Waldenstrom Macroglobulinemia: The Discovery and What Lies Ahead

PETER DeNARDIS ignored his doctor's first recommendation to be checked out. A blood test, biopsy and PET scan later revealed Waldenstrom macroglobulinemia. - PHOTO BY SARAH TORTOREA

PETER DeNARDIS ignored his doctor's first recommendation to be checked out. A blood test, biopsy and PET scan later revealed Waldenstrom macroglobulinemia. - PHOTO BY SARAH TORTOREA

In 2003, during a routine check on Peter DeNardis’s blissfully quiet Crohn disease, his gastroenterologist noticed something off in the bloodwork. He gave DeNardis a phone number, which he, of course, ignored. “I didn’t follow up,” he confesses, until his doctor called back to check on him. “It’s really important you follow up on that,” he recalls his doctor telling him.

DeNardis realized later he’d been downplaying his nosebleeds and generally rundown feeling. “Maybe it’s just sinuses,” he had thought. “I tend to have nosebleeds, but not like I was having at the time.” Chastened, he called the number — a hospital hematology department — and before long was booked for more extensive blood work, a bone marrow biopsy and a PET scan.

The tests revealed Waldenstrom macroglobulinemia, which is a rare cancer of the lymphatic system. Only about 1,500 cases are diagnosed in the United States each year — about 2 percent of all blood cancers. Also called lymphoplasmacytic lymphoma, it was lumped with multiple myeloma until 1944 when the Swedish physician Jan Gosta Waldenström described its uniqueness: increased viscosity (thickness) of blood as a result of high levels of a large protein, which is known as immunoglobulin M (IgM).

Waldenstrom macroglobulinemia is twice as common in men as in women, more common among Caucasians, and typically emerges in the mid-60s. DeNardis was 43 at the time. “Not only was I lucky enough to get it,” he says dryly, “but also I got it at an earlier age than normal.”

Lymphomas often develop from the misfiring of natural immune processes. For example, if you were to inhale a particle of flu virus, your B lymphocytes — white blood cells that are part of your immune system — would recognize the virus as foreign, triggering the lymphocyte to transform into a plasma cell that would make an antibody to the virus. “IgM is the first line of defense against any foreign protein,” explains Stephen M. Ansell, M.D., Ph.D., a hematologist at Mayo Clinic in Rochester, Minnesota. “In Waldenstrom macroglobulinemia, that process gets stuck.”

The result is a bunch of very active cells that proliferate in the bone marrow, crowding out healthier cells and making a very sticky antibody that gums up sensitive tissues, like nerve sheathes and the retina.

When a rare cancer is diagnosed at a community hospital, the doctor in charge does not usually have firsthand experience with it. Physicians try, but the first thing DeNardis heard was that he and his wife should put his affairs in order and delay treatment. He sought a second opinion. At a larger research hospital in Pittsburgh, his next doctor took a more aggressive line: Begin treatment immediately, using the common combination of fludarabine, cyclophosphamide and Rituxan (rituxumab).

“I tolerated it pretty well. I got a little fatigued, but I was still able to work every day,” DeNardis says.

Cyclophosphamide and fludarabine are classic chemotherapy agents, developed in 1953 and 1968, respectively. Rituxan was in the first wave of the next generation of targeted therapy; these drugs take aim at the unique genetics of each tumor and patient. In 1997, Rituxan was the first-ever Food and Drug Administration (FDA)-approved targeted cancer drug for use in patients with B-cell non-Hodgkin lymphoma that no longer responded to other treatment.

Because it is an antibody that targets a receptor on immunoglobin-producing B-cell lymphocytes, Rituxan was already being tried as Waldenstrom treatment, borrowed from other lymphoma regimens. DeNardis sought out the International Waldenstrom’s Macroglobulinemia Foundation (IWMF) online support groups, which buzzed with debate about the new drug. And the combination worked, giving him a six-year break from symptoms.

Now the IWMF channels are abuzz, as the targeting strategies pioneered with Rituxan are maturing. In 2015, Imbruvica (ibrutinib) became the first drug approved by the FDA for Waldenstrom macroglobulinemia. Several other drugs using similar targeting strategies are in promising trials, and other agents using different targets are moving forward.

IDENTIFYING MUTATIONS

“The results are getting better and better, and the prognosis for patients actually has improved substantially,” says Ansell. “The key question then becomes what’s the best strategy when you have a long road to travel. It’s now clearly a marathon, not a sprint.”

One of the challenges in treating rare cancers is getting enough people into clinical trials to generate meaningful results. The flip side of this problem is that doctors can be somewhat creative in their approach. With no obvious treatment options until Imbruvica’s approval, Waldenstrom macroglobulinemia treatments over the last few decades borrowed liberally from a range of lymphoma treatments.

In 1999, Steven Treon, M.D., Ph.D., was a young oncological researcher working in multiple myeloma, where he had worked on the development of monoclonal antibody therapy. One afternoon in Boston, he met with a Waldenstrom support group and was surprised when more than 100 patients showed up. Many wanted to know more about Rituxan.

“Up to that time, there was very little for Waldenstrom. What little we had borrowed very heavily from other diseases, predominantly multiple myeloma, and those therapies were not working,” he says. Sometimes the therapy was worse than the disease, and patients died.

The IWMF boosters encouraged him, and they raised research money to ensure his commitment. In 2005, the Bing Center for Waldenstrom’s Macroglobulinemia, for which Treon serves as director, was officially formed at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, both in Boston. Among its major accomplishments has been the identification of the MYD88 mutation seen in more than 90 percent of patients with Waldenstrom. The gene helps doctors tell Waldenstrom macroglobulinemia from similar B-cell disorders and is now used as a diagnostic marker for the disease.

Next came the discovery of the CXCR4 mutation, which occurs in up to 30 percent of patients with Waldenstrom. Both genes have a clear effect on the disease when mutated and lowered treatment response.

DIAGNOSIS DILEMMA

KLEPAC was told she had two years to live in 2001 following a Waldenstrom macroglobulinemia diagnosis. - PHOTO BY SARAH TORTOREA

KLEPAC was told she had two years to live in 2001 following a Waldenstrom macroglobulinemia diagnosis. - PHOTO BY SARAH TORTOREA

Following the cellular signaling pathway mediated by MYD88 led Treon and his colleagues to Bruton’s tyrosine kinase (BTK), a piece of cellular biochemistry that — no surprise — plays a critical role in B-cell maturation. This was precisely the research needed for targeted therapy. The gene had been discovered in 1993, while a molecule designed to shut it down had been lurking on lab benches since the late ‘90s. Treon led a clinical trial of the BTK inhibitor Imbruvica in 63 previously treated patients with Waldenstrom macroglobulinemia. The drug delivered a 91 percent overall response rate — 77 percent with a major response. The study published in the New England Journal of Medicine supported the approval of Imbruvica for Waldenstrom in 2015. Marcia Klepac had six years to prepare for her Waldenstrom macroglobulinemia diagnosis. In 1995, a routine blood test picked up an anomaly, and her doctor said she had monoclonal gammopathy of undetermined significance (MGUS), often a precursor to Waldenstrom or multiple myeloma.

“MGUS is quite challenging because many (patients) actually never develop a malignant process. One has to be very careful not to tell them they have a lymphoma when they don’t,” says Ansell. “Indolent disease can be even trickier, smoldering in the background for years. You could treat them and be patting yourself on the back for a fantastic result and have got that result anyway from just observing.”

That was Klepac’s dilemma when her Waldenstrom macroglobulinemia diagnosis became official in 2001. Her diagnosing physician wanted to treat, while the second opinion suggested waiting. She waited, and it was another year before the disease turned aggressive: nosebleeds, extreme fatigue, night sweats, day sweats. Her first treatment, cladribine with Rituxan — now used for hairy cell leukemia — went poorly. Her disease flared in response to the Rituxan, and she began to bleed from the eyes. “I knew something was drastically wrong,” she recalls. “My eyes were engorged with blood.”

Her doctor next suggested cyclophosphamide, doxorubicin, vincristine and prednisone plus Rituxan (R-CHOP), a standard treatment for non-Hodgkin lymphoma. But she wanted nothing more to do with chemotherapy and made an appointment in Boston to meet Treon. He also suggested R-CHOP first, then a trial for Campath (alemtuzumab), which failed. Then she found a trial for Genasense (oblimersen), another targeted drug that still hasn’t been approved.

It stabilized her disease at first, but then she relapsed. This was in 2003, and over the next 11 years, Klepac participated in multiple clinical trials — eight in total. Among the treatments she tried: Velcade (bortezomib), Velcade plus Rituxan, enzastaurin, Farydak (panobinostat) and Afinitor (everolimus) plus Rituxan plus Velcade. Throughout these, the best response she ever achieved was minimal — a 25 percent reduction in disease burden. “It’s amazing that you can keep going,” she says. “My quality of life was OK.”

By the time the Imbruvica trials opened, she knew she wanted it, but she had done too many trials to qualify. Instead she found another BTK inhibitor, spebrutinib, being tested at Cleveland Clinic in Ohio. It worked for a time, but then her disease grew very aggressive. Imbruvica still hadn’t been approved by the FDA for Waldenstrom, but her oncologist could prescribe it, and in early 2014 she began treatment. Finally, she experienced a good partial remission. Her IgM dropped significantly in just a few weeks, and it continues to drop. Her white blood cell and platelet counts also soared. “I couldn’t believe those were my real blood tests,” she says.

A GIANT LEAP

She’s still on it, four years later. In 2001, the best guesses gave her two years. “I was prepared to die,” says the now 73-year-old. “I just feel like it’s surreal that I’m even here.” Is it ironic that after so many trials, she wasn’t even on the trial that made the difference? That’s not how she sees it. “I was very, very involved with every decision that was made with treatment because I just could not leave that up to somebody else,” Klepac says. “I had to buy into and feel good about it or otherwise I couldn’t go through with it. I would feel helpless.”

“In a short period of time, we have giant leaps forward. And if you look at Waldenstrom it really is an example of how we are winning the war on cancer,” says Treon. Imbruvica continues to impress. Five years after the trial, the progression-free survival numbers continue to improve. In June, the FDA granted a priority review for Imbruvica in combination with Rituxan as a treatment option across all lines of therapy for patients with Waldenstrom macroglobulinemia. This was based on the phase 3 iNNOVATE trial, which showed that the combination lowered the risk of disease progression or death by 80 percent versus Rituxan alone.

And there are many BTK inhibitors in the pipeline. Zanubrutinib (BGB-3111) and Calquence (acalabrutinib) are both in clinical trials. Calquence was approved last year for mantle cell lymphoma.

Judith Trotman, M.D., director of the Clinical Research Unit in the Hematology Department at Concord Hospital in Sydney, Australia, gives zanubrutinib a glowing review after watching it act in a phase 2 trial. “That was quite a phenomenal experience, as a clinician, to see these patients get so well, so quickly. And, I believe, with minimal side effects,” she says. If it achieves final regulatory approval, it could have other beneficial effects. “I hope they jolly well get to market and drive these prices down,” Trotman adds.

Among the promising results, oncologists are particularly curious about the head-to-head trial of zanubrutinib and Imbruvica. Whereas zanubrutinib is very tightly focused on BTK, Imbruvica acts on a slightly broader level, shutting down related processes as well. “I think we’re going to find out if a very targeted BTK inhibitor is a better or a less good thing (compared with) a targeted — but maybe not quite as clean — inhibitor such as Imbruvica,” says Ansell.

“Even within BTK inhibitors, I think it’s important for all of us to recognize that there are going to be potentially fundamental differences in their mechanisms of action,” agrees Treon.

But that’s not all. Treon is running a trial of Imbruvica with ulocuplumab, a CXCR4 inhibitor, hoping to close the gap for patients who don’t respond well to Imbruvica because of their CXCR4 status.

And then there is Venclexta (venetoclax), a B-cell lymphoma 2 inhibitor that targets the suicide mechanisms of cancer cells. Approved in 2016 for use in a subset of patients with chronic lymphocytic leukemia, it also shows promise in Waldenstrom macroglobulinemia in combination with Imbruvica.

As exciting as Imbruvica is for the typical patient with Waldenstrom, it’s not enough. “We want to be pushing the envelope in terms of combinations for younger patients," argues Trotman. “Taking a tablet every day and waiting until your disease progresses years down the track is not an appealing solution. Should we be trying to get these patients a sustained complete response and, ideally, the ability to stop therapy?”

Ansell, as excited as he is about Imbruvica, agrees the tradeoffs for different patient groups are real.

“We actually have a number of frontline therapeutic options which are usually very successful in treating the disease,” he says. “However, the treatments are expensive.”

With Imbruvica, for example, the patient takes a pill every day for the foreseeable future, at a price tag of about $150,000 per year. Treanda (bendamustine) and Rituxan, meanwhile, runs about $120,000 for a four- to six-month course of treatment.

“You get similar outcomes when these drugs are used as the first treatment that are now approaching five-plus years,” says Ansell. Treanda and Rituxan are considerably cheaper and may offer a significant treatment holiday as well, he adds.

There are risks that go with the rewards. Immunotherapy is another hot field, with lots of excitement around checkpoint inhibitors, such as Opdivo (nivolumab) and Keytruda (pembrolizumab).

Trotman’s group was running a trial combining zanubrutinib with an investigational PD-1 inhibitor called tislelizumab (BGB-A317). The result was nearly disastrous for two patients, who developed reactions to standard blood transfusions. Both patients developed life-threatening uncontrolled hemolytic anemia, where red blood cells are destroyed faster than they can be replaced.

“This was quite a profound immune response that was triggered by the addition of the PD-1 inhibitor in both patients,” Trotman says. “We latched on to it quickly because they were treated contemporaneously at one institution.” They have no explanation, but published the event quickly to raise a warning flag.

The mysterious challenges of cancer are redoubled in rare cancers. If Waldenstrom macroglobulinemia was a common cancer, there might be a pattern in the rare events. But in rare cancers, the rare events are so unique that they can be inscrutable.

That’s true for DeNardis again. His disease is back, sometimes. Sort of. The doctors can’t find testable traces of Waldenstrom in his blood or his bone marrow, yet solid tumors keep recurring in his body. They know they need to treat it, but will the new agents coming out of the lab do the trick?

“The pace of development, especially for our disease, is amazing and it continues to surprise me,” says DeNardis. “I don’t know if it’s going to help me because I have unusual manifestations of an already unusual disease.”