Recombinant Thrombomodulin Safely Controls Disseminated Intravascular Coagulopathy in Acute Promyelocytic Leukemia – Results from the Japanese Pediatric Leukemia/Lymphoma Study Group AML-P05 Study
Authors: Yuza Yuki , Takahashi Hiroyuki , Moritake Hiroshi , Terui Kiminori , Hasegawa Daiichiro , Koike Kazutoshi , Ogawa Atsushi , Inoue Masami , Tomizawa Daisuke , Taga Takashi , Tawa Akio , Adachi Souichi 
Published: October 2019

Abstract
[Background] Acute promyelocytic leukemia (APL) cells induce dysregulation of coagulation and fibrinolysis, and most of the cases are complicated with disseminated intravascular coagulopathy (DIC) at the time of diagnosis. Administration of all-trans retinoic acid (ATRA) rapidly corrects dysregulation and improves DIC. But in some cases, management of DIC with ATRA alone is very difficult because addition of chemotherapeutic agents may reactivate fibrinolytic state. Thus the control of DIC is still an issue for the initial management of APL even in the ATRA era. Recombinant thrombomodulin (rTM) improves DIC by inhibiting excessive coagulation through the activation of protein C cascade (Saito H, et al. J Thromb Haemost 2007), and was approved in Japan for the treatment of DIC induced by severe infection or hematological malignancy in 2008. However, because activated protein C also facilitate fibrinolytic pathway by inhibiting plasminogen activator inhibitor-I, administration of rTM may lead to severe hemorrhage complication in patients with APL. Therefore, we retrospectively analyzed its efficacy and safety in pediatric APL.
[Object & Methods] This study included 45 cases; 42 who registered to the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-P05 study (UMIN Clinical Trials Registry, # UMIN000000645) and responded to the questionnaire and 3 cases outside the study. Questionnaire regarding the use of rTM and efficacy and safety issues, such as “Worst DIC score according to the diagnostic criteria of the Japanese Ministry of Health and Welfare (worst DIC score)” and “Days until resolution of DIC score from diagnosis of DIC (DIC duration)” were investigated.
[Results] Among 45 cases analyzed, 38 (84%) were diagnosed to complicate with DIC, and 9 (24%) among them used rTM by physician’s decision. In these 9 cases (rTM+ group), mean duration of rTM administration was 13.8 days (7–24 days). WBC count and FDP level at diagnosis of APL were not different between rTM+ group and rTM-NOT used group (rTM- group). In rTM+ group, mean value of “Worst DIC score” was 5.8 and mean “DIC duration” from diagnosis was 16.8 days, both of them were not statistically significant with those in rTM- group (5.4 and 13.0 days, respectively). However, median “DIC duration” from commencement of rTM (11.5 days) seems shorter than “DIC duration” from diagnosis of DIC in rTM- group (13.0 days), although the difference was not statistically significant. Regarding safety issues, there was no death or severe hemorrhage in rTM+ group, while 3 cases (10%) of severe hemorrhage due to uncontrolled DIC were reported in rTM- group, with fatal brain hemorrhage in 1 case (3%) among them. There was no significant difference of induction rate between rTM+ group (1 case, 11%) and rTM- group (3 cases, 10%), although 2 cases of ATRA-refractory APL in rTM+ group who were additionally treated with arsenic trioxide.
[Conclusions] In this retrospective analysis investigating efficacy and safety of rTM in the management of pediatric APL-related DIC, there were no significant differences regarding the efficacy of rTM because of the limited cases of rTM+ group. However, it is notable that there was no severe hemorrhage or death in rTM+ group. rTM seems to be safely used for the management of pediatric APL-related DIC.

Disclosures
No relevant conflicts of interest to declare.