If Anand P. Jillella, MD, has his way, no future patient with acute promyelocytic leukemia (APL) will experience a delay in treatment or lack for an expert consult—and few, if any, will die of this condition.
Mortality from APL is much higher than most oncologists think, especially during the first 30 days, and these early deaths can be prevented, according to Dr. Jillella, Professor of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta, who has developed an algorithm and an intervention program that will be validated in a trial by the Eastern Cooperative Oncology Group/American College of Radiology Imaging Network (ECOG/ACRIN).
As a result of his passion and personal quest, and having examined the problem of APL-related mortality for 8 years, Dr. Jillella has become a foremost expert on APL. “I’m really a transplant doctor,” he said in an interview with The ASCO Post, “but I’ve become obsessed with APL.”
Dr. Jillella shares credit with his colleague, Vamsi K. Kota, MD, Assistant Professor of Hematology and Medical Oncology at Emory, who is co–principal investigator with Dr. Jillella on the upcoming ECOG/ACRIN trial.
APL was first described in 1950 as a hyperacute fatal illness associated with a hemorrhagic syndrome. The condition remained highly fatal until its genetic profile was identified and all-trans retinoic acid (ATRA, aka tretinoin) became the established treatment. While APL is now largely curable, too many patients still die, he said.
“Early deaths from APL can and should be prevented. Anything short of this is totally unacceptable,” Dr. Jillella commented.
At the recent Debates and Didactics in Hematology and Oncology conference in Sea Island, Georgia, Dr. Jillela presented an APL patient-care strategy that has two components: use of a simplified algorithm, and prompt and frequent consultation with his team of experts.
Mortality Greatly Underestimated
Dr. Jillella pegged the population-wide survival rate at around 65%—much worse than the generally accepted figure of 85% to 90% demonstrated in large cooperative group trials.
“These numbers are for highly selected patients treated under a protocol and perhaps by experts. This is not what happens to these patients in the real world,” he pointed out.
Misconceptions about APL occur because the condition is uncommon, affecting fewer than 1,000 patients a year in the United States. The average oncologist/hematologist rarely if ever sees these patients, and this lack of experience can be fatal for the patient, he suggested.
“A single mistake can result in the demise of the patient because APL is hyperacute, and there are often nuances that need to be identified. If you don’t know what you are doing right away, you can kill the patient,” he noted.
Surveillance, Epidemiology, and End Results (SEER) data, recently analyzed by researchers at The University of Texas MD Anderson Cancer Center, Houston, opened the eyes of the medical community to the seriousness of APL.1 The analysis over time showed 5-year survival to be 18% between 1975 and 1990, improving to 52% between 1991 and 1999, and to 64% for the years 2000 to 2008; for the most recent period, 1-year survival was 71%.
“Still, the survival rate of 90% in multicenter trials is not a reflection of the outcome in the general population. The death rate of 5% to 10% is a gross underestimate. And mortality is not just a problem in small community practices but also in big, sophisticated cancer centers,” he emphasized.
Risk Greatest in First 30 Days
Researchers worldwide have examined early deaths in APL (days 1 to 30), showing fairly consistent mortality rates in the 30% range. “One in three patients dies within the first month, even in countries with sophisticated health care and good record-keeping, such as the United States and Sweden,” he pointed out.
Patients are most likely to die from internal bleeding (70%), differentiation syndrome (ie, treatment toxicity, 20%), and infection (10%). Very few patients die as a result of relapse.
The first 30 days are critical, and risk diminishes thereafter. “If we get patients through the first month, it’s basically a ‘home run,’” he said. He believes that improvements in survival rates will come not through drug development but through the reduction in early deaths. Success in reducing early mortality could push survival estimates into the 90% range, he predicted.
Finding a Plan of Action
Dr. Jillella’s particular interest in APL began while he was Chief of Hematology/Oncology at the Medical College of Georgia (now Georgia Regents University). His team treated 19 patients with APL between 2005 and 2009, of whom 7 died. The 11 survivors are now in remission and presumed cured.
“We admitted we were not doing well with these patients. Our goal in 2009 was to fix the problem that we saw,” he said. “I reviewed the literature and conference abstracts. I attended national meetings. I talked to experts. I had an external consultant review my death charts, to see if we were doing things right. It seemed no one else was seeing this problem: either they were not looking, or they did not acknowledge it,” he continued.
“We found a proactive way of treating APL and preventing complications, rather than worrying about them once they occur,” he said.
Dr. Jillella and colleagues created a “culture of awareness” in the states of Georgia and neighboring South Carolina. They simplified what was once a 15-page document, creating a 1.5-page checklist, based on standards of care, to guide management. The strategy involves rapid diagnosis and initiation of therapy, aggressive management of coagulopathy, prevention of differentiation syndrome, and prophylaxis and aggressive treatment of infection. What makes this protocol really effective is its emphasis on prompt and frequent consultation with an APL expert.
“We function as a resource for the physician caring for the patient. And we call the doctor; we don’t wait for the doctor to call us. We have gotten good at this, and we can predict what’s going to happen to the patient tomorrow, and 2 days from now. That’s a big help to physicians who infrequently see APL,” he said. “We are currently helping to manage three patients, and we are in constant contact with their doctors.”
Dr. Kota added that this arrangement allows very sick patients to be treated locally. “This is intensive treatment, and patients need to be close to their families. Bringing them to a specialized center may not be appropriate from the patient’s point of view.”
APL is a medical emergency that should be immediately treated with ATRA, the physicians emphasized. “If you suspect this diagnosis, there is no downside to treating it immediately. You can always step back, but withholding treatment will be detrimental to the patient,” Dr. Jillella added.
The algorithm alone “is not a panacea,” he emphasized. “It’s extremely important to call someone who treats APL on a day-to-day basis.”
Implementing the Plan
Dr. Jillella and Dr. Kota disseminated their protocol by actually visiting every oncology practice throughout Georgia and South Carolina. They urged any oncologist/hematologist to immediately alert the Emory program when APL is suspected, where they could receive an immediate consultation and frequent telephone follow-up.
“We literally went to every practice, and we mailed out flyers with our protocols and our pictures,” Dr. Jillella said. “We think that 90% of practitioners in two states (and a few other practices in Florida and North Carolina) know about us, and they call us as soon as a patient is seen—or even before one is transferred to their center. They have our cell phones and we have been available 24/7 for the past 4 years.” Dr. Kota estimated that the program helps an average of three new patients per month.
The 37% mortality rate that Dr. Jillella observed among his own patients prior to instituting the algorithm (median follow-up, 2,358 days) was greatly improved after 2009. He and his colleagues have now treated 61 patients, of whom only 3 died (median follow-up, 255 days), for a mortality rate of 4.9%.
Commenting on his protocol, he said, “When we had treated nine patients and none died—while three should have—we knew we were onto something.”
Program Will Expand
Drs. Jillella and Kota have sought funding to expand his program and to more rigorously validate the intervention. They received a grant from the Leukemia & Lymphoma Society through its Therapy Acceleration Program, for work in two states. That program began accruing July 1, 2013, and will enroll 120 patients over 3 years.
More recently ECOG/ACRIN signed on to help expand the program’s scope. The goal of EA9131 is to prospectively assess 30-day mortality and to collect survival data using the ECOG/ACRIN mechanism. Physician education, use of the algorithm, and consultations with national experts in several sites will be key components of the study. They hope this study will be expanded nationwide.
“We are tremendously excited about this program and this study,” Dr. Jillella said. “We think it will change the outcome in these patients, and that our model will evolve into a global paradigm whereby a physician in South Korea, for instance, can text us and get an immediate reply.”
Dr. Kota proposed an even larger objective: that the APL program serve as a model for other challenging diseases. “By collaborating and co-managing patients, we have done much better in APL,” he noted. “I think we can replicate this model in other diseases.” ■
Disclosure: Drs. Jillella and Kota received grant funding from the Leukemia & Lymphoma Society.
References
1. Chen Y Kantarjian H, Wang H, et al: Acute promyelocytic leukemia: A population-based study on incidence and survival in the United States, 1975-2008. Cancer 118:5811-5818, 2012.
