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Grachev, A.1; Zvonkov, E.1; Ryzhko, V.1; Gribanova, E.1; Galtceva, I.1; Smolyaninova, A.1; Koroleva, D.1; Kapranov, N.1; Nedoluzhko, A.2; Nakastoev, I.1; Okhota, V.1; Novikova, A.1; Savchenko, V.1

doi: 10.1097/01.HS9.0000566560.36343.e6
Publication Only: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

1National Research Center for Hematology

2National Research Center «Kurchatov Institute», Moscow, Russian Federation

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Waldenstrom Macroglobulinemia (WM) is still considered an incurable IgM-secreting lymphoplasmacytic lymphoma. The role of intensive induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) in the management of patients with WM has not been established.

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To study the effectiveness of intensive induction chemoimmunotherapy and its combination with ibrutinib followed by ASCT in patients with untreated WM.

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A total of 8 treatment naive patients with WM were enrolled in our study between March 2017 and February 2019 years. Median age was 55.5 years (range 34-62 years) and 6 (75%) were men. Three patients were treated with 4 cycles of alternating of R-EPOCH (rituximab, doxorubicin, etoposide, vincristine, cyclophosphamide, prednisolone) in conventional doses and R-BAC (rituximab, bendamustin, cytarabine) in conventional doses - group No1. Five patients were treated with 4 cycles of alternating of R-EPOCH + ibrutinib 420 mg daily and R-BAC + ibrutinib 420 mg daily - group No2. Response was assessed using modified IWWM-6 criteria.

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According to IPSSWM - 1,4 and 3 patients, were considered as being at low, intermediate, and high risk respectively. Indications for treatment included hyperviscosity - related symptoms in 8 (100%) patients, anemia in 8 (100%), lymphadenopathy and splenomegaly in 7 (87.5%), constitutional symptoms in 6 (75%) and thrombocytopenia 2 (25%). At baseline, median serum total protein was 115 g/l (range 101-130 g/l), median serum IgM monoclonal protein was 53 g/l (range 39-74 g/l), median hemoglobin was 7.8 g/dl (range 5.6-10.5 g/dl), median β-2-microglobulin was 4.32 mg/l (2.8-9.3 mg/l). High serum LDH activity was in 3 (37.5%) patients, albumin less than 30 g/l was in 3 (37.5%) patients. In 6 (75%) patients the MYD88L265P mutation was detected and CXCR4 mutation was not detected in any patients. Deletion of 17p was identified in one patient but mutation of the TP53 gene determined using by Sanger sequencing of the coding region (exons 1(2)-11) was not identified in any patients. All evaluable patients have completed 4 cycles of induction therapy. Partial response (PR) was attained in 8 (100%). Median hemoglobin increased to 12.7 g/dl (range 12.1- 13.7 g/dl) and regression of all baseline symptoms occurred in all cases. Two patients in group No1 and 3 in group No2 subsequently underwent ASCT, the preparative regimen was CEAM (lomustine, etoposide, cytarabine, melphalan). Very good partial response was achieved in one patient after ASCT and in 4 patients serum IgM monoclonal protein continued to decline (tab.). Median observation without progression from the end of therapy is 8 (range 1-17) months and we continue our research.



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The combination of intensive immunochemotherapy with ibrutinib leads to rapid and deep decline of serum IgM monoclonal protein and regression of baseline symptoms of WM. Applying of ibrutinib as part of chemoimmunotherapy for a limited period of time results in a lower financial burden compared to its long-term use. ASCT as part of first line therapy leads to improve in the outcomes and may be a safe, feasible, and reasonable therapeutic option for young WM patients. Perhaps, residual serum IgM monoclonal protein is due to the presence of clonal plasma cells in the bone marrow after treatment and is considered as residual disease. Applying targeted therapy might possibly to eliminate this pathological clone.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.