A 66-year-old male was diagnosed with CLL in 2009 based on the incidental detection of lymphocytosis on routine laboratory studies. Peripheral blood flow cytometry showed a monoclonal B-cell population expressing CD19, CD20, CD5, and CD23. CD20 was dimly expressed. The cells were negative for CD10, ZAP70, and CD38. FISH analysis did not show CCND1-IGH fusion, extra signals or deletions of ATM, trisomy 12, 13q, 17p deletion, or TP53 aberrancies. Bone marrow biopsy showed 45% involvement by CLL. He was maintained on observation, with monthly infusions of intravenous immunoglobulin due to hypogammaglobulinemia accompanied by frequent infections. Six years after diagnosis, systemic treatment was indicated because of progressively worsening lymphadenopathy, fatigue, unintentional weight loss, and splenomegaly. Absolute lymphocyte count was 13,300/microL, hemoglobin 15 g/dl, and platelet count was 243/microL. He was enrolled on a clinical trial comparing Bendamustine-Rituximab (BR) with or without the class I phosphoinositol-3-kinase delta inhibitor idelalisib. Cytogenetics were repeated as part of trial enrolment and PCR analysis showed unmutated IgHV and absence of TP53 aberrations. A repeat FISH analysis was similar to prior. He was randomized to the idelalisib arm however study drug was discontinued after four weeks due to grade 3 diarrhea and rash. He completed six cycles of BR with resolution of leukocytosis and lymphadenopathy.
Two years after treatment completion, his disease recurred with development of fatigue, worsening lymphocytosis, and lymphadenopathy. Concomitantly he also complained of decreased vision in his right eye. He did not have any pre-existing ocular abnormalities.
Initial visual acuity examination was counting fingers at one foot for the right eye and 20/25 for the left eye. Intraocular tensions and ocular motility were normal. Confrontational visual fields revealed a right partial outer temporal visual field deficit. Slit lamp bio-microscopy of both eyes showed trace keratic precipitates, moderate anterior chamber inflammation, and sheets of vitreous cells. Funduscopic examination of the right eye revealed vitreous haze, blurred disc margins, diffuse vascular sheathing in the posterior pole, and multiple creamy lesions in the nasal macula and inferonasal to the optic nerve (Figure 1B). Exam of the left eye was notable for a small, subtle, creamy lesion nasal to the optic disc, and otherwise normal appearing optic nerve, macula, and vessels. Optical coherence tomography (OCT) images of the right eye showed full thickness retinal infiltration by a hyperreflective material corresponding to the inferonasal lesion on fundus photographs (Figure 2A) with a sharp demarcation between normal and abnormal retina at the edge of the lesion. OCT images of the macula showed multiple retinal pigment epithelial detachments (PEDs) (Figure 2B). Wide field fluorescein angiography (FA) revealed leakage in nasal macula and inferonasal to the disc on late frames (Figure 1A). FA of the left eye revealed trace leakage corresponding to the lesion nasal to the disc, but without a corresponding PED or retinal infiltrate on OCT.
A focused uveitis workup was negative for syphilis, tuberculosis, toxoplasmosis, or sarcoidosis. MRI of the brain and orbits with and without contrast revealed diffuse leptomeningeal enhancement. Patient underwent a pars plana vitrectomy with vitreous biopsy, which was inconclusive. A lumbar puncture [LP] was done with the cerebrospinal fluid (CSF) showing an atypical lymphoid infiltrate. CSF flow cytometry was positive for involvement by a small population (3% total cells) of CLL/SLL cells, expressing CD19, CD5, Cd23, CD20 (dim), and SIG-lambda (negative for FMC7), confirming CNS relapse. He received two cycles of intrathecal cytarabine.
Concurrently, the patient also experienced vertigo, muscle spasms, imbalance, and seizures which were treated successfully with levetiracetam.
In September 2017, he was started on Ibrutinib at a dose of 560 mg daily for CNS penetration. Within 4 weeks, the patient reported a significant improvement in vision in both eyes except for some peripheral visual field defect, tunnel vision and scotomatas in the right eye. He did not experience any further seizures. A repeat MRI brain showed resolution of leptomeningeal enhancement, and CSF flow cytometry showed 1% involvement by CLL/SLL cells, thought to be peripheral blood contamination. Best corrected visual acuity at 8 months follow up improved to 20/40 and 20/20 in right and left eyes, respectively. Bio-microscopy was notable for resolution of vitritis, decrease in the size of the retinal lesions with resultant focal retinal atrophy and scarring on the right (Figure 1C and 2C).
He subsequently developed intolerance to ibrutinib, manifested by grade 3 diarrhea with urgency and fecal incontinence, unresponsive to supportive measures, and extensive bruising. He was switched to the second generation BTK inhibitor, acalabrutinib at a dose of 100 mg twice daily. He has tolerated that drug extremely well and, after a year, remains asymptomatic and in a clinical remission. His vision, including peripheral, continues to improve, such that he is now able to drive and ride a bicycle. He no longer requires anti-seizure medications. Physical examination reveals no lymphadenopathy or splenomegaly. Latest CBC shows a WBC of 5100/ul including 1200 lymphocytes, hemoglobin of 13.8 g/dl, and platelets of 222,000/ul.