Clinical Availability of All-Trans Retinoic Acid (ATRA) for Patients with Suspected Acute Promyelocytic Leukemia – Why National Guidelines May Not be Followed

Background: All-Trans Retinoic Acid (ATRA, Tretinoin, Vesinoid, Teva Pharmaceuticals Industries, North Wales, PA) serves as a uniform backbone in the care and management of patients with acute promyelocytic leukemia (APL). While first investigated as a salvage therapy for patients with relapsed or refractory disease, current National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) guidelines call for its early use in patients suspected of having APL even prior to the genetic confirmation of the disease. Because ATRA can significantly mitigate disseminated intravascular coagulopathy (DIC), one of the early complications of APL, the NCCN and ELN guidelines support the prescription of ATRA as soon as there is a clinical suspicion of the diagnosis. As a regional referral center for the care of patients with advanced myeloid malignancies, we receive numerous requests for the transfer of care for patients suspected of having APL. Yet many of the referring centers have not instituted treatment with ATRA, typically due to a lack of access to the medication in the referring hospital’s formulary. Therefore, we conducted an exploratory analysis of the clinical availability of ATRA for patients with a suspected diagnosis of APL and also to explore the potential hurdles limiting the availability of this drug.

Methods: We divided the United States into six geographical regions: Northwest, Southwest, Central, Southeast, Northeast, and the Great Lakes. A state from each of these regions was selected (Washington, Arizona, Missouri, Georgia, Massachusetts, and Michigan). To select the 120 hospitals, an online hospital directory – American Hospital Directory (ahd.com) was utilized. We went to each state’s specific hospital list page and assigned a number to all hospitals with a bed capacity of greater than 100. We then entered these numbers into a random number generator and selected the first 20 hospitals to be generated (excluding repeats). We then asked the following set of questions to the inpatient pharmacist of the hospital: 1. Does your hospital treat Acute Leukemia or do they refer to other hospitals; 2. Do you have All Trans Retinoic Acid (oral) – 10 mg tablets on the formulary or available in stock as a non-formulary request; 3. If no, why not.

Results: Based upon the responses we received, ATRA was available in less than half of the hospitals queried (46%) (Table 1). There were no identifiable differences in the percentages based upon hospital size (inpatient beds) or academic versus non-academic status of the hospital. Interestingly, of the hospitals that refer to other institutions for the care of their leukemia patients, only 19% (8/43) had ATRA on their formulary or available in stock as a non-formulary request that could act as a bridge prior to the transfer. The analysis identified three common barriers to the availability of ATRA in these hospitals including: a) that it has not been recently requested by a physician and therefore was not available, b) the inpatient pharmacist had never heard of the drug, and c) that the hospital relied on associated hospitals or cancer centers to provide the drug to the patient.

Conclusion: While national guidelines support the rapid introduction of ATRA as soon as there is a morphologic consideration for APL, the majority of hospitals caring for these patients can not rapidly institute therapy due to a lack of availability of the medication. Moreover, only 19% (8/43) of hospitals that we studied that refer patients to tertiary care centers can provide ATRA as a bridge prior to their transfer. While much has been written about the early 30-day mortality seen in patients with APL, we can not specifically comment on the impact of these findings on the rates of mortality of APL patients treated in hospitals without ready access to ATRA versus those with the medication available on formulary. However, we propose that these findings should spur an investigation of this possibility together with a call by hematologists nationwide to their formulary committees to ensure that this lifesaving medication is available to patients in as timely a manner as possible.