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No more hand-me-down therapies for WM

Erilyn Riley Print | Email | Discuss
Published: 09/30/13
Steven Treon, MD, PhD
Credit: Dana-Farber
Cancer Institute

NEW YORK, NY—Until recently, therapies to treat Waldenström’s macroglobulinemia (WM) have been borrowed from lymphoma, chronic lymphocytic leukemia, or myeloma.

But with our increased understanding of targeted signaling and the possibilities of novel therapies for this disease, WM is entering a new era, according to an expert.

“We now have the ability to create targeted therapy for Waldenström’s macroglobulinemia,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

And this means moving away from an age of “hand-me-down therapies,” he added.

Dr Treon reviewed the current NCCN guidelines for WM and the new directions made possible by whole-genome sequencing at the recent NCCN 8th Annual Congress: Hematologic Malignancies.

Anemia is the most common reason for treating WM patients, but treatment is not always necessary, Dr Treon said. Watch-and-wait is a perfectly acceptable strategy to follow. In fact, 40% of the WM patients at his institution are under observation.

The NCCN guidelines recommend starting treatment if the patient is anemic with a hemoglobin count less than 10 g/dL or thrombocytopenic with a platelet count less than 100,000/μL.

Patients also require treatment if they have symptomatic hyperviscosity, moderate or severe peripheral neuropathy, symptomatic cryoglobulinemia, cold agglutinemia, autoimmune-related events, or amyloidosis.

Recommended treatments

The NCCN recommends single agents—including chlorambucil, cyclophosphamide, nucleoside analogues, immunomodulators, rituximab, and ofatumumab—and combination therapies with rituximab—including bortezomib and bendamustine.

Dr Treon pointed out a few considerations when dealing with these agents. For instance, with cyclophosphamide-containing regimens, those with dexamethasone and ritixumab are preferred over CHOP and CVP.

“[W]e tend to discourage their usage because we see a lot of neuropathy as a result of vincristine,” he said.

However, rituximab can be problematic in WM because of immunoglobulin M (IgM) flare, which occurs in half of all WM patients. IgM levels above 4000 mg/dL can induce hyperviscosity, which can be life-threatening. So rituximab should be avoided until IgM is in the safe range.

Rituximab can also potentiate symptoms of IgM neuropathy, cryoglobulinemia, and cold agglutininemia. And for the 15% of WM patients who do not tolerate rituximab, the NCCN guidelines suggest ofatumumab. 

Nucleoside analogues were the mainstay of therapy until the mid-2000s, when investigators recognized that they conferred an increased risk of transformation to myelodysplastic syndrome or acute myeloid leukemia. In addition, nucleoside analogues should be avoided in patients who may be eligible for autologous stem cell transplant.

Bendamustine is an excellent option for bulky disease, Dr Treon noted. And in the frontline setting, bendamustine-rituximab is superior to CHOP-R (Rummel et al. Lancet 2013). However, it should be used with caution in younger patients, since the long-term safety of bendamustine has yet to be established.

Bortezomib is most effective in WM when it is combined with dexamethasone and rituximab, Dr Treon said. This combination has an estimated progression-free survival that exceeds 4 years. When administered twice weekly, bortezomib can cause grade 3 peripheral neuropathy, but once-weekly administration attenuates peripheral neuropathy.

In the salvage setting, the patient’s previous regimen may be repeated if he or she had more than 3 years of benefit from the treatment. And autologous stem cell transplant should be considered for multiply relapsed cases.

Future directions

Dr Treon elaborated on the discovery of the mutation in the MYD88 gene, which “finally gave us a genomic target in this disease.”

MYD88 L265P is a somatic mutation that is prevalent in WM, occurring in up to 100% of WM patients studied. MYD88 acts as an adaptor protein signal for the Toll-like receptor/IL-1R signaling pathway, and disruption of MYD88 signaling induces apoptosis of L265P-expressing WM cells.

MYD88 plays a pivotal role in exciting Bruton’s tyrosine kinase. By using a BTK inhibitor, like ibrutinib, the MYD88 L265P complex expressing WM cells is prevented from forming.

This knowledge inspired investigators to conduct a phase 2 study of ibrutinib in relapsed/refractory WM (Treon et al. ICML-12 abst 067).

The first 35 patients evaluated had a rapid drop in IgM levels and a profound increase in hematocrit in the first 6 cycles of therapy. Ibrutinib elicited an overall response rate of 83% and had a good overall safety profile.

Earlier this year, the FDA granted ibrutinib breakthrough status, and approval is anticipated next year.

The NCCN guidelines for WM are available at


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