PMC6346143_01
Clinical course of rituximab monotherapy in lymphoproliferative disease exacerbation. Timeline of treatment of LIP with low and standard dose of rituximab following the typical therapeutic regimen (i.e., escalating dose of prednisolone and intravenous immunoglobulin). Figure show 5-year-long period, rituximab monotherapy, and PET findings contrary to clinical trial NCT027893972). (A) Quantitative and functional evaluation of leading parameters of lymphoid interstitial pneumonia (2): IgM level, beta2-microglobulin (beta2m), spleen size, and pulmonary restriction (FVC) were presented. All spirometric measurements were performed according to the recommendations of the European Respiratory Society. Prednisolone therapy and immunoglobulin dosage adjustment (to 0.5 g/kg repeated every 21 days) were ineffective. Progression of the disease corresponds with high beta2-microglobulin and very high level of non-monoclonal IgM paraproteinemia, spleen size, but without typical signs of malignancy. After corticosteroids withdrawal and rituximab monotherapy fast and significant increase of forced vital capacity (FVC) was observed as well as decrease of splenomegaly. After rituximab therapy IgM - paraproteinemia, the sign of lymphoproliferative disease, pulmonary restrictive disease resolved. The clinical improvement corresponds with less IgG consumption/IVIG requirement. (B) PET imaging of therapeutic response in LIP. Bottom panel shows corresponding PET-tomography before, after the first (150 mg/m2), second and third course (both-375 mg/m2) of rituximab monotherapy. The maximal standardized uptake value (SUV) in pulmonary granulomas are shown. Before therapy the highest uptake of (18)F-fluoro-deoxyglucose was seen in spleen and pulmonary granulomas with lymphoid tissue: SUV was shown. PET.PET findings are useful and more representative than high-resolution CT scans of the chest (data not shown).
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B cells repertoire analysis as described previously. Before the therapy spleen extended to the iliac crest (27 cm, see Figure 1 bottom panel): subileus was observed due to the pressure on intestines. Progressive LPD was observed with hyperviscosity, paraproteinemia, high beta2M and IgM level (Figure 1 upper panel). The patient did not receive other concomitant medication. The sixth dose (Figures 1, 2) was delayed due to spontaneously resolved temporary neurological sign. Unexpectedly, after rituximab therapy the LPD was stopped (Figure 1B, as shown in PET). Restrictive pulmonary disease and FVC systematically improved and finally normalized (Figure 1A). Figures 1, 2) in line with LIP regression and FVC increase. Fortunately, rituximab therapy was a glaring alternative for IVIG escalation: It also reduced IgG requirements by up to 40% of adjustment dose (Figure 1A). The serological and clinical effectiveness (IgM, FVC and PET finding) of both schedules were comparable, but more significant reduction of beta2M was observed after 150 mg/m2 of rituximab (Figure 1A).
Evolution of peripheral lymphocytes populations. Immunomodulatory effect of rituximab on cellular compartment. Pleiotropic influence of low (150 mg/m2) rituximab dose. Data expressed as absolute numbers per mul. The cell counts were analyzed during LIP exacerbation - multiorgan lymphoproliferative disease development. Typical low level of invariant natural killer T (NKT), natural killer (NK), and regulatory T cells (Treg) was observed. After rituximab therapy abnormal innate immunity - absolute number of NK and NKT cells increased, but gradual decrease of FoxP3+ regulatory T cells was observed with increase activated CD38+T cells (not shown). Leukocyte counts analyses were done by the Sysmex Automated Hematology System. Flow cytometry was performed using a FACS Calibur flow cytometer (Becton Dickinson) and a count of lymphocyte subset was calculated by the frequency multiply the lymphocyte counts.
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The patient did not receive other concomitant medication. The sixth dose (Figures 1, 2) was delayed due to spontaneously resolved temporary neurological sign. Figures 1, 2) in line with LIP regression and FVC increase. Fortunately, rituximab therapy was a glaring alternative for IVIG escalation: It also reduced IgG requirements by up to 40% of adjustment dose (Figure 1A). Parallel cytometric lymphocyte analysis is organized as a timeline (Figure 2). T cells (NKT, CD3+56+) increased temporarily after low and standard dose (Figure 2). Therefore, initial NK/NKT ratio (2.7) decreased during LPD progression, but it increased after the initial low dose of rituximab (Table 1).