PMC5994293_01
B-CLL characterization. (a) Bone marrow biopsy (HE): in September 2015, there was a 70% nodular and interstitial infiltration of small lymphocytes. (b) Bone marrow smear (MGG): in January 2016, numerous small lymphocytes, with clumped chromatin and scanty cytoplasm, smudge cells, and a few erythroblasts were detected. Dot plots illustrating cerebral spinal fluid (CSF), immunophenotyping CD5+/CD19- T cells (red dots) and CD19+/CD5+ B-CLL cells (black dots) in October 2015 (c) and in August 2017 (d). Magnification: (a) x40 (left), x100 (center), and x600 (right) and (b) x100.
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We re-evaluated the disease, and a bone marrow study revealed a 70% CLL involvement, confirmed by FC, biopsy analysis (Figure 1(a)), and aspirate analysis (Figure 1(b)). During IC treatment, in October 2015, CSF re-evaluation by FC revealed an infiltration degree of 84.3% (Figures 1(c) and 2). Since then, ibrutinib therapy has been maintained, without further interruptions or dose reductions, and CSF analysis by FC has shown a continuous decrease in the number of infiltrated CLL cells (towards a minimum of 0.3% on the last analysis, Figure 1(d)).
Evaluation of the CNS response and the clinical outcomes over time. (a) Flow cytometry analysis of the CSF over time, illustrating the % of CLL cells detected. The absolute number of counted CLL cells present in the diluted sample is shown underneath the percentage of cells detected, in dark grey. (b) Treatment course followed, illustrating therapy combinations and ibrutinib interruptions as well as the patient's clinical outcomes. Triple IC with methotrexate, cytarabine, and prednisone was administered 15 times, biweekly, but did not result in a positive response. Liposomal cytarabine was given 2 times (on the 10th and on the 24th of November 2015) but led to no response and might have led to the worsening of the neurologic symptoms due to a toxic myelitis. After resolution of the first toxicity (grade-2 hematuria), systemic high-dose methotrexate was administered together with ibrutinib. Whole-brain radiotherapy was administered (30 Gy/10 fr, in a regimen of 3 Gy/cycle/day, from the 24th of November until the 9th of December 2016) to decrease the CSF infiltration. After the first interruption, ibrutinib was restarted at 140 mg/day and then weekly increased to 280 mg/day and to 420 mg/day. After the second interruption, it was restarted at full dose (420 mg/day).
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The FC analysis of the CSF revealed the presence of 35.2% of monoclonal B cells, 995 cells/microL, compatible with B-CLL infiltration (Figure 2). The combination of high-dose methotrexate with ibrutinib seems to have led to a decrease in the % of CNS infiltrating CLL cells from 66.7% to 23.8% (Figure 2). Meanwhile, because there was still a 23.8% CLL infiltration of the CSF, CNS radiotherapy was delivered, in November 2016, as denoted in Figure 2.