Recombinant Human Soluble Thrombomodulin Safely and Effectively Rescues Acute Promyelocytic Leukemia Patients From Disseminated Intravascular Coagulation.

Abstract 2226

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) with a high mortality rate, mostly attributable to intracranial hemorrhage caused by disseminated intravascular coagulation (DIC). Almost all patients with APL develop DIC. The introduction of all-trans retinoic acid (ATRA) into the induction chemotherapy regimen has revolutionized the treatment of individuals with APL, with nearly 90% of newly diagnosed APL patients achieving complete remission and over 70% of patients surviving longer than 5 years. However, population-based studies have shown that the early death-rate during induction chemotherapy remains extremely high with nearly 30% incidence and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required.

Recombinant human soluble thrombomodulin (rTM) comprises the active, extracellular domain of TM, and inactivates coagulation. A phase III trial comparing efficacy and safety between rTM and low-dose heparin showed that rTM significantly improved DIC associated with hematological malignancies or infections. This clinical trial excluded almost all patients with APL, because concomitant use of ATRA was prohibited. The use of rTM for the treatment of DIC was approved in Japan in be 2008.

In this study, we treated individuals for DIC caused by APL (n=9) using rTM in combination with ATRA and chemotherapy, and compared the clinical outcomes with historical control patients (n=8) treated with ATRA and/or chemotherapy. Two control patients developed intracranial vascular incidents. On the other hand, no bleeding related mortality was noted in rTM-treated patients. Percentage change of FDP and change of fibrinogen were significantly higher in the rTM group than the control group (repeated measures ANOVA, p=0.041 and p=0.045, respectively). Interestingly, treatment with rTM significantly reduced the transfusion units of FFP required to maintain plasma levels of fibrinogen above 150 mg/dl (0.63 ± 0.93 U/d vs. 4.3 ± 1.6 U/d, p=0.001). Notably, treatment with rTM rescued patients from DIC earlier than historical controls (log rank test, p=0.019). These results suggest that administration of rTM should be considered for the treatment of individuals with DIC associated with APL.