Background

Patients with acute promyelocytic leukemia (APL) patients present disseminated intravascular coagulation (DIC) that can result in life-threatening hemorrhagic complications. In 2008, the anticoagulant thrombomodulin alfa (TM-α, recombinant human soluble thrombomodulin) was approved for the treatment of DIC in Japan. After commercial launch, only small case series have been described in APL patients, and data from larger patients cohort are awaited. We accessed the clinical safety and beneficial effects of TM-α treatment in DIC patients with APL, by evaluating data on the open-label, multicenter, post-marketing surveillance study cohort.

Patients andMethods

A retrospective evaluation was carried out on a cohort of 172 patients with APL from the open-label, multicenter, post-marketing surveillance study of TM-α in Japan. Of all 172 patients, 31 were relapse/refractory APL patients and 141 were newly diagnosed. The newly diagnosed APL patients were generally received all-trans retinoic acid (ATRA) and anthracycline-containing induction therapy followed by consolidation therapy as previously reported by the Japan Adult Leukemia Study Group (Yanada et al, Eur. J. Haematol. 2007). The relapse/refractory APL patients were received arsenic trioxide, tamibarotene, and/or gemtuzumab ozogamicin. Early death (death within 30 days from the start of antileukemic treatment), severe hemorrhagic events, and the improvement of coagulopathy were analyzed.

Results

The study population consisted of 97 males and 75 females, with a median age of 58 (range 10 - 88). TM-α was administration by 380 ± 52.5 U/kg/day and the duration of dosing was 7.0 ± 6.3 days. In most patients (81 %), TM-α was started on or before the start of antileukemic treatment. Within the first 30 days, 12 patients (7 %) had severe hemorrhage and there were 24 (14 %) early deaths. Six of those (3.5% of 172 patients) were due to hemorrhage. TM-α treatment rapidly and significantly improved coagulopathy regardless of concomitant ATRA treatment (Table 1).

Table 1

Amount (or rate) of change in hemostatic parameters before and after TM-α administration

With ATRAWithout ATRAp
Median (Q1, Q3)nMedian (Q1, Q3)n
Rate of change      
 FDP -0.8 (-0.9, -0.6) 97 -0.9 (-0.9, -0.7) 46 .483 
 TAT -0.8 (-0.9, -0.8) 21 -0.8 (-0.9, -0.6) 12 .139 
 PIC -0.8 (-0.9, -0.6) 22 -0.8 (-0.9, -0.6) 12 .732 
Amount of change      
 Fibrinogen, mg/dL 85 (19,154) 111 84 (42,181) 43 .635 
 PT ratio -0.11 (-0.25, -0.01) 108 -0.11 (-0.24, 0.01) 45 .750 
 APTT, sec 1.4 (-1.0, 5.6) 102 1.1 (-2.4, 4.3) 41 .311 
 Platelet count, x 104/μL 1.7 (0.2, 3.5) 113 0.0 (-1.3, 1.6) 50 <.001 
 AT, % -2.0 (-11.0, 11.0) 53 -6.0 (-13.5, -1.0) 23 .163 
 PC, % 27.5 (18.0, 39.8) 8 0 (-5.0, 14.8) 7 .073 
With ATRAWithout ATRAp
Median (Q1, Q3)nMedian (Q1, Q3)n
Rate of change      
 FDP -0.8 (-0.9, -0.6) 97 -0.9 (-0.9, -0.7) 46 .483 
 TAT -0.8 (-0.9, -0.8) 21 -0.8 (-0.9, -0.6) 12 .139 
 PIC -0.8 (-0.9, -0.6) 22 -0.8 (-0.9, -0.6) 12 .732 
Amount of change      
 Fibrinogen, mg/dL 85 (19,154) 111 84 (42,181) 43 .635 
 PT ratio -0.11 (-0.25, -0.01) 108 -0.11 (-0.24, 0.01) 45 .750 
 APTT, sec 1.4 (-1.0, 5.6) 102 1.1 (-2.4, 4.3) 41 .311 
 Platelet count, x 104/μL 1.7 (0.2, 3.5) 113 0.0 (-1.3, 1.6) 50 <.001 
 AT, % -2.0 (-11.0, 11.0) 53 -6.0 (-13.5, -1.0) 23 .163 
 PC, % 27.5 (18.0, 39.8) 8 0 (-5.0, 14.8) 7 .073 

The rate of change was defined as the value at the end of TM-α administration divided by the value at baseline. The amount of change was defined as the value at the end of TM-α administration minus the value at baseline divided by the value at baseline.

ATRA, all-trans retinoic acid; FDP, fibrin and fibrinogen degradation products; TAT, thrombin-antithrombin complex; PIC, plasmin α2-plasmin inhibitor complex; PT, prothrombin time; APTT, activated partial thromboplastin time; AT, antithrombin; PC, protein C

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Conclusions

Although anticoagulation therapy during APL chemotherapy may induce severe hemorrhagic complication, our findings suggest that supportive care with TM-α ameliorates coagulopathy and reduces the risk of hemorrhagic early deaths in patients with APL.

Disclosures:

Watanabe:Asahi Kasei Pharma Corporation: Employment. Honda:Asahi Kasei Pharma Corporation: Employment.

Topics:
acute promyelocytic leukemia, disseminated intravascular coagulation, thrombomodulin, tretinoin, activated partial thromboplastin time measurement, blood coagulation disorders, antithrombin iii, antithrombins, hemorrhage, plasmin

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2013 by The American Society of Hematology
2013
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