DIC associated with hematological malignancy is understood to be a type of DIC that exhibits a hemorrhagic tendency with hypercoagulation and hyperfibrinolysis [1, 2], but no reports appear to have investigated the characteristics of DIC by detailed classification regarding disease type. We investigated the clinical features of DIC associated with hematological malignancy, especially acute leukemias, and the safety and efficacy of TM-α by detailed classification based on the FAB classification .
Among AML, M3 was the most common in this cohort, and TM-α was used for many cases of DIC with bleeding. Next, TM-α was used for DIC associated with M2, M4, M1, and M5; DIC can therefore be seen to be widely associated with AML subtype. Among ALL, L2 was the most common in this cohort, followed by L1. These results were consistent with reports that DIC is frequently associated with M3, M5, M1, M4, M2 of AML, and L2 of ALL [4, 5]. Furthermore, this study revealed that many cases of DIC are seen in other L1.
Among coagulation and fibrinolysis markers, FDP or D-dimer was high in almost all DIC associated with hematological malignancy, indicating that DIC associated with hematological malignancy is characterized by hypercoagulation and hyperfibrinolysis. Ribeiro et al. showed that DIC was associated with a decrease in the remission rate of acute leukemia, reducing outcomes in children , and Fenaux et al. reported that lethal bleeding due to DIC associated with APL was a major cause of remission failure . Uchiumi et al. reported that the survival period tended to be longer in the non-DIC group than in the DIC group among cases of AML (except for APL), although the difference was not significant . Dixit et al. considered that careful monitoring for DIC was necessary in all cases, because DIC associated with leukemia showed bleeding symptoms in 40.3% and leukemia patients developed DIC associated with bleeding or infection after day 7 from start of chemotherapy . These are important data that DIC or coagulopathy associated with hematological malignancy and during chemotherapy are directly linked to treatment results and the prognosis of patients.
M3 and Ph + ALL showed typical hyperfibrinolytic DIC characteristics with high PIC and low fibrinogen level. In most DIC pathologies, FDP and D-dimer increase in parallel. However, in hyperfibrinolytic DIC, not only fibrin degradation, but also fibrinogen degradation progresses, and a dissociation between FDP and D-dimer values (that is, a significant FDP increase and slight D-dimer increase) are observed. Avvisati et al. reported that M3 patients with hyperfibrinolysis showed sufficiently increased plasmin activity to develop acquired α2-antiplasmin deficiency . Also in this cohort, in M3, a dissociation between FDP and D-dimer values was observed. On the other hand, no such dissociation between FDP and D-dimer values was observed in Ph + ALL, because annexin II expression on these cells appeared to be not as high as in M3. In M7, APTT was prominently extended, and bleeding symptoms at baseline were frequent.
In this cohort, the frequency of bleeding symptoms at baseline ranged from about 30–40% for acute leukemia and from about 10–30% for non-leukemia. Frequency of bleeding symptoms at baseline was > 50% for M7 (57.1%) and M3 (56.5%). The most common pathological classification causing fatal cerebral hemorrhage was M3 (43.9%), which requires treatment and hemostasis management [15, 16]. Fibrinogen < 100 mg/dL was a risk of bleeding in studies on adult ALL . Bleeding was often severe in adults with L2 and L1 . Serious bleeding during induction of M3 was significantly associated with low fibrinogen and high white blood cell counts of ≥20,000/µL in addition to PT prolongation [19, 20]. The findings of the present study are consistent with these reports.
Asakura et al. reported the safety and effectiveness of TM-α focusing on patients with DIC associated with hematological malignancy according to underlying diseases such as AML, APL, ALL, lymphoma, MDS, and “other” in the same cohort as this study . In that report, the overall JMHW DIC resolution rate was 55.9%, the overall 28-day survival rate was 70.7%, the overall ADR rate was 6.3%, and the bleeding-related ADR rate was 4.6% .
The DIC resolution rate ranged from 45.5–94.4%, and the 28-day survival rate ranged from 54.5–100% among subtypes. The DIC resolution rate increased in the order of L1 and Ph + ALL, all of which exceeded 70%, indicating that the DIC resolution rate was generally high for lymphoid tumors and generally low for M6, M7, and MDS-overt AML. The 28-day survival rate increased in the order of L3, Ph + ALL, M3, L2, L1, and M1, indicating that the survival rate was generally high for lymphoid tumors and myeloid tumor such as M3 and M1, and generally low for M7 and MDS-overt AML.
The DIC resolution rate and the 28-day survival rate approximate the percentage improvements in the underlying disease. Thus, supportive therapy such as DIC treatment becomes important with the appropriate chemotherapy in the early days of AML and ALL.
In M3 and M7, in which the frequency of pre-existing bleeding was high, the total ratios of disappeared, improved, or unchanged symptoms in the clinical course of bleeding symptoms after TM-α administration were 94.7% and 100%, respectively, indicating that TM-α, which has both anticoagulant and antifibrinolytic effects, may represent a good treatment for those types of DIC that exhibit hemorrhagic tendencies with hypercoagulation and hyperfibrinolysis. Except in M6, M7, and MDS-overt AML, for which there were relatively few cases, DIC scores were significantly improved for most of the treatments in all subgroups.
Some limitations need to be considered when interpreting the results obtained from the present investigation. As all patients in this study were treated with TM-α, investigation of the incidence of DIC and the current status of treatment intervention in Japan was not completely possible. In addition, detailed analyses of the onset of DIC in leukemia, such as whether DIC was due to leukemic disease including kinds of cytogenetic abnormalities, or instead due to treatments such as chemotherapy, could not be examined. However, this investigation was conducted by the continuous registration format and under conditions of actual clinical usage. The FAB classification does not include cytogenetic judgments, but may be applicable in most clinical cases in the DIC treatment of leukemia that gives us many opportunities for determination at an initial stage of diagnosis or treatment. This investigation also provides new useful information about the efficacy and safety profile of TM-α with regard to types of acute leukemia that could not be sufficiently obtained from previous studies.
Epidemiological studies of DIC with leukemia remain limited to old reports. In the future, we must investigate and clarify the incidence, severity, and causes of DIC in true clinical practice, and clarify the characteristics of DIC patients who should be treated using anticoagulant therapy.