Gaining Ground

From Paths of Progress Fall/Winter 2014

Advances in Supportive Care for Cancer Patients

by Elizabeth Dougherty

At first, Eve Pallang thought she’d pulled a muscle shoveling snow. Two urgent care visits later, in March 2013, the 33-year old newly trained nurse learned she had acute lymphoblastic leukemia, a highly malignant cancer of the white blood cells. Chemotherapy knocked down the disease, but not completely. She tried an experimental drug, with the hope that it would ready her for the next step in her oncologist's treatment plan.

Pallang needed a bone marrow transplant.

Bone marrow transplants, also called hematopoietic stem cell transplants, have been used to treat leukemia and other blood cancers since the early 1970s. First, potent chemotherapy erases a patient's immune system, then a cancer-free replacement is transplanted from the patient or a donor. The procedure can be curative, says Paul Richardson, MD, clinical disease program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC), but the procedure is also necessary. Without it, patients like Eve will die of their diseases.

Like many aggressive cancer therapies, bone marrow transplant (BMT) is not without risk. Tragically, complications such as infections, organ failures, or rejection of the graft can cut short the lives of some patients who may be on the verge of a cure. Some have transplants early while they are still healthy, as a first and only resort, while for others, some very sick, BMT is a last resort. But all who elect for such bold therapy have hope, so Richardson and others at DF/BWCC have dedicated their careers to finding ways to protect patients at their most vulnerable moments. Their efforts to improve supportive care have led to new therapies that are preventing deaths from the complications of aggressive cancer therapies. At the same time, supportive care research is opening up new avenues for the treatment of cancer itself.

Clearing the Way for Cures

As a junior attending physician at DF/BWCC in the early 1990s, Richardson saw his first cases of veno-occlusive disease (VOD) of the liver. The condition is caused by chemotherapy prior to BMT that damages the numerous small blood vessels that percolate within the liver. It occurs in a range of patients (varying from 5 to 60 percent, depending on age and health). As a trainee, he'd been told to look out for the disease.

"If it occurs, your patient is very likely to die," he recalls being told. The only treatment at the time was a clot-buster that opened the damaged blood vessels, but also caused an unacceptably high rate of life-threatening bleeding.

Richardson set out to find another solution. A little-known drug called defibrotide came to his attention. Instead of busting through blockages, the drug promised to stabilize the linings of blood vessels, shoring up the vessel walls while simultaneously clearing them. With the cooperation of Gentium, the small Italian pharmaceutical company that manufactures defibrotide, he gained permission to try the drug for compassionate use.

Soon after, a 28-year-old patient developed severe VOD after undergoing BMT to treat relapsed Hodgkin lymphoma. Her VOD progressed rapidly and the clot-buster did not help. But after 12 days of defibrotide, she improved. Later, with prolonged therapy, she completely recovered. Doctors mobbed around the poster Richardson presented about her case at the 1995 annual meeting of the American Society of Hematology. "It was the first case ever described of a drug working for VOD," Richardson says.

Richardson and his team expanded their studies to a larger group of patients. Because VOD is an uncommon condition that occurs early after transplant when patients are extremely vulnerable, it is challenging to study new drugs for its treatment. Over the years, however, clinical trials showed that defibrotide cut death rates from VOD by about half and raised response rates from less than 10 percent to about 30 to 40 percent.

A partnership with a pediatric BMT group at Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center, initially led by Eva Guinan, MD, and then by her colleagues Leslie Lehmann, MD, and Christine Duncan, MD, allowed Richardson and colleagues to evaluate the drug in children. Children tend to receive higher-dose chemotherapy prior to BMT and to be more vulnerable to VOD. "Outcomes in kids with VOD were as bad as in adults, but with defibrotide, kids seem to do really well," says Richardson.

In 2006, to gain approval for the drug, Richardson and colleagues designed a phase 3 clinical trial to test defibrotide in patients with severe VOD and advanced multi-organ failure. The study results showed that 24 percent of patients who received defibrotide recovered fully from severe VOD, more than double that of a contemporary and rigorously selected historical control group of patients who did not receive the drug.

Based on this data, defibrotide received approval in September 2013 from the European Medicines Agency for the treatment of VOD. Approval is still under review by the U.S. Food and Drug Administration (FDA), although defibrotide is now available through an expanded access program in the U.S. for patients with less-severe, though still potentially life-threatening, forms of VOD – as was the case for patient Eve Pallang.

Within three days of her transplant, Pallang's petite 110-pound frame had gained 20 pounds from fluid retention and her liver had failed, symptoms of VOD. Richardson and the DF/BWCC BMT study team, Vincent Ho, MD, Philippe Armand, MD, PhD, Joseph Antin, MD, and Robert Soiffer, MD, recommended defibrotide. Within two weeks, the weight was coming off and her liver had returned to normal. "It worked," says Pallang. "I was just so happy that I was fortunate enough to receive it."

Infection Fighter

Another barrier to BMT successes are infections. Infectious disease doctor Francisco Marty, MD, got his start supporting cancer patients with infections in the early 2000s. During his fellowship, he couldn't help but notice the guesswork involved in treating infection in cancer patients. One patient died from complications from an unnecessary antifungal medication, while another died for lack of treatment for a fungal infection that went unchecked. "We can't have these patients we're trying to save from cancer die from infections that are diagnosable and preventable," he says.

Finding solutions became his mission. In 2003, Marty joined Dana-Farber permanently. He and his colleagues started a weekly half-day infectious disease clinic. Today, he is part of a group of five doctors committed to improving infectious disease care for cancer patients. Between them, they are developing new diagnostics and therapeutics for fungal and viral infections, as well as preventive solutions such as vaccines.

Of the many problems he sees in the clinic, cytomegalovirus (CMV) infection after bone marrow transplant is a common occurrence without a complete solution. CMV, a type of herpes virus, causes little more than a fever or swollen glands in most adults before the immune system controls it. The virus lies dormant in about 60 percent of U.S. adults.

But in transplant patients, particularly BMT patients, the immune system is compromised, allowing the virus to escape and blossom into a potentially life-threatening infection. Doctors can detect CMV infection and treat it with antiviral drugs. But the first-line drug, valganciclovir, causes a drop in white blood cells, which makes patients more susceptible to bacterial and fungal infections, so much so that attempts to use this drug to prevent CMV created risks that outweighed the benefits. Second-line drugs can cause kidney damage. Even with several treatment options, overall survival is lower for post-transplant patients who develop CMV.

In 2009, another option emerged. An experimental drug named CMX001 was proving in test tube and animal studies to be effective against a wide range of viruses, including CMV. Originally developed as an agent against smallpox, CMX001 is an easily distributed pill form of an existing intravenous drug. It also has minimal risk of kidney toxicity, so Marty and colleagues around the country launched a study to determine whether it might be effective in the prevention and treatment of CMV in transplant patients.

The phase 2 trial recruited 230 BMT patients from 27 centers and randomized them to receive CMX001 or a placebo after transplant for two to three months, or until CMV infection required an alternate intervention. The results, published in 2013 in the New England Journal of Medicine, showed the drug cut the risk of CMV to nearly a fourth, from 37 percent to 10 percent of patients, and indicated a safe effective dose of 100 mg twice weekly. Marty and colleagues in the U.S., Canada, and Europe have since launched a phase 3 trial to collect the evidence needed to seek FDA approval for the drug.

Marty is quick to mention that other drugs are also in play to treat CMV in transplant patients. "Many people are working to bring a second wave of drugs to prevent and treat this infection more safely and effectively," he says.

Supportive Care and Beyond

Work being done to treat serious BMT complications is also proving valuable in directly treating some forms of cancer. For example, the efforts of Richardson and his Dana-Farber colleagues to improve supportive care for BMT patients dovetailed with similar efforts for multiple myeloma patients.

In tests in animal models, the researchers, including Constantine Mitsiades, MD, PhD, and Kenneth Anderson, MD, investigated defibrotide's ability not only to reverse VOD, but also to make sure it didn't undermine the efficacy of other anti-cancer agents.

It turned out that defibrotide added to the effectiveness of the mix of antitumor agents; with defibrotide, tumors grew more slowly and animals survived longer. The researchers quickly learned that defibrotide has multiple effects on the tumor microenvironment, the normal cells and tissues that surround, communicate with, and sometimes support, a tumor. Defibrotide appears to negate some of this support, making tumor cells more prone to die and less likely to grow.

Those effects occurred not just in laboratory and animal models of multiple myeloma, but also of breast, lung, and colorectal cancer, suggesting that defibrotide might someday have broad applicability as part of combined therapy for cancer. A recent early phase trial of defibrotide combined with melphalan, prednisone, and thalidomide showed encouraging results in patients with relapsed/refractory multiple myeloma.

While it was laboratory work that revealed defibrotide's potential, it was the struggles of patients that provided the first clues. "Our patients show us more than anything what their needs are," says Richardson. Taking those bedside observations back to the bench is the essence of supportive care, creating big differences for patients, and big advances for therapy.

Paths of Progress Fall/Winter 2014 Table of Contents