Clinical Challenges: Preventing Early Mortality in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia, accounting for roughly 5% to 15% of cases. What makes APL distinctive is that while it is an aggressive form of acute myeloid leukemia, it is very curable if treated in time.

Ever since all-trans retinoic acid (ATRA) was first used in 1985 to successfully treat a 5-year girl in China after the failure of anthracycline-based chemotherapy, APL has evolved into one of the great success stories in leukemia treatment. With the use of regimens containing ATRA and arsenic trioxide (ATO), long-term overall survival rates of 90% to 95% are possible in low- and intermediate-risk APL, as well as in high-risk disease.

However, not all patients with APL have such favorable outcomes.

While very curable, “it has a very high upfront mortality,” Dale Bixby, MD, of the University of Michigan Medical School in Ann Arbor, told MedPage Today. “And the main cause of that early mortality is an inappropriate activation of the blood clotting pathways — disseminated intravascular coagulopathy (DIC). DIC is not unique to APL, but is seen more frequently than in other subtypes of acute leukemias. And that complication is the main reason for the mortality we see upfront.”

Early death rates can approach 30%, depending on the study, with most occurring within the first month from diagnosis, said Bixby.

A Medical Emergency

According to recommendations from an expert panel of the European LeukemiaNet, this risk of early mortality means patients with APL should be immediately hospitalized and managed as a medical emergency. ATRA and measures to counteract coagulopathy should be initiated immediately based solely on the clinical suspicion of APL.

“If we can get the patient diagnosed and initiated on treatment, and the DIC doesn’t end up causing complications, then the patients are most often cured,” Bixby said. “So, recognizing the diagnosis early through both morphologic examination of the patient’s blood and/or bone marrow biopsy, recognizing the unusual cell appearance of the leukemic cells we see in APL, and initiating ATRA as soon as possible is appropriate patient care, while awaiting final genetic confirmation of the diagnosis.”

The European LeukemiaNet panel also recommended that APL patients should be managed “by an experienced team in centers with documented rapid access to genetic diagnosis, a broad range of blood products, as well as ATRA, ATO, and chemotherapy.”

“You need people who are experienced in managing APL,” Anand Jillella, MD, of Georgia Cancer Center at Augusta University, told MedPage Today.

The rarity of APL means that most oncologists/hematologists will rarely encounter it, Jillella said. “I think the biggest problem with early death in APL is not so much the aggression of the disease, but not having experience managing these patients. That is the biggest risk for early mortality, in my opinion.”

In a study published in JCO Oncology Practice, Jillella and a team of researchers carried out a prospective multicenter trial in which they evaluated whether an algorithm focused on prevention and early treatment of the three main causes of death (bleeding, differentiation syndrome, and infection), as well as co-management of patients by community oncologists and APL experts at academic institutions, could help reduce early mortality. They found this treatment strategy resulted in a low early mortality rate and high 1-year survival in patients treated at community centers, with similar rates at academic centers.

Out of a population of 118 patients evaluated in the study, 10 died early (six non-high risk and four high-risk patients), for an early mortality rate of 8.5%. The induction mortality rate was similar between community (8.2%) and academic (8.8%) centers. Similarly, there was no difference in survival at 1 year depending on location of therapy. At a median follow-up of 27 months, 84.5% of patients in the cohort were alive.

“The key is learning how to manage the drugs and how to manage the complications of the drugs,” Jillella said. “The algorithm is not a panacea. More important is having access to experts who have experience with APL. Experience is not replaceable.”

How Available Is ATRA?

While it is imperative that patients with newly diagnosed APL — or a suspicion of that diagnosis — receive treatment in a timely manner, a study published last year in the Journal of the National Comprehensive Cancer Network suggests ATRA is not readily available in many hospitals.

“We often receive transfer requests from other hospitals to help manage patients with APL,” explained Bixby, who was the study’s senior author. “For years we’ve being hearing from physicians that while they had a suspicion of APL, they were not able to initiate treatment with ATRA to stave off DIC prior to transfer, and it was simply because their hospital didn’t have it available.”

Bixby and his colleagues conducted a telephone survey of 120 randomly selected hospitals from different regions in the U.S. and found that only 31% had ATRA immediately available. The reasons included the fact that the drug had not recently been requested, the inpatient pharmacist was not familiar with ATRA, or the facility relied on associated hospitals or cancer centers to provide the drug.

In addition to these barriers, Bixby and his colleagues suggested an underlying cause of ATRA unavailability is “the relatively rare incidence of APL (2.7%) combined with the cost to stock ATRA (average wholesale price of $2,988.16 for 100 tablets of 10 mg each), possibly leading to a perception that there is no significant benefit to having ATRA on formulary.”

Furthermore, Bixby noted that ATRA is only FDA approved for patients with APL who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. Thus, “manufacturers can’t promote it, and can’t provide assistance for off-label use,” he pointed out, despite the fact that the consensus guidelines recommend its use as part of frontline therapy for low/intermediate and high-risk disease.

Based on previous research, Bixby said, “we do believe that a significant delay in treatment can affect the long-term prognosis for these patients.”

For example, there are some studies suggesting that most early deaths in patients with APL result from hemorrhage. Another study showed that when ATRA was administered within 24 hours of a diagnosis of suspected APL, the early death rate due to hemorrhage was 33%. However, when ATRA was administered more than 24 hours after the initial suspicion of diagnosis, the death rate due to hemorrhage increased to over 70%.

The ultimate goal of their study, Bixby said, was to “get a message out to the hematology community that this is a real clinical problem.”

“While many times hematologists aren’t necessarily on the pharmacy and therapeutics committees of their hospitals, they need to petition their colleagues who are on them to say that although APL is a rare diagnosis, these patients’ lives are at stake,” he continued. “And we need ATRA available for these patients, even if they are gong to be transferred, because it is necessary to stabilize them while awaiting transfer to larger academic medical centers.”