Beneficial Effect Of Anticoagulants In The Management Of Patients With Acute Promyelocytic Leukemia (APL): Results Of a Multicenter, Retrospective Epidemiologic Study Of The Disseminated Intravascular Coagulation Patients In Japan
Authors: Kawasugi Kazuo , Yamamoto Tadashi , Shirafuji Naoki , Ikezoe Takayuki , Chi SungGi , Ogino Yoshitaka , Takezako Naoki 
Published: October 2019

Abstract

Background
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.
In Japan, the conventional therapies for coagulopathy, such as low molecular heparin (LMWH), danaparoid sodium, and synthetic protease inhibitors were aggressively administered in addition to blood transfusions in DIC patients with APL. In 2008, a new anticoagulant, recombinant human soluble thrombomodulin (rTM) was approved for the treatment of DIC in Japan. Therefore, we accessed the difference of clinical safety and beneficial effects among these anticoagulant treatments in DIC patients with APL, by evaluating data on the multicenter, retrospective epidemiologic study of the DIC patients.

Patients and Methods
Patients with DIC associated with newly diagnosed APL were recruited from January 2000 through December 2012 in 3 Japanese hematology centers. APL was defined according to FAB classification and was confirmed by the presence of t(15;17) and/or the PML-RARα fusion gene. DIC was evaluated by the diagnostic criteria of the Japanese Ministry of Health and Welfare. The treatment algorithm for newly diagnosed APL patients was generally based on the protocol proposed by the Japan Adult Leukemia Study Group (JALSG). The concomitant use of fresh frozen plasma, platelets, and/or other anticoagulant drugs were generally based on the recommendation of the JALSG protocol as follows: Platelet concentrate and fresh frozen plasma were transfused to maintain platelet counts ³30 × 109/L and plasma fibrinogen levels ³150 mg/dL, respectively.
Early death (death within 30 day from APL diagnosis), severe hemorrhagic events, and improvement of coagulopathy were analyzed between rTM and other anticoagulants treatment. The time to disappearance of hemorrhagic symptoms between the two groups were analyzed by the Kaplan-Meier method and the log-rank test.

Results
DIC developed at diagnosis in 64 APL patients. 35 patients with DIC were treated with rTM (rTM group) and 29 patients with DIC were treated with LMWH, danaparoid sodium, and/or synthetic protease inhibitors (control group). There were no significant differences in age nor gender between rTM group and control group. Number of patients treated with ATRA alone and ATRA plus chemotherapy were 7 and 28 in the rTM group, and 10 and 19 in the control group. Early death rate for the rTM group was significantly lower than that for the control group (14% vs. 38%, P=0.043). Two patients developed intracranial hemorrhagic early death in the control group. On the other hand, no severe hemorrhagic event and mortality was noted in the rTM group. The time to disappearance of hemorrhagic symptoms was shorter for the rTM group than the control group (P=0.021).

Conclusions
These findings suggest that supportive care with rTM in combination with ATRA and chemotherapy ameliorates coagulopathy and reduces the risk of hemorrhagic early deaths in patients with APL than other anticoagulants.

Disclosures:
No relevant conflicts of interest to declare.