Waldenström macroglobulinemia: From biology to treatment Ilyas Sahin 1, *, Houry Leblebjian 2, *, Steven P. Treon 1 , Irene M. Ghobrial 1 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 2 Pharmacy Department, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA * These authors have equal contribution Corresponding author: Irene M. Ghobrial, MD Medical Oncology, Dana-Farber Cancer Institute, 450 Brookine Ave Boston, MA, 02115 Phone: (617)-632-4198 Fax: (617)-632-4862 Email: [email protected]Key words: biology, Waldenström macroglobulinemia, MYD88, bruton tyrosine kinase, treatment Running title: Waldenström macroglobulinemia Abstract: 117; Text: 6127; Table: 2; References: 116 1
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Waldenström macroglobulinemia: From biology to treatment
Ilyas Sahin1,*, Houry Leblebjian2,*, Steven P. Treon1, Irene M. Ghobrial1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA, USA
2Pharmacy Department, Dana-Farber Cancer Institute, Harvard Medical School,
zoster (1.6%); hematoma (1.6%); and epistaxis (1.6%). Attainment of major
responses was impacted by mutations in CXCR4. The major response rate was
77% for patients with wild-type CXCR4 vs. 30% in those with WHIM-like CXCR4
mutations.
Conclusion
Waldenstrom macroglobulinemia is a distinct lymphoproliferative disorder with
specific epigenetic/genetic aberrations, and characterized by production IgM
monoclonal secretion and lymphoplasmacytic cells in the BM. With the change in
understanding the pathogenesis of WM, many new targets and therapies have
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emerged within the past couple of years. Current therapies used in the upfront or
relapsed setting include alkylating agents, bendamustine, nucleoside analogues,
bortezomib and the monoclonal antibody rituximab. Newer options include
everolimus and ibrutinib. However, targeted therapies are still warranted and
recent revelations from whole genome sequencing have provided opportunities
for their development.
Expert commentary & five-year view
To date there are no FDA approved therapeutic agents for treatment of WM.
Recently, whole genome sequencing helped us identify specific mutations in
subgroups of patients with WM (eg. MYD88 L265P mutation which is present in
over 90% of WM) which provides the framework for the investigation of BTK
inhibitors like ibrutinib. These newer agents show improved responses and lower
long term toxicities. In addition, many of the newer agents are orally administered
which makes them more convenient for patients. Some of the challenges for the
future of WM include combining of agents to achieve higher response rates, and
prolonged survival for patients, but with less toxicity.
Key Issues
Recent findings demonstrated that MYD88/IRAK signaling pathway might
have a critical role in pathogenesis of WM.
Somatic mutations in MYD88 are found in over 90% of WM patients,
which may help to differentiate WM from other B cell malignancies.
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Current research efforts in inhibtion of BTK and IRAK signaling might
provide better treatment strategy for WM.
Many treatment options are available for WM patients and some of these
include rituximab, bortezomib, cyclophosphamide, and nucleoside
analogues fludarabine and cladribine which are less commonly used.
Novel agents under study are showing promising results as a single agent
or in combination. Some of these include everolimus, ibrutinib, as well as
the newer proteasome inhibitors carfilzomib and oprozomib.
There is a need for studies with PFS and OS as endpoints combined with
quality of life assessment as well as randomized phase III studies to
evaluate the benefit of different treatments for patients with WM.
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Table : Workup for WM
Table 2: Response Definitions
Response Category Definition
Complete response (CR) Absence of serum monoclonal IgM protein by
immunofixation
Normal serum IgM level
Complete resolution of extramedullary disease*
Morphologically normal bone marrow aspirate
Very good partial response (VGPR) Monoclonal IgM protein is detectable
≥90% reduction in serum IgM level from baseline
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Complete resolution of extramedullary disease*
No new signs or symptoms of active disease
Partial response (PR) Monoclonal IgM protein is detectable
≥50% but<90% reduction in serum IgM level from baseline
Reduction in extramedullary disease*
No new signs or symptoms of active disease
Minor response (MR) Monoclonal IgM protein is detectable
≥25% but<50% reduction in serum IgM level from baseline
No new signs or symptoms of active disease
Stable disease (SD) Monoclonal IgM protein is detectable
<25% reduction and <25% increase in serum
IgM level from baseline
No progression in extramedullary disease*
No new signs or symptoms of active disease
Progressive disease (PD) ≥25% increase in serum IgM level from
lowest nadir (requires confirmation) and/or
progression in clinical features attributable to the disease
*i.e. lymphadenopathy and splenomegaly
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Financial and competing interests disclosure
IM Ghobrial is on the advisory board for Onyx, BMS and Celgene and receives research lab support from Genzyme and BMS. SP Treon receives research support from honoraria, and consulting fees from pharmacyclics, janssen pharmacuticals, and onyx pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
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• Phase I study of ibrutinib, BKT inihbitor, showed activity in patients with relapsed/refractory B-cell malignancies including Waldenström's macroglobulinemia.