article provides questionable insights into the role of BTKis in the resolution of WM-related PN, whereas promising neurologic results were reported after BTKi exposure in rituximab-refractory patients.9
In conclusion, although acknowledging the importance of describing such results in a field that lack specific reports, we look forward to more appropriate data from the ongoing dedicated prospective trials (offering BTKi monotherapy or in combination with rituximab10-12) that are supported by validated neurologic scales and by neurophysiological and biologic data.
Contribution: C.B. conceptualized the letter; and B.F., A.S., S.R., E.A., I.D., A.V., and S.F. contributed to writing the manuscript and brainstorming the discussion.
Conflict-of-interest disclosure: S.F. is a consultant for Janssen, EUSA Pharma, AbbVie, and Sandoz; on the advisory board of Janssen, EUSA Pharma, Recordati, Incyte, Roche, AstraZeneca, Italfarmaco, and CSL Behring; received speakers' honoraria from Janssen, EUSA Pharma, Recordati, Lilly, BeiGene, Gilead, and Gentili; and received research funding from Janssen, Gilead, and MorphoSys. A.V. reports serving on scientific boards organized by Johnson & Johnson, AbbVie, AstraZeneca, BeOne Medicine, Takeda, and CSL Behring. S.R. reports receiving speaker's honoraria from BeiGene. The remaining authors declare no competing financial interests.
Correspondence: Simone Ferrero, Department of Molecular Biotechnology and Health Sciences, University of Turin, via Genova 3, 10126 Turin, Italy; email: simone.ferrero@unito.it.
