Clinical challenges: Prevention of early mortality in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia, accounting for approximately 5-15% of cases. What sets APL apart is that although it is an aggressive form of acute myeloid leukemia, it is highly curable if treated in time.

Since all-trans retinoic acid (ATRA) was first used in 1985 to successfully treat a 5 year old girl in china after the failure of anthracycline-based chemotherapy, PLA has become one of the great success stories in the treatment of leukemia. 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 APLs, as well as in high-risk diseases.

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

Although highly curable, “it has a very high initial mortality,” said Dale Bixby, MD, of the University of Michigan Medical School in Ann Arbor. MedPage today. “And the main cause of this early mortality is 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 sub -types of acute leukaemias. And this complication is the main reason for the mortality that we see from the outset.”

Early mortality rates can approach 30%, according to the study, with most occurring within the first month of diagnosis, Bixby said.

A medical emergency

According to the recommendations of a European LeukemiaNet expert group, this early mortality risk means that patients with APL should be immediately hospitalized and treated as a medical emergency. ATRA and countermeasures for coagulopathy should be initiated immediately on the sole basis of clinical suspicion of APL.

“If we can get the patient diagnosed and started on treatment, and the DIC doesn’t end up causing complications, then patients are most often cured,” Bixby said. “Thus, early recognition of the diagnosis through morphological examination of the patient’s blood and/or bone marrow biopsy, recognition of the unusual cellular appearance of leukemic cells that we see in APL and the Initiation of ATRA as soon as possible constitutes appropriate care for the patient, pending definitive genetic confirmation of the diagnosis.

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

“You need people who are experienced in managing APL,” said Anand Jillella, MD, of Augusta University’s Georgia Cancer Center. MedPage today.

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

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

Of a population of 118 patients evaluated in the study, 10 died prematurely (six patients without risk and four patients at high risk), for an early mortality rate of 8.5%. The induction mortality rate was similar between community (8.2%) and university (8.8%) centers. Similarly, there was no difference in 1-year survival by treatment location. At the median follow-up of 27 months, 84.5% of patients in the cohort were alive.

“The key is learning how to manage medications and how to deal with medication complications,” Jillella said. “The algorithm is not a panacea. The most important thing is to have access to experts who have experience with PLA. Experience is not replaceable.”

What is ATRA availability?

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

“We often receive transfer requests from other hospitals to help manage APL patients,” explained Bixby, who was the study’s lead author. “For years we’ve heard doctors say that even if they suspected APL, they weren’t able to initiate treatment with ATRA to prevent DIC before transfer, and that was simply because their hospital didn’t have it available.”

Bixby and colleagues conducted a telephone survey of 120 randomly selected hospitals in different parts of the United States and found that only 31% had ATRA available immediately. Reasons included that the drug had not been requested recently, the hospital pharmacist was unfamiliar with ATRA, or the facility relied on associated hospitals or cancer centers to supply the drug.

In addition to these hurdles, Bixby and colleagues suggested that an underlying cause of ATRA’s unavailability is “the relatively rare incidence of APL (2.7%) combined with the cost of storing ATRA (average wholesale price of $2,988.16 for 100 tablets of 10mg each), which might give the impression that there is no significant benefit to having ATRA on the formulary.”

Additionally, Bixby noted that ATRA is only FDA-approved for patients with APL who are refractory or have relapsed after anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. . Thus, “manufacturers cannot promote it and cannot provide support for off-label use,” he stressed, despite the fact that consensus guidelines recommend its use in the first line treatment for low/intermediate and high risk patients. sickness.

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

For example, some studies suggest 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 rate of early death due to haemorrhage was 33%. However, when ATRA was given more than 24 hours after initial suspicion of the diagnosis, the bleeding mortality rate increased to more than 70%.

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

“Although hematologists are often not necessarily members of the pharmacy and therapeutics committees of their hospitals, they should ask their colleagues who are on them to say that although APL is a rare diagnosis, the lives of these patients is at stake,” he continued. . “And we need ATRA available for these patients, even if they are going to be transferred, because there is a need to stabilize them pending transfer to larger academic medical centers.”

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    mike bassett is a writer specializing in oncology and hematology. He is based in Massachusetts.

Disclosures

Bixby consulted Takeda.

Jillella didn’t divulge anything.

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