Unique Trial Aims to Decrease Early Deaths in Patients with Rare Leukemia

January 3, 2018, by NCI Staff

It’s not often that a cancer clinical trial recruits a handful of oncologists to staff a round-the-clock help desk of sorts for their peers. But that’s the case for a unique NCI-funded trial that is attempting to address a serious problem for patients who have a very rare cancer, acute promyelocytic leukemia (APL).

Because of treatment advances over the past several decades, long-term survival has increased dramatically in people diagnosed with APL.

The goal of the trial, however, is to see if this 24/7 support can help more patients with APL survive the first few weeks of treatment.

In some countries, approximately one-third of patients with APL die within a month of beginning treatment. The deaths are due largely to a host of complications that are common with this cancer and its treatment. The situation in the United States is a little better, with an estimated death rate within the first month of approximately 17% overall and nearly 25% in patients age 55 or older.

Initial management of patients with APL can be very difficult, said the trial’s co-principal investigator, Anand Jillella, M.D., chief of the Division of Hematology/Oncology at the Medical College of Georgia (MCG).

“But if patients can get through the first month, virtually all are cured,” Dr. Jillella said. “The [overall] relapse rate is approximately 2%.”

So, in this trial, Dr. Jillella and a group of oncologists at several other large cancer centers with experience treating APL are making themselves available at any time—by cell phone, email, and text—to help clinicians at participating hospitals across the country get their patients over the initial, potentially deadly, hump.

Unique Complications, Few Patients

There are no recent data on APL diagnoses in the United States, but Dr. Jillella estimates that its annual incidence is approximately 3,000.

APL, a form of acute myeloid leukemia, was once highly fatal and poorly understood. But research conducted over the past several decades has transformed APL into one of the most treatable cancers.

Based on research conducted initially in China in the 1990s, two therapies—All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), in combination with a class of chemotherapy drugs known as anthracyclines—now form the backbone for APL treatment.

The rarity of this cancer, and the often “peculiar” complications caused by the disease and its treatments, are the principal reasons for early deaths among patients with APL, explained the trial’s other lead investigator, Vamsi Kota, M.D., of the Emory University Winship Cancer Institute in Atlanta.

Because APL is so rare, most oncologists have very little experience treating it, Dr. Kota said.

“Most hospitals probably treat fewer than five patients a year,” he explained. “Smaller hospitals may treat just one patient every 2–3 years.”

And although ATRA and ATO are highly effective, their use can give rise to a wide range of side effects, many of which are a set of complications collectively called differentiation syndrome. These complications can include high fevers and severe fluid accumulation that can lead to rapid organ failure.

The problem for clinicians is recognizing why these complications are occurring and understanding the best way to treat them, Dr. Kota said.

In someone with APL, for instance, a fever may often be caused by differentiation syndrome rather than by an infection. The treatment for fever in a patient with APL would include steroids, he continued.

“But in general, for a patient with an infection you wouldn’t use steroids, so that’s where the dilemma comes in,” he said. Failure to recognize and appropriately treat these complications, Dr. Kota continued, “can quickly lead to the demise of the patient.”

Following a Successful Model

The nationwide trial, led by the ECOG-ACRIN clinical trials group and conducted at centers that are part of the NCI Community Oncology Research Program (NCORP), grew out of a similar study conducted by Drs. Jillella and Kota in Georgia and South Carolina.

In the years preceding that study, Dr. Jillella and his colleagues at MCG conducted an exhaustive review of the charts of patients with APL who had died at their own institution and at several other large institutions.

The review “showed a lot of problems,” Dr. Jillella said. Patient complications, he continued, “were not being managed properly.”

From that review, they developed clinical guidelines for managing patients with APL. But given that quick, decisive action can be critical for patients with APL, a 15-page clinical guideline is not necessarily helpful for clinicians “who are seeing these patients only once every 3–4 years, and you have a patient in crisis coming in on the Friday of a holiday weekend,” Dr. Jillella said.

So they developed and, over time, refined a simpler 2-page checklist. With staff using the clinical guidelines and simplified checklist, there were no early deaths among the next 9–10 APL patients treated at MCG.

“We thought, ‘We’re on to something,’” Dr. Jillella recalled.

The MCG team (which at the time included Dr. Kota) spread the word about the approach to nearly all oncology practices that see patients with leukemia in Georgia and South Carolina (and a few in neighboring states). “We told them, ‘If you have any [patients with APL], call us, no matter when, and we will help,’” he said.

Their invitation to help has been well received, Dr. Kota said.

“It really is a partnership between physicians,” he continued. Other oncologists “have to believe in the concept and be willing to share their patients’ [clinical experience] with us. The goal is the betterment of the patient, and that’s …why they’ve been so willing to call.”

The results of the effort largely duplicated what had been achieved at MCG. Over more than 4 years and among 165 patients treated at both academic and community-based hospitals, there were only 11 early deaths —6.6% of patients treated—three of whom were age 70 or older, a group at particularly high risk.

Investigators involved with the new, nationwide trial are following a nearly identical approach. The experts “on call” now include oncologists at six large academic medical centers who have treated a relatively large number of patients with APL and are intimately familiar with the guidelines and checklist.

The trial’s on-call investigators have visited or called the participating NCORP centers in their own geographic regions to educate staff about the trial, Dr. Kota said.

So far, 9 patients have been enrolled, with a goal of enrolling 200. Clinicians at participating sites are asked to call one of the consulting investigators within 3 days of diagnosing a new patient with APL, Dr. Kota explained.

“We want to help them from the beginning to prevent complications,” he said.

Maintaining a Standard, Saving Lives

Rubina Qamar, M.D., an oncologist at St. Luke’s Medical Center in Milwaukee, consulted with Dr. Jillella to treat one of the patients enrolled in the trial thus far. In her last 5 years at St. Luke’s, Dr. Qamar said that she has treated five patients with APL.

Dr. Jillella “was incredibly approachable and answered all my questions over several emails,” she added. He also followed up with her afterward to see how her patient was doing.

“Fortunately, this patient did very well,” she said.

It’s not uncommon for clinicians to reach out to national experts about “difficult or unusual cases,” Dr. Qamar noted. But this is the first time she’s been part of a trial where there was a set group of experts available at any time.

In addition, the St. Luke’s team embraced the idea of having patient management protocols that were very clearly outlined and standardized, she said. “We loved this idea and were eager to participate.”

The study is definitely different than most cancer clinical trials, Dr. Kota stressed.

“It’s not a trial that’s testing a new treatment or trying to change standards of care,” he continued. “We’re trying to maintain a standard of care for a group of patients who, if that care is provided, we know what we can accomplish.”