Genetics Should Aid in Treating Waldenstrom's Macroglobulinemia

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Steven P. Treon, MD, PhD

According to Steven P. Treon, MD, PhD, mutations inMYD88andCXCR4can effectively be used to tailor treatment for patients with Waldenström’s macroglobulinemia (WM).

“Linking biological data to clinical data is beginning to identify clinically distinct subgroups with different disease characteristics and outcomes,” said Treon, director of the Bing Center for Waldenström's Macroglobulinemia and physician at Dana-Farber Cancer Institute,  during a "How I Treat" session at the inaugural ASH Meeting on Hematologic Malignancies . “Mutational testing identifies patients with actionable mutations that may respond to specific therapy. Additionally, poor prognostic genetic markers have an additive effect. We need to consider novel approaches for these patients within the context of clinical trials.”

Ibrutinib (Imbruvica) became the first FDA-approved therapy indicated specifically for patients with WM as of January 2015. The approval was based on a phase II study published inThe New England Journal of Medicine(NEJM), which found the overall response rate (ORR) with the potent BTK inhibitor was 90.5% with a major response rate (MRR) of 73%.

However, responses to the therapy appeared to vary based on molecular signatures, specifically alterations inMYD88andCXCR4. In those withMYD88-mutated/CXCR4wild-type tumors (n = 36), the ORR was 100% and the MRR was 91.7%. In WM withMYD88andCXCR4^WHIMalterations, the ORR was 85.7% and the MRR was 61.9%. However, in those with both wild-typeMYD88andCXCR4(n = 5), the ORR was 60% and the MRR was 0%.

TheMYD88^L265Pvariant is the most prevalent mutation in patients with WM, found in 93% to 97% of patients with this disorder. “CXCR4^WHIMmutations were found almost exclusively in patients with WM who have theMYD88^L265Pvariant and convey resistance to ibrutinib,” Treon noted.

“The updated response rates for this trial are notable for the lack of major responses in patients with wild-typeMYD88on Sanger sequencing,” Treon said.

Despite the promise demonstrated by ibrutinib and the ability to tailor therapy based on mutation status, observation should still be used preferentially for patients with asymptomatic WM, according to Treon.

“These patients should still be observed until the onset of symptoms,” he noted; however, “genetic complexity develops early before clinical symptoms develop.”

In order to determine when to initiate therapy, Treon referenced the NCCN guidelines for WM, which call for:

• Hemoglobin less than or equal to 10 g/dL on the basis of disease
• PLT <100,000 per cubic millimeter on the basis of disease
• Symptomatic hyperviscosity
• Moderate/severe peripheral neuropathy
• Symptomatic cryoglobulins, cold agglutinins, autoimmune-related events, amyloid.

In the past, the genetic basis of WM was not defined, leaving clinicians to rely on therapies designed to treat lymphoma or myeloma. As a result, traditional treatment options for symptomatic patients include rituximab (Rituxan) alone, or in combination with alkylators, nucleoside analogs, or proteasome inhibitors.

In general, the ORR with rituximab is in the range of 25% to 40%; however, 40% to 60% of patients will development immunoglobulin M (IgM) flares, which promote hyperviscosity crisis and IgM-related morbidity. To avoid this condition, Treon urged colleagues to be aware of several clinical sequelae:

• Symptomatic hyperviscosity possible in patients with high serum IgM of >4,000 mg/dL.
• IgM neuropathy, cyroglobulins, cold agglutinins. Consider plasmapheresis.
• For patients with IgM >4,000 mg/dL or symptomatic HV: Avoid rituximab until IgM is in “safe range” either by plasmapheresis or chemotherapy without rituximab.

Rituximab intolerance is observed in about 10% to 15% of patients with WM and occurs late during induction or in maintenance treatment, Treon said. He emphasized that rituximab intolerance does not indicate response failure.

“Hypotension, rigors, flushing, throat closure, and urticarial are among the more common symptoms [of intolerance],” he noted. “A switchover to ofatumumab is tolerated in 80% of rituximab-intolerant patients and a test dose of 300 mg of ofatumumab is recommended.”

Treon also touched on hypogammaglobulinemia in WM, noting that most patients have IgA and IgG hypogammaglobulinemia at baseline. However, both IgA and IgG will commonly decline with B-cell depleting therapies, such as rituximab. Rituximab maintenance should be stopped and intravenous immunoglobulin should be considered in patients with recurring sinobronchial infections.

In discussing nucleoside analogs in WM, Treon said that fludarabine and cladribine produce similar results. The risk of transformation or myelodysplastic syndrome/acute myeloid leukemia is 10% to 15%. Additionally, these therapies should be avoided in patients who are candidates for autologous stem cell transplant, Treon advised.

Other options include cyclophosphamide-based therapy, which can be given as R-CHOP, CVP-R, CPR, or CDR. Adriamycin and vincristine may be dispensed since they do not appear to impact response rates or progression free survival (PFS). CDR carries a lower risk of neutropenia and neuropathy, with a median PFS of approximately three years without maintenance. With this approach, stem cell collection potential is preserved and long-term toxicity risks are modest.

Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia.N Engl J Med. 2015; 372:1430-1440.