Genomics Now Driving Treatment of Waldenström’s Macroglobulinemia


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Steven P. Treon, MD, PhD

Patients had a robust benefit after ibrutinib, with rapid responses, rapid reduction of IgM, and improvements in hemoglobulinemia. Genomics are playing a major role in helping us predict who will benefit from ibrutinib.

—Steven P. Treon, MD, PhD

The treatment of Waldenström’s macroglobulinemia has been greatly impacted by an understanding of its genomics, according to Steven P. Treon, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center and Massachusetts General Hospital Cancer Center, Boston. Dr. Treon brought listeners up to date on this lymphoma subtype at the 2015 Annual Congress on Hematologic Malignancies, sponsored by the National Comprehensive Cancer Network (NCCN).1

“Waldenström’s macroglobulinemia is a disease where I can see 20 patients in a day, and no 2 will present the same. There is a lot of diversity in presentation,” noted Dr. Treon.

For example, although Waldenström’s macroglobulinemia is a lymphoma, it rarely presents with adenopathy or splenomegaly (20%), but these features are common at relapse (60%). “This factors into our treatment,” he added.

For most patients, disease is centered in the bone marrow, which can lead to cytopenias. For others, morbidity stems from immunoglobulin M (IgM) production: hyperviscosity syndrome, IgM neuropathy, cryoglobulinemia, and cold agglutinemia.

Waldenström’s macroglobulinemia has a strong familial predisposition (20%–25%) and is common among those of Ashkenazi Jewish ancestry (20%) but rare among African Americans (< 5%). It can begin as a prodrome of IgM monoclonal gammopathy of undetermined significance, with likely progression to Waldenström’s macroglobulinemia.

“Thankfully, with new treatments, overall survival has been improving,” noted Dr. Treon. A recent analysis of the SEER database, for which Dr. Treon was senior author, documented median overall survival of 8 years.2

Getting a Handle on the Genomics

“The future is optimistic, because we finally have a handle on the genomics,” Dr. Treon said. A somatic mutation in the MYD88 gene, MYD88L265P, is identified in more than 90% of patients and in more than 50% of patients with IgM monoclonal gammopathy of undetermined significance. “It is an early oncogenic driver of this disease,” he remarked.

The identification of MYD88 L265P has made it easier to discern Waldenström’s macroglobulinemia from other conditions that secrete IgM, including marginal zone lymphoma and chronic lymphocytic leukemia. MYD88 testing by polymerase chain reaction is, therefore, essential in the workup of suspected cases.

The second most common mutation involves the CXCR4 gene, which plays a pivotal role in trafficking cells toward the bone marrow. The WHIM-like CXCR4 C–tail mutation (CXCR4WHIM) occurs in 30% to 40% of patients with Waldenström’s macroglobulinemia, usually in association with MYD88L265P. Unlike the “almost singular nature” of MYD88 mutations, more than 40 types of mutations affect the CXCR4 gene, largely nonsense and frameshift mutations, which are associated with a high disease burden and increased serum IgM levels. “The patient with hyperviscosity crisis is likely to have one of the CXCR4 mutations,” Dr. Treon indicated.

CXCR4 mutation, however, is not a marker for worse overall survival, but lack of the MYD88 mutation is. Patients with wild-type MYD88 disease had more than a 10-fold increased risk of dying, according to a 2014 study led by Dr. Treon.3

The discovery of the MYD88 mutation also led to an understanding of the signaling pathways that foster this tumor. Two key pathways are triggered as a result of this aberration—one involves the protein IRAK and the other involves Bruton’s tyrosine kinase. Both pathways ultimately result in activation of nuclear factor kappa B (NF-kB), a growth and survival factor. Knowledge of this pathway has opened the door for targeted treatment with the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Observation, Plasmapheresis

Since the disease is largely indolent, most patients with Waldenström’s macroglobulinemia do not require immediate treatment. “In fact, 30% to 40% are simply followed,” Dr. Treon said. However, patients with symptomatic hyperviscosity; moderate/severe peripheral neuropathy; and symptomatic cryoglobulins, cold agglutinins, autoimmune-related events, and amyloid should be considered for treatment.

Plasmapheresis is a good initial intervention for certain subsets of patients: those with symptomatic hyperviscosity, severe cryoglobulinemia, and cold agglutinemia (with blood warmers); rapidly progressing IgM-associated neuropathy (but not chronic IgM neuropathy); IgM > 4,000 mg/dL (pre-rituximab [Rituxan]); and progressive renal failure due to IgM pathology (but not due to other causes).

“IgM is a bulky molecule and is mostly in the bloodstream, so plasmapheresis is effective in rapidly bringing down IgM levels,” he indicated. “In addition, in the setting of rituximab, IgM can rise rapidly. In these patients, plasmapheresis can get that IgM level down before they end up with hyperviscosity crisis.” However, Dr. Treon added, “plasmapheresis should be regarded as a temporary supportive measure, not definitive treatment.”

Optimizing Rituximab

Rituximab is an important drug in Waldenström’s macroglobulinemia, since almost all patients express CD20. Single-agent rituximab produces responses in 20% to 40%, but since time to disease progression is short, the drug should not be used alone as the initial intervention.

Rituximab can also induce an IgM flare. A rise of IgM above 4,000 mg/dL can trigger a hyperviscosity crisis and worsen symptoms of neuropathy, cryoglobulinemia, and cold agglutinins. In this situation, rituximab should be avoided and plasmapheresis considered.

Approximately 15% of patients will develop intolerance to rituximab in the form of infusion reactions, usually toward the end of induction. These patients can be switched to ofatumumab (Arzerra; a 300-mg test dose is recommended).

Rituximab combinations should increase the rates of complete and very good partial responses, and thus prolong the time to disease progression. Such drugs have included cyclophosphamide, nucleoside analogs, proteasome inhibitors, and bendamustine (Treanda).

Clinicians should avoid using rituximab in combination with doxorubicin and vincristine, since these drugs do not appear to impact response rates or progression-free survival. Nucleoside analogs have fallen out of favor for Waldenström’s macroglobulinemia, because they increase the risk of transformation and negatively impact stem cell collection.

The most acceptable three drug-regimen is cyclophosphamide, dexamethasone, and rituximab (CDR), said Dr. Treon. However, there is interest in substituting bendamustine for cyclophosphamide, based on the study by Rummel and colleagues of bendamustine/rituximab, vs R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone).4 In the subset of patients with Waldenström’s macroglobulinemia, a median progression-free survival was 69.5 months in the bendamustine/rituximab arm, vs 28.1 in the R-CHOP arm (P = .0033).

Proteasome Inhibitors and Maintenance Therapy

Proteasome inhibitors have become a mainstay of treatment, and the combination of bortezomib (Velcade)/dexamethasone/rituximab has been associated with progression-free survival beyond 4 years. Dr. Treon and colleagues are currently evaluating carfilzomib (Kyprolis)/lenalidomide (Revlimid)/dexamethasone; early results are promising. The second- and third-generation proteasome inhibitors could be an important component of treatment in Waldenström’s macroglobulinemia, since they are less likely than bortezomib to produce neuropathy, he pointed out.

Maintenance therapy appears to prolong remission and even survival in Waldenström’s macroglobulinemia; however, clinicians should watch for worsening of hypogammaglobulinemia and recurring sinobronchial infections with maintenance rituximab. These infections can be difficult to control with antibiotics. Intravenous immunoglobulin can be given to severely affected patients.

Treatment With Ibrutinib

Taking advantage of Bruton’s tyrosine kinase as an important factor in Waldenström’s macroglobulinemia, ibrutinib is emerging as a targeted therapy in relapsed/refractory disease. In a study reported this year by Dr. Treon and his team, 91% of patients responded; major responses were seen in 73%, and very good partial responses or better were seen in 16%, with ibrutinib at 420 mg/d.5

“Patients had a robust benefit after ibrutinib, with rapid responses, rapid reduction of IgM, and improvements in hemoglobulinemia. Genomics are playing a major role in helping us predict who will benefit from ibrutinib,” he noted.

In the updated analysis, 69% of patients were free of disease progression at 2 years, and 95% were alive, after a median of two prior therapies. Major responses in his study were completely absent among patients lacking mutations in both MYD88 and CXCR4 but were observed in 91.7% of patients with mutated MYD88 and wild-type CXCR4 and in 61.9% in patients with mutations in both genes.

Based on this study, ibrutinib received Breakthrough Therapy designation from the U.S. Food and Drug Administration for Waldenström’s macroglobulinemia and is included in the NCCN Guidelines for untreated and previously treated patients. ■

Disclosure: Dr. Treon reported no potential conflicts of interest.

References

1. Treon SP: Advances in Waldenström macroglobulinemia. 2015 NCCN Annual Congress: Hematologic MalignanciesTM. Presented October 17, 2015.

2. Castillo JJ, Olszewski AJ, Kanan S, et al: Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: An analysis of the Surveillance, Epidemiology and End Results database. Br J Haematol 169:81-89, 2015.

3. Treon SP, Cao Y, Xu L, et al: Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 123:2791-2796, 2014.

4. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203-1210, 2013.

5. Treon SP, Tripsas CK, Meid K, et al: Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med 372:1430-1440, 2015.

 



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