Patience Needed: WM Is Incurable, but Survival Is Long

Pam Harrison

May 23, 2018

ROSEMONT, Illinois — Successful management of Waldenstrom's macroglobulinemia (WM) begins by recognizing that this rare type of non-Hodgkin's lymphoma does not require immediate treatment upon diagnosis. Rather, physicians need to wait until patients meet symptomatic criteria before introducing treatment, experts concurred here.

Each year in the United States, about 1500 patients are newly diagnosed with WM.

Rouleaux formation, Waldenstrom's macroglobulinema.

Experts in this disease gathered here at the International Waldenstrom's Macroglobulinemia Foundation (IWMF) 2018 Forum, which is dedicated to educating patients and caregivers about the disease.

"We cannot cure WM — WM is incurable — yet patients with WM tend to survive a long time. In our clinic, for example, the median survival is anywhere between 15 and 17 years," Jorge Castillo, MD, clinical director, Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, told Medscape Medical News.

With such prolonged survival, it is highly unlikely that relatively short bursts of treatment will alter outcomes. In addition, "more treatment promotes resistance, so each time the disease comes back, it is going to be more difficult to treat," Castillo added.

For these reasons, experts who manage WM wait until patients meet established criteria before initiating treatment. The most common criteria is anemia, which gives rise to fatigue and shortness of breath and impairs patients' ability to carry out the activities of daily living.

Another symptom that drives initiation of treatment is peripheral neuropathy. As explained by Jeffrey Matous, MD, medical director, Colorado Blood Cancer Institute in Denver, peripheral neuropathy is caused by abnormal levels of immunoglobulin M (IgM).

A sky-high level of IgM, which is produced by WM cells, is pathognomonic for WM.

"IgM can make the blood more viscous," Matous explained. Hyperviscosity can cause easy bruising, headaches, nose bleeds, and blurred vision.

When high levels of IgM attack the nerves, patients can develop peripheral neuropathy, especially in a precursor syndrome of WM known as IgM MGUS (monoclonal gammopathy of undetermined significance), which is a challenge to treat even for WM experts, Matous acknowledged.

A less common symptom of WM that merits intervention is Raynaud's phenomenon.

Another pathognomonic sign of WM is evidence of a mass of lymphoplasmacytic (LPL) cells on bone marrow biopsy.

"When you have issues with WM, it can either be the direct result of the LPL cells growing and taking over the bone marrow, or it can be from the production of IgM from WM cells, or both," Matous explained.

Once the LPL cells infiltrate the bone marrow, patients can develop enlarged lymph nodes or an enlarged spleen, both of which require intervention, he added.

WM is best thought of as occurring in distinct phases: active, or symptomatic, WM, which requires treatment; and asymptomatic, or "smoldering," WM, which does not.

Many, although not all, patients with smoldering WM go on to develop symptomatic WM. For patients with smoldering WM, the lifetime risk of developing symptomatic WM is 70% to 80%.

"These are the patients I watch very carefully, more carefully than those with IgM MGUS," Matous said.

Physicians should never intervene solely on the basis of high IgM counts, according to consensus guidelines, which state that a high IgM level is not in itself a reason to treat.

"The most important thing for physicians to remember when evaluating patients for WM is to actually talk to the patient, because patients will tell you almost every time if they require treatment or not," Matous emphasized.

How the patient feels is the most important thing by far and away that dictates intervention. Dr Jeffrey Matous

"And if I hear that they feel fine, I don't care what their IgM level is. How the patient feels is the most important thing by far and away that dictates intervention," he added.

Personalize Treatment

Because the presentation of WM can be so diverse, treatment should be personalized to fit with each clinical presentation, the speakers agreed.

Factors to consider when deciding whether or not to treat include the patient's age, symptoms, the toxicity profile of whatever regimen is deemed most appropriate, and the mutational status of the WM clone.

"To give you an example, if a patient is young, I would rather not expose them to chemotherapy so that I don't increase their risk of secondary leukemia," Castillo noted.

If a patient works with their hands, "I would rather not give them bortezomib [Velcade, Takeda] so we can prevent neuropathy," he added.

Some patients fear taking pills and so would have difficulty with daily doses of ibrutinib (Imbruvica, Pharmacyclics), "so not only do we have to keep in mind the presentation and the genomics of the disease but also patient preference and the toxicity of the drugs to personalize treatment," Castillo emphasized.

Physicians need not worry about the comparative efficacy of the available drugs used in treating WM, he commented, because the drugs are similar in efficacy. The adverse events associated with the drugs differ, however.

For instance, the efficacy of chemotherapy used in combination with rituximab (Rituxan, Genentech) is "very similar to the efficacy we get with the proteasome inhibitors, such as bortezomib, in combination with rituximab," he said. "This in turn is very similar to the use of ibrutinib, so efficacy is not what drives my decisions in most patients but rather the toxicity they might experience," Castillo emphasized.

Matous noted that in deciding on treatment, he considers the age of the patient. With a younger patient, "I am more likely to want to treat them to a complete remission (CR) or as near a CR as possible and be more aggressive with my treatment," he told Medscape Medical News. However, Matous acknowledged that treatment rarely leads to CRs in WM.

For older patients, Matous often aims to treat to just below the threshold at which their disease gives rise to symptoms.

"When we treat people, it is not necessary for everybody to drop their WM levels down to zero. If we just drop them back below the threshold where they were causing trouble, very often that results in a very long survival with excellent quality of life," he emphasized.

Final Treatment Considerations

A discovery in 2012 changed the way WM was viewed. That year, said Steven Treon, MD, PhD, director, Bing Center for Waldenstrom's Macroglobulinemia, a highly distinguishing mutation, the L265P mutation in the MYD88 gene, was identified and was subsequently found to be present in more than 90% of patients with WM.

"Not only do WM patients have the mutation, but anywhere from 50% to 90% of patients with the precursor condition, IgM MGUS, have it as well," Treon noted in a webinar published by the center.

"What this tells us is that MYD88 mutation is probably an early driver of the pathology associated with this disease," he observed.

This proved to be a real game changer, Treon explained, because it opened up the possibility not only of being able to diagnose WM with a high degree of accuracy using genomic testing but also of discovering a drug that turns off the mutated gene, effectively stopping the disease in its tracks.

That drug turned out to be ibrutinib, which targets the Bruton's tyrosine kinase (BTK) pathway, which is turned on by the mutated MYD88 gene.

"This is a crucial finding, as it showed that MYD88 can bind to the activated form of BTK, and if you use this drug in cell lines, you can block BTK from binding to MYD88 and short-circuit this particular system," Treon explained.

Major Clinical Success

That ibrutinib has met with major clinical success in the treatment of WM was amply demonstrated by two studies presented here during the IWMF Educational Forum. Both studies were originally presented at the annual meetoing of the American Society of Hematology in December 2017 and were updated and discussed at the forum.

Ibrutinib received approval by the US Food and Drug Administration for the treatment of WM in 2015 for all lines of therapy, including frontline treatment.

Results from the first study to evaluate ibrutinib as frontline therapy were highly encouraging.

That study was conducted by Treon and colleagues at the Bing Center. Thirty treatment-naive, symptomatic WM patients, all of whom expressed the MYD88 L265P mutation, received ibrutinib 420 mg/day until disease progression or unacceptable toxicity.

Importantly, from 40% to 45% of untreated WM patients carry the CXCR4 mutation, which confers clinical drug resistance to ibrutinib.

In the frontline study, patients underwent treatment with ibrutinib for a median time of 8.1 months. Treatment response was similar between patients who carried the CXCR4 mutation and those who carried the wild-type gene — meaning there was no inherent resistance to the drug, the investigators reported.

At 8.1 months, the overall response rate was 97%, and the major response rate was 80%, they said. Another 17% of patients achieved a very good partial response (VGPR), although no CRs were observed in the cohort.

The median serum IgM level declined from 4380 to 1786 mg/dL, while the hemoglobin level increased from 10.3 g/dL at baseline to 13.6 g/dL at study endpoint. Bone marrow involvement also decreased from 65% at study entry to 20% at study endpoint (P ≤ .0001 for all comparisons).

Treatment was well tolerated, although symptoms of joint pain, bruising, and rash were observed, the researchers noted.

Pivotal Clinical Trial

An update of a pivotal clinical trial in which 63 WM patients who had received at least one prior line of therapy reported that patients may continue taking ibrutinib over the long term and continue having a good response to it.

The median time that patients in this study continued taking ibrutinib was 46.6 months, Treon and colleagues report.

"Improvements in responses occurred with prolonged treatment," they add, "with overall and major response rates of 90.4% and 77.7%, respectively," they state.

Again, no CRs were achieved, but 27% of patients in the trial achieved a VGPR.

The median serum IgM level also plummeted, from 3520 mg/dL at baseline to 821 mg/dL at study endpoint; the median hemoglobin level increased from 10.5 g/dL to 14.2 g/dL; and median bone marrow involvement dropped from 60% at study enrollment to 20% at follow-up (P < .0001 for all comparisons).

Median progression-free survival (PFS) had not yet been reached at follow-up for those with wild-type CXCR4. For those who carried the mutated version, median PFS was 45 months.

"Ibrutinib is a really important drug in WM, and it works well for the great majority of patients," Matous confirmed.

It is also well tolerated by most patients, he added.

But it is not for everybody, although the drug is the only agent targeted against WM that has been developed.

"Firstly, it's a drug that patients take indefinitely, and when they hear 'indefinitely,' they hear 'forever,' " Matous explained.

Ibrutinib also may be effective at inhibiting the BTK pathway inside WM cells — "but that is not the only way that WM cells misbehave, so it does not achieve really deep remissions in our patients," he continued.

In addition, the drug is expensive — in the United States, it costs around $130,000 a year per patient.

"Ideally, we want to find treatments that do a better job at eradicating the disease, not just stymying it temporarily while patients take the medicine," Matous said.

Castillo concurred, adding that ibrutinib cannot be considered a classic cancer drug in that it does not kill malignant cells the way chemotherapy does.

Rather, the BTK inhibitor modulates the function of the cell, and when the drug is discontinued, there is a risk the disease will rebound.

"As long as patients take their pills, the disease is under control, but in some patients, when ibrutinib is discontinued, they will rebound," Castillo confirmed.

"So we need to be mindful of this, and when patients lose their response to the drug, we don't automatically stop treatment. We add a new treatment and continue with ibrutinib and overlap both treatments for about a month or 2 until we know the new treatment is working, and then we can stop ibrutinib," he added.

Dr Castillo has served as a consultant to Janssen, Merck, and Pharmacyclics and has received research funding from AbbVie, Gilead Sciences, Janssen, Millennium Pharmaceuticals, and Beigene. Dr Matous has received grant and research support from Dana Farber Studies and has served as a consultant for the Celgene Multiple Myeloma Advisory Committee. He has also received speakers' fees from Celgene. Dr Treon has served as a consultant and has received research funding from Pharmacyclics.

International Waldenstrom's Macroglobulinemia Foundation (IWMF) 2018 Forum. Presented May 18, 2018.

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