NANOSNET

I've seen a 68y German man with Waldenstrom lymphoplasmacytic lymphoma diagnosed in 1997. Initial treatment with CVP chemotherapy was ineffective, he had fludarabine and epirubicin in 1998 with good response.  In 2001 he developed a right arm lesion which was found to be diffuse large B cell lymphoma and this responded to radiotherapy.  At that time he also had rituxumab and bendamustine.  In 2005 he had systemic illness with splenomegaly and retroperitoneal lymphadenopathy, and had six cycles of FCR chemotherapy.  In 2016 he had increasing IgM and developed thrombocytopaenia, which responded well to bortezomib, rituxumab, and dexamethasone.  In 2020 he developed dysphasia, suspected to be a stroke, but MRI and LP found this to be Bing Neel CNS infiltration of the lymphoplasmacytic lymphoma.  He had intrathecal methotrexate and intrathecal ritxumab without response but improved very well with ibrutinib (Imbruvica, a Bruton's tyrosine kinase inhibitor).  On a higher dose he had palpitations but he remains on the lower dose of 140 mg twice daily.  All this is to say he has had a long history and lots of medications.

He presented with gradual bilateral faded and hazy vision over 1-2 years and he had right cataract surgery with a colleague that made a small improvement for him.  He was referred as the vision did not recover to normal (corrected acuity around 6/15 in both eyes).  I found normal 24-2 VF but very reduced colour vision in both eyes and temporal RNFL thinning and diffusely thinned ganglion cell layer (temporal disc pallor to match).  It has a symmetrical quality like a mitochondrial metabolic pattern of optic neuropathy.

He has a normal omnivorous diet and has never had a poor or restricted diet, never had exposure to toxins or prolonged antibiotic treatments (or Tb treatment).  He has no family history of vision loss.  We investigated with blood count, electrolytes, CRP, ACE, ANA, Syphilis, B12, folate, thiamine (all normal).  The MRI was normal, no findings to suggest active Bing Neel infiltration, and the lumbar puncture was clear with no cells and normal protein, nothing to see on cytology or flow cytometry or CSF electrophoresis. 

So the impression is that he might have a side effect of ibrutinib.  My reading about Bruton's tyrosine kinase is that it has a number of intracellular downstream effects, which I suppose could affect metabolism in the most vulnerable RGC of the papilomacular bundle. 

I would love to hear your experience: is optic neuropathy a known side effect of ibrutinib?  Do you recommend other investigations -  I should check LHON mutations, would you test for autosomal mutations (which ones)?  Do you think a change of BTKI would potentially protect his vision better than continued ibrutinib?

Best wishes