A Successful Model To Decrease Early and Preventable Deaths In Acute Promyelocytic Leukemia (APL) Through The Use Of a Simplified Algorithm and Expert Support In Experienced As Well As Smaller Leukemia Treatment Centers In The US
Authors: Jillella Anand P. , Kolhe Ravindra B. , Awan Farrukh , Natrajan Kavita , Kota Vamsi 
Published: October 2019

Abstract

Background
APL is a highly curable malignancy with reported survival above 90% in many large co-operative group studies. The most recent GIMEMA trial in low and intermediate risk patients showed an expected survival of 98% in the ATRA/Arsenic trioxide arm and 91% in the ATRA/chemotherapy arm. The early mortality was very low as with other large trials. These spectacular results are not evident in studies from cancer registry data. 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 also show that the early mortality is 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) 70%, differentiation syndrome (DS) 20% and infection 10%. HC are unique to this condition and are due to DIC seen in majority of patients. Current trials that are using a risk adapted strategy, using new drugs, changing the sequence, withholding maintenance treatment etc may result in a modest improvement in survival. However the intervention most likely to improve survival in the general population in the US is to decrease early deaths. We report our results showing that the use of a set of streamlined treatment guidelines along with support from experts can decrease early deaths in APL.

Methods
At Georgia Regents University, between 7/2005 and 6/2009, 19 patients were diagnosed with APL. 7 patients (5 high-risk and 2 low-risk) died during induction resulting in an unusually high and unacceptable mortality rate of 37%. All patients who survived induction are in remission at present. The high early death rate prompted us to develop a simple 1.5 page treatment algorithm that focuses 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 guidelines available to smaller outlying leukemia treatment centers and helped the treating oncologists manage the patient during induction.

Results
From 11/2010 to 05/2013, we treated 8 patients at GRU and helped manage 14 patients at 8 practices. Age range was 21-70 years. Nine patients were high-risk, eight intermediate and five low-risk. There were no deaths during induction. Only 1 patient (4.5%) had HC and eight had DS.

Conclusions
While we recognize that this is a small cohort, our own experience and recent SEER based studies show that early mortality is a significant problem in the United States. We show that a streamlined treatment algorithm that we developed independently due to our poor outcome along with help from experts will lead to better outcomes in this curable disease. A similar approach pioneered by investigators in Brazil clearly shows this to be an effective model to decrease early deaths in APL. We believe our experience warrants large scale implementation of our strategy in an attempt to decrease early mortality in APL. We were awarded a $1.68 million grant by the Leukemia Lymphoma Society to implement this protocol in the states of Georgia and South Carolina with a population of 15 million over a 3 year period.

Disclosures:
Jillella: Lymphoma Leukemia society: Research Funding. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals Inc.: Speakers Bureau. Kota:Teva: Speakers Bureau; Ariad: Advisory board, Advisory board Other.