Utility Of D-Dimer As a Marker For Differentiation Syndrome and Infections In Acute Promyelocytic Leukemia (APL)

Acute Promyelocytic Leukemia is a highly curable malignancy with cure rates of greater than 90% in most co-operative group trials.  However, population based studies indicate that the survival is much lower with up to 30% early deaths.  The most common causes of early deaths are bleeding, differentiation syndrome and infection. Early identification and management of these three complications is essential if the outcomes are to be improved further. Bleeding in APL is secondary to disseminated intravascular coagulation (DIC) a peculiar complication of the disease and coagulation panel including d-dimer, fibrinogen levels, prothrombin time, activated partial thromboplastin time are commonly used as markers of DIC. There are presently no available tests to identify DS or infection early and are entirely clinical diagnoses. Here we report the importance of d-dimer levels as probable markers of DS or infection during induction treatment for APL.

We performed a retrospective chart review on forty one patients diagnosed with Acute Promyelocytic Leukemia and treated with ATRA from September 2005 – June 2013 from Georgia Regents University and those referred here from surrounding treatment centers.  Data obtained included D-Dimer levels at diagnosis, daily d-dimer levels when available, dates of differentiation syndrome from start of treatment and dates of infectious complications when available which was obtained from progress notes and microbiology lab and radiology reports.

41 consecutive APL patients were evaluated for this study. One patient refused treatment and 15 patients did not have coagulation labs (specifically d-dimer) done throughout the course of induction treatment and had to be excluded. Age range of all the patients treated was 21-75 years. There were seven deaths overall and 21 patients had some evidence of DS. The diagnosis of DS was made clinically as per standard guidelines. We included 25 patients in whom there were d-dimer levels done throughout the hospitalization in this study. In these 25 patients, all had an increase in d-dimer levels after an initial drop as the DIC is corrected. 6 patients did not have any complications. In 4 patients the rise in d-dimer was followed by infectious complications. In the other 15 patients, their hospitalization was complicated by DS. In these 15 patients,  6 had elevation in d-dimer prior (0-5 days) to development of DS. In 3 patients the DS developed followed shortly by an elevation in d-dimer. The correlation between d-dimer elevation and DS could not be clearly ascertained from the available documentation in the other 6 patients.

APL is a curable malignancy but early deaths leads to poor outcomes outside of clinical trials. Early identification of the complications of the disease and treatment will allow us to further improve the outcomes in the community. D-dimer is an acute phase reactant and is elevated in any inflammatory state. From our data, the elevation in d-dimers following an initial decrease after correction of coagulopathy secondary to DIC might be marker of differentiation syndrome and or infection. These two conditions are pro-inflammatory states and might explain the increase in d-dimers observed. A larger scale validation is essential to confirm this observation which then might lead to more prompt identification of the complications and ultimately improved outcomes.

No relevant conflicts of interest to declare.