Decreasing Early Deaths in Acute Promyelocytic Leukemia (APL) By Using a Simplified Treatment Algorithm and Establishing a Network with Academic and Community Centers in USA
Authors: Jillella Anand , Arellano Martha , Bashey Asad , Vidito Sarah I. , Stuart Robert K. , Leung Caleb , Sitchenko Kaitlin , Gaddh Manila , Heffner Leonard T , Kolhe Ravindra B. , Galipeau Jacques , Langston Amelia , Kota Vamsi K 
Published: October 2019

Abstract
Background: APL is a highly curable malignancy with reported survival above 90% in many large co-operative group studies. A recent study with use of ATRA/Arsenic versus ATRA/chemotherapy in low and intermediate risk patients showed an expected survival of 99% and 91% respectively. These spectacular results are not evident in the general population. A recent study from US SEER data showed that the 1 and 5 year relative survival in APL patients is 71% and 65%. Studies from Swedish Cancer Registry and Brazil showed that the early deaths (ED) can be approximately 30%. This is in contrast to observation in clinical trials where the early mortality is around 5%. The common causes of death are hemorrhagic complications (HC), infection, differentiation syndrome (DS) and multi-organ failure. It is now agreed that decreasing early deaths is a high priority at all leukemia treatment centers and will improve population wide survival. We report results of our prospective trial using a set of streamlined treatment guidelines along expert support that has been highly effective in reducing ED.
Methods: The high ED rate in APL prompted us to develop a single page treatment algorithm with emphasis on quick diagnosis, prompt initiation of therapy and proactive and aggressive management of all the major causes of death during induction. More importantly we made our treatment protocol available to smaller outlying treatment centers and guided the treating oncologist/hematologist during induction. We were awarded a grant by the Leukemia Lymphoma Society (LLS) to implement this protocol in the states of Georgia and South Carolina to cover 15 million people over a 3 year period. We partnered with 3 other large leukemia treating centers and the study was approved by the respective institutional review boards. Aggressive outreach effort were made by visiting most of the leukemia treatment centers in both states to publicize the concept and educate the treating physicians about ED. Physicians called one of the leukemia treating physicians at the larger centers when a diagnosis of APL was suspected or confirmed and all patients were co-managed till the end of induction. Patients were consented using a telephone consent approved by the IRB for obtaining treatment information. There were no exclusion criteria but 3 patients were excluded for refusing transfusion support for religious reasons.
Results: From 11/2010 to 06/2015, we treated a total of 106 patients. 40 patients were managed at large leukemia treatment centers and 66 were managed in the community at 18 practices spread across Georgia, South Carolina and neighboring states. Median age was 52 years (range 21-87 years) and 53% were males. Out of a total of 106 patients, there were 7 deaths (6.6%) with cause of death being bleeding due to DIC (n=3), multi organ failure and differentiation syndrome (n=3) and infection (n=1). 5/7 deaths were in patients older than 60 years with 3 being in patients above 70 years. Deaths occurred in both academic (2/40, 5%) and community centers (5/66, 7%). 3 patients died after induction from non APL causes which were metastatic colon cancer, infection not related to the APL treatments and another 87 year old patient who refused treatments and opted for hospice care.
Conclusions: Our experience clearly shows that a streamlined treatment algorithm along with help from experts will result in better outcomes in this most curable hematological malignancy. A similar approach pioneered by investigators in Brazil (IC-APL consortium) confirmed this to be an effective intervention to decrease early deaths in APL. We believe our experience warrants large scale implementation of our protocol and is presently approved as an ECOG/ACRIN trial.
Figure 1. Survival in APL patients treated using the algorithm and network of treatment centers. Figure 1. Survival in APL patients treated using the algorithm and network of treatment centers.

Disclosures
Jillella: Leukemia Lymphoma Society: Research Funding. Stuart:Novartis: Research Funding. Galipeau:Emory University: Patents & Royalties. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding.