Timing of Rituximab/Fludarabine in Waldenström’s Macroglobulinemia May Avert Hyperviscosity.
Authors: Nichols Gwen L. , Savage David G. 
Published: April 2020

Abstract
The consensus panel from the Second International Conference on Waldenström’s Macroglobulinemia (Semin Oncol. 2003 Apr;30(2):121–6) recommended patients with WM treated with Rituximab be watched closely during treatment for hyperviscosity and an initial surge in IgM. The panel noted that some patients have clinically significant hyperviscosity symptoms after Rituximab, including cardiovascular and central nervous system events. Investigators have also seen these rises in patients treated with Rituximab followed by Fludarabine. We have had two trials using Fludarabine/Rituximab in combination, and have treated 6 patients with the diagnosis of WM in the context of these trials. Fludarabine was given at a dose of 30mg/m2 daily for 4 days, followed on the 5th day by Rituxan at 375 mg/m2. IgM quantitation and viscosity were tested prior to the first dose of Rituximab, and again at between 2 and 4 weeks post-treatment. The patient information is summarized below.
WM patients - Fludarabine/Rituximab
AGE IgM/VISC PRIOR RX # CYCLES ADV. EVENTS NEXT IGM RESP BM/IgM RESP LENGTH #pt with prior Rituximab/followed by Fludarabine, * patients still responding by IgM 64 7260/4.3 none 8 none 7200 8%/478 57 mos* 64 1770/1.7 none 8 none 2320 3%/749 11 mos* 63 5470/2.4 5130 8 none 5130 3%/491 18 mos 71 6000/3.4 Rituximab/Flu# 4 cytopenia 4000 15%/2102 18 mos* 55 4800/4.5 none 6 cytopenia 1135 12%/400 16 mos 71 2420/1.4 Rituximab 8 anemia 1600 nd/267 9 mos
The patients ranged in age from 55 to 71. They held the diagnosis of WM for between 2 and 8 years prior to treatment. All patients responded to the combination therapy. Only one of the 6 patients had an elevation in IgM from 1770 to 2320 at the first time point after the Rituximab treatment. All other patients had a decrease or remained stable. No patients had clinically significant hyperviscosity. All patients began treatment with more than 80% lymphoplasmacytoid cells in the bone marrow, and all responded (3–15% lymphoid cells at 1 month post-Rx). Of interest, the maximum response to therapy has not been reached for 3 of the 6 patients, ranging from 11 months to 57 months, and their IgMs continue to fall. Three patients have had small increases in their IgM levels at 9, 16 and 18 months, including the two patients treated with fewer than 8 cycles of therapy. None of these patients have had worsening of blood counts or have required further therapy. Adverse events were those expected (cytopenias) but none required transfusion or hospitalization, and were successfully treated with cytokines. Two patients have had successful stem cell harvesting post-therapy. Patient #4 had previously been treated with Rituximab followed by Fludarabine, and had discontinued this therapy because of rapid increase in IgM and viscosity. This patient did not have an elevation in the IgM when given the same drugs in the opposite order. This is a small patient sample, and it is possible that the peak IgM was missed. However, the excellent responses using Fludarabine followed by Rituximab, especially in those patients with high starting IgMs and viscosities, is encouraging. While these results are preliminary, we believe the combination of Fludarabine/Rituximab, giving the Fludarabine prior to Rituximab may be successful in decreasing or eliminating the paradoxic elevation in IgM seen in some WM patients given Rituximab. The regimen appears efficacious and safe. Further studies to address the efficacy of this regimen in a larger number of WM patients are warranted.