Clinical Features of DIC According to the French-american-british (FAB) Classification in Patients With Acute Leukemia and Thrombomodulin Alfa Treatment – Cross-sectional Analysis of a Post-marketing Surveillance Study Cohort –

doi:10.21203/rs.3.rs-262863/v1

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Clinical Features of DIC According to the French-american-british (FAB) Classification in Patients With Acute Leukemia and Thrombomodulin Alfa Treatment – Cross-sectional Analysis of a Post-marketing Surveillance Study Cohort –

https://doi.org/10.21203/rs.3.rs-262863/v1

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Background: The aims of this study were to analyze the clinical features of a large number of cases with disseminated intravascular coagulation (DIC) associated with acute leukemia, and to clarify the safety and efficacy of thrombomodulin alfa (TM-α) using the French-American-British (FAB) classification of hematological malignancies.

Methods: We retrospectively examined 644 patients with acute leukemia in post-marketing surveillance for TM-α.

Results: M3, M2, M4, M1, and M5 subtypes of acute myeloid leukemia (AML), and L2 and L1 subtypes of acute lymphoblastic leukemia (ALL) have been found more frequently among patients with DIC. Bleeding symptoms at baseline were more frequent in M3 and M7 subtypes. Fibrinogen concentrations were lower and plasmin-plasmin inhibitor complex values were higher in M3 and Philadelphia-positive (Ph+) ALL. Overall DIC resolution rate was 60.2% with higher rates in L1 and Ph+ ALL, lower in M1, and generally higher in ALL than in AML. The overall survival rate was 79.8%, generally high, with higher survival rates in L3, Ph+ ALL, and M3. In M3 and M7, with high frequencies of pre-existing bleeding, TM-α improved bleeding symptoms. Post-administration DIC scores in each subtype were significantly improved compared with pre-administration scores, except in M6, M7, and MDS-overt AML.

Conclusions: This study showed the clinical features of DIC associated with acute leukemia among FAB classifications and also elucidated the safety and efficacy profiles of TM-α by detailed classification based on the FAB classification in clinical practice.

Trial registration: The clinical characteristics and treatment outcomes of patients with DIC treated with TM-α between May 2008 and April 2010 were retrospectively analyzed by subgroup analysis of post-marketing surveillance data.

Internal Medicine

disseminated intravascular coagulation

hematological malignancy

FAB classification

thrombomodulin

post-marketing surveillance

Disseminated intravascular coagulation (DIC) associated with hematological malignancy is understood as a type of DIC that exhibits hemorrhagic tendencies with hypercoagulation and hyperfibrinolysis [1, 2]. However, hematological malignancies include a wide variety of diseases, such as leukemia, malignant lymphoma, and multiple myeloma. In addition, various pathological conditions such as acute, chronic, myeloid, and lymphoid types are included under the concept of leukemia. DIC associated with hematological malignancy should therefore be considered by disease subtype.

The French-American-British (FAB) classification [3] and the World Health Organization (WHO) classification have both been used to classify hematological malignancy. The WHO classification has been widely used in clinical practice, but the FAB classification is also still used. Within the field of DIC research into hematological malignancies, analysis according to the FAB classification has been historically reported [4–6]. The FAB classification is still useful, when cytogenetic information of acute myeloid leukemia has not been fully obtained for the WHO classification.

The frequency of DIC appears higher in acute myeloid leukemia (AML) than in acute lymphoblastic leukemia (ALL) [4]. Within AMLs, the frequency of DIC is known to be particularly higher in M3, such as acute promyelocytic leukemia (APL) [4]. APL is most frequently associated with hyperfibrinolytic-type DIC and presents with bleeding manifestations, due to the overexpression of annexin II on APL cells. Among AMLs (other than APL), M5, M1, M4, and M2 subtypes have been found more frequently in patients with DIC [4]. Among ALLs, the frequency of DIC was higher in T-cell ALL than in non-T-cell ALL, and higher in L2 than in L1 [4]. Among children, L2 in ALL and M3, M4, and M5 in AML were found more frequently in patients with DIC [5]. Although some reports have described the incidence and clinical significance of DIC using FAB classifications like these, all such reports are quite old (published between 1986 and 2007), focused on AML and ALL, and included only limited numbers of DIC cases. No recent comprehensive epidemiological studies on DIC have thus focused on hematological malignancies as a broad group.

Thrombomodulin alfa (TM-α) is a recombinant human soluble thrombomodulin. We have previously investigated the efficacy and safety of TM-α in a multicenter, randomized, clinical trial in Japan [6]. We showed that both resolution rate and disappearance rate of bleeding symptoms were significantly better in the TM-α group than in the heparin group among patients with DIC associated with hematological malignancy [6]. TM-α gained approval for the indication of DIC in 2008 in Japan. An all-case registered post-marketing surveillance (PMS) of TM-α has since been conducted [7]. Asakura et al. reported the safety and effectiveness of TM-α, with a focus on patients with DIC associated with hematological malignancy according to underlying diseases such as AML, APL, ALL, lymphoma, myelodysplastic syndrome (MDS), and others [8]. This study investigated the clinical features of DIC associated with each acute leukemia group as subdivided by the FAB classification, and clarified the safety and efficacy of TM-α according to detailed classifications based on the FAB classification.

Design and Data Collection

We conducted this cross-sectional analysis of data from 644 patients with AML and ALL from the PMS study cohort for TM-α (from 2008 to 2010). The PMS for TM-α was conducted in accordance with the Japanese Society on Thrombosis and Hemostasis Post-Marketing Surveillance Committee for Recomodulin Injection and the guidelines for Good Postmarketing Study Practice, as required by the Japanese Ministry of Health, Labour, and Welfare. We used existing data without personally identifiable information throughout our study. This study was therefore exempted from local institutional review and formal approval, as well as the requirement for informed consent. The original PMS study was an open-label, multicenter, non-interventional, prospective, observational cohort study of patients with DIC who received TM-α [7]. The study included a total of 4,342 patients with heterogeneous underlying diseases treated using TM-α. The subject cohort population in the present analysis was restricted to all patients with DIC associated with hematological malignancy.

Patients were consecutively registered at the initiation of TM-α treatment and were prospectively monitored during the observation period. All patients received TM-α for the treatment of DIC according to the package insert for Recomodulin Injection. The standard dose of TM-α was 380 U/kg/day, the same dose used in the previous phase III trial (0.06 mg/kg/day) [6]. No limitation was placed on either the administration period of TM-α or the concomitant use of other anticoagulant drugs, blood preparations, or any drugs for the treatment of complications. Patients were diagnosed at the participating institutions. Subtype of hematological malignancy was classified based on the description on the case report form. AML and ALL patients were classified based on the FAB classification or Philadelphia chromosome status as determined at an initial stage of diagnosis or treatment as far as possible.

Evaluation

We investigated the clinical features of DIC associated with hematological malignancy and the safety and efficacy of TM-α by detailed classification. In 644 patients associated with acute leukemia in the PMS, DIC resolution rates, DIC improvement rates, 28-day survival rates, underlying disease improvement rates, clinical course of bleeding symptoms, changes in coagulation and fibrinolytic markers, and rates of adverse drug reaction (ADR) and bleeding-related ADR were investigated by detailed classification based on the FAB classification.

The degree of coagulopathy was evaluated by calculating the DIC score according to the diagnostic criteria of the Japanese Ministry of Health and Welfare (JMHW) or that of the International Society of Thrombosis and Haemostasis (ISTH) (Table S1, see Additional file 1) [9, 10]. DIC resolution rates and DIC improvement rates were evaluated at the end of TM-α administration. Resolved DIC status was defined according to JMHW DIC criteria or ISTH DIC criteria. DIC improvement and underlying disease improvement were both evaluated by the attending physician. The 28-day survival rates were evaluated on Day 28 from the start of TM-α administration. The clinical course of bleeding symptoms was evaluated at the end of TM-α administration, as previously described [6, 7].

Fibrin and fibrinogen degradation products (FDP), D-dimer, platelet count, fibrinogen, prothrombin time (PT) ratio, activated partial thromboplastin time (APTT), thrombin-antithrombin complex (TAT), plasmin-α2 plasmin inhibitor complex (PIC), and antithrombin (AT) were measured at each institute. Changes in coagulation and fibrinolytic markers before and after TM-α administration were evaluated.

Rates of ADR and bleeding-related ADR were evaluated from the start of TM-α administration to Day 28 after the end of TM-α administration. Safety data were coded using preferred terms from the Japanese version of the Medical Dictionary for Regulatory Activities (MedDRA/J).

Data analysis

In the descriptive analysis of baseline characteristics, numerical data are expressed as medians (Q1, Q3; interquartile range). Changes in DIC score from baseline to that of the day after the last administration were examined using the Wilcoxon signed-rank test. Statistical significance was determined with a 2-sided p value < 0.05. P-values were calculated for sample sizes of six or more. All analyses were performed using SAS version 9.4 software (SAS Institute, Cary, NC) by EPS Corporation (Tokyo, Japan) according to the statistical analysis plan. Approval for this study (approval no. 30 − 019) was obtained from the appropriate ethics committees and institutional review boards.

Patient characteristics

A total of 644 patients with DIC associated with acute leukemia from the PMS study cohort for TM-α (May 2008 to April 2010) were analyzed (Fig. 1). Of these, 509 patients had AML and 135 patients had ALL (Table 1). AML was subdivided into nine subtypes: M0 (n = 24); M1 (n = 52); M2 (n = 133); M3 (n = 168); M4 (n = 54); M5 (n = 48); M6 (n = 12); M7 (n = 7); and MDS-overt AML (n = 11). ALL was subdivided into four subtypes: L1 (n = 37); L2 (n = 72); L3 (n = 9); and Philadelphia-positive (Ph+) ALL (n = 17). Baseline characteristics of the 644 patients are shown by underlying disease in Table 1.

Table 1

Baseline demographics and TM-a administration regimens by subtype.
Subtype	AML (n=509)
Subtype	M0	M1	M2	M3	M4	M5	M6		M7		MDS-overt AML
n	24	52	133	168	54	48	12		7		11
Age (years), n	67.5 (31.5, 77), 24	61 (49.5, 71.5), 52	64 (55, 70), 133	58 (44, 70), 167	63 (48, 72), 54	57 (29, 71), 48	58.5 (53, 67), 12		4 (1, 60), 7		68 (52, 77), 11
Sex: male	21 (87.5)	29 (55.8)	77 (57.9)	96 (57.1)	35 (64.8)	35 (72.9)	9 (75.0)		5 (71.4)		8 (72.7)
Severity of underlying disease: mild/moderate/severe/unknown	2 / 7 / 15 / 0	5 / 12 / 35 / 0	7 / 32 / 93 / 1	10 / 46 / 112 / 0	2 / 10 / 42 / 0	2 / 14 / 32 / 0	0 / 0 / 12 / 0		0 / 0 / 7 / 0		1 / 2 / 8 / 0
History of CNS bleeding risk	1 (4.2)	4 (7.7)	8 (6.0)	14 (8.3)	2 (3.7)	3 (6.3)	0 (0.0)		1 (14.3)		0 (0.0)
DIC duration before TM-α (days), n	0 (0, 1.5), 24	0 (0, 1), 52	0 (0, 1), 133	0 (0, 1), 168	0 (0, 1), 54	0 (0, 1.5), 48	0 (0, 1), 12		5 (1, 8), 7		0 (0, 2), 11
Bleeding symptoms at baseline	7 (29.2)	18 (34.6)	35 (26.3)	95 (56.5)	17 (31.5)	14 (29.2)	4 (33.3)		4 (57.1)		2 (18.2)
Organ symptoms at baseline	6 (25.0)	5 (9.6)	23 (17.3)	28 (16.7)	10 (18.5)	17 (35.4)	3 (25.0)		6 (85.7)		4 (36.4)
Dose of TM-α (U/kg/day), n	379 (277, 381), 24	380 (372, 382), 52	380 (363, 380), 133	380 (370, 381), 168	380 (351, 380), 53	373 (330, 380), 48	380 (359, 380), 12		348 (320, 422), 7		373 (275, 380), 11
Duration of TM-α use (days), n	6 (5, 7), 24	6 (4.5, 7), 52	6 (5, 7), 133	7 (6, 8.5), 168	6 (6, 7), 54	6 (3.5, 6), 48	5.5 (3, 6.5), 12		6 (3, 12), 7		7 (6, 8), 11
FDP (μg/mL), n	31.9 (21.6, 99.6), 24	58.5 (26.3, 130.3), 48	39.9 (21.0, 107.0), 122	67.4 (38.7, 112.4), 159	44.6 (19.9, 112.0), 49	55.7 (29.3, 95.9), 44	46.0 (28.0, 85.0), 9		40.6 (21.0, 63.2), 4		41.5 (12.6, 120.0), 11
D-dimer (μg/mL), n	18.1 (7.7, 38.6), 14	28.9 (7.0, 69.6), 36	20.0 (8.6, 39.1), 93	26.0 (9.5, 54.2), 138	22.0 (7.2, 45.0), 33	24.6 (15.3, 55.2), 33	8.6 (1.5, 29.3), 9		10.2 (4.7, 45.0), 6		16.5 (9.9, 60.0), 10
Fibrinogen (mg/dL), n	273 (146, 436), 23	292 (142, 466), 49	281 (189, 396), 127	127 (84, 216), 166	275 (167, 390), 52	173 (105, 338), 47	378 (282, 459), 12		466 (435, 500), 7		161 (133, 226), 11
PT ratio, n	1.23 (1.18, 1.34), 24	1.26 (1.15, 1.41), 46	1.25 (1.14, 1.39), 121	1.25 (1.14, 1.44), 158	1.26 (1.12, 1.43), 48	1.32 (1.18, 1.63), 41	1.21 (1.17, 1.40), 11		1.11 (1.02, 1.14), 7		1.29 (1.21, 1.44), 10
APTT (s), n	36.0 (28.7, 45.3), 21	33.6 (28.6, 38.1), 47	34.1 (30.0, 40.0), 126	29.6 (27.0, 33.8), 161	36.4 (32.2, 42.3), 51	37.0 (32.6, 41.5), 46	35.1 (31.4, 41.6), 12		41.7 (31.5, 53.9), 6		40.8 (36.1, 52.2), 11
TAT (ng/mL), n	3.8 (1.2, 6.4), 2	16.7 (9.6, 55.7), 14	16.1 (7.7, 30.9), 39	31.7 (16.8, 48.5), 63	17.5 (11.3, 35.3), 19	18.3 (10.8, 29.6), 16	6.5 (3.4, 24.7), 3		17.2 (10.6, 23.7), 2		17.6 (8.8, 46.2), 6
PIC (μg/mL), n	5.2 (3.1, 13.6), 4	9.4 (3.8, 13.2), 15	4.6 (2.4, 8.4), 33	12.7 (9.4, 16.3), 59	4.4 (2.1, 9.2), 18	5.0 (3.1, 16.4), 15		8.7 (5.5, 14.9), 4	3.5 (0.0, 6.9), 2	2.4 (1.3, 4.6), 5
AT (%), n	70.0 (64.0, 82.1), 13	84.6 (74.0, 97.6), 30	86.0 (70.4, 97.0), 90	105.0 (89.0, 114.0), 123	81.8 (71.0, 93.0), 37	88.0 (81.0, 104.0), 33		86.0 (58.2, 102.1), 7	75.8 (70.0, 87.0), 6	67.5 (49.9, 81.6), 8

Subtype	ALL (n=135)
Subtype	L1	L2	L3	Ph+ ALL
n	37	72	9	17
Age (years), n	26 (10, 59), 37	52 (28.5, 66), 72	44 (26, 64), 9	56 (35, 67), 17
Sex: male	22 (59.5)	36 (50.0)	8 (88.9)	8 (47.1)
Severity of underlying disease: mild/moderate/severe/unknown	3 / 12 / 22 / 0	2 / 22 / 48 / 0	0 / 3 / 6 / 0	3 / 2 / 12 / 0
History of CNS bleeding risk	1 (2.7)	4 (5.6)	1 (11.1)	1 (5.9)
DIC duration before TM-α (days), n	0 (0, 1), 37	0 (0, 1), 72	0 (0, 1), 9	0 (0, 1), 17
Bleeding symptoms at baseline	9 (24.3)	26 (36.1)	2 (22.2)	3 (17.6)
Organ symptoms at baseline	7 (18.9)	17 (23.6)	3 (33.3)	4 (23.5)
Dose of TM-α (U/kg/day), n	380 (366, 384), 37	380 (372, 380), 72	376 (342, 380), 9	380 (366, 386), 17
Duration of TM-α use (days), n	6 (4, 7), 37	6 (6, 8), 72	6 (5, 6), 9	6 (6, 7), 17
FDP (μg/mL), n	36.2 (21.5, 87.4), 30	39.4 (21.2, 94.2), 64	61.4 (35.4, 76.2), 6	40.5 (27.5, 149.0), 16
D-dimer (μg/mL), n	11.7 (2.5, 21.7), 21	18.2 (5.8, 36.7), 53	34.1 (26.9, 54.5), 7	30.0 (6.7, 111.8), 15
Fibrinogen (mg/dL), n	270 (134, 395), 34	259 (145, 403), 71	252 (126, 413), 9	196 (131, 310), 16
PT ratio, n	1.23 (1.12, 1.37), 31	1.22 (1.10, 1.41), 66	1.19 (1.07, 1.32), 9	1.14 (1.09, 1.28), 16
APTT (s), n	33.5 (27.1, 43.4), 35	34.7 (28.1, 42.2), 67	32.8 (26.6, 43.2), 9	26.2 (24.4, 32.2), 15
TAT (ng/mL), n	6.2 (4.6, 55.6), 6	20.4 (14.5, 27.1), 20	47.6 (47.6, 47.6), 1	29.8 (18.7, 50.2), 6
PIC (μg/mL), n	1.3 (1.3, 3.9), 5	5.5 (3.2, 7.3), 22	5.5 (1.4, 9.6), 2	11.4 (6.1, 13.0), 6
AT (%), n	86.5 (75.0, 103.5), 24	91.0 (76.0, 105.0), 50	66.8 (53.0, 89.1), 5	109.5 (95.0, 120.9), 12

Data are given as n (%) or median (IQR). TM-α, thrombomodulin alfa; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndromes; Ph+, Philadelphia-positive; CNS, central nervous system; DIC, disseminated intravascular coagulation; FDP, fibrin and fibrinogen degradation products; PT, prothrombin time; APTT, activated partial thromboplastin time; TAT, thrombin-antithrombin complex; PIC, plasmin α2-plasmin inhibitor complex; AT, antithrombin.

The proportion of male patients was higher (≥70%) as compared to females in M0, M5, M6, M7, MDS-overt AML, L1, and L3. Median age for most of these diseases was around 52–68 years, with the exceptions of M7 (4 years), L1 (26 years), and L3 (44 years). Frequency of bleeding symptoms at baseline ranged from about 20–35% for many subtypes and was low in Ph + ALL (17.6%) and MDS-overt AML (18.2%), and high in M7 (57.1%) and M3 (56.5%). Median duration of DIC before TM-α administration was 0 days; that is, TM-α was administered on the same day as DIC diagnosis, except for M7 (5 days). Median duration of TM-α administration was 6–7 days, except for M6 (5.5 days). Median dose was near 380 U/kg/day.

Clinical features at baseline

Clinical features at baseline are shown in Table 1. Markedly abnormal values of each hemostatic marker were as follows. Median concentration of FDP at baseline was > 40 µg/mL for M3 (67.4 µg/mL), L3 (61.4 µg/mL), M1 (58.5 µg/mL), M5 (55.7 µg/mL), M6 (46.0 µg/mL), M4 (44.6 µg/mL), M7 (40.6 µg/mL), and Ph + ALL (40.5 µg/mL). Median concentration of D-dimer at baseline was > 20 µg/mL for L3 (34.1 µg/mL), Ph + ALL (30.0 µg/mL), M1 (28.9 µg/mL), M3 (26.0 µg/mL), M5 (24.6 µg/mL), and M4 (22.0 µg/mL). Median concentration of fibrinogen at baseline was < 150 mg/dL for M3 (127 mg/dL), and > 400 mg/dL for M7 (466 mg/dL). Median PT ratio at baseline was > 1.25 for M5 (1.32), MDS-overt AML (1.29), M4 (1.26), and M1 (1.26). Median APTT at baseline was > 40 s for M7 (41.7 s) and MDS-overt AML (40.8 s). Median AT at baseline was ≤70% for L3 (66.8%) and MDS-overt AML (67.5%). Although the number of cases was small, median TAT at baseline was > 30.0 ng/mL for L3 (47.6 ng/mL) and M3 (31.7 ng/mL), and median PIC at baseline was > 10 µg/mL for M3 (12.7 µg/mL) and Ph + ALL (11.4 µg/mL).

Safety

Safety outcomes are shown in Table 2. The ADR rate was high in M6 (16.7%), L3 (11.1%), and L1 (10.8%). The serious ADR rate was high in L3 (11.1%). The bleeding-related ADR rate was > 5% for L3 (11.1%), L1 (8.1%), Ph + ALL (5.9%), M1 (5.8%), M4 (5.6%), and M2 (5.3%). The serious bleeding-related ADR rate was > 5% for L3 (11.1%) and L1 (8.1%).

Table 2

Safety outcomes of TM-α in DIC patients associated with hematological malignancy by subtypes.
Subtype	AML									ALL
	M0	M1	M2	M3	M4	M5	M6	M7	MDS-overt AML	L1	L2	L3	Ph + ALL
Adverse drug reaction (ADR) rate	0.0 (0/24)	7.7 (4/52)	6.0 (8/133)	7.1 (12/168)	7.4 (4/54)	4.2 (2/48)	16.7 (2/12)	0.0 (0/7)	0.0 (0/11)	10.8 (4/37)	1.4 (1/72)	11.1 (1/9)	5.9 (1/17)
Bleeding-related ADR rate	0.0 (0/24)	5.8 (3/52)	5.3 (7/133)	3.6 (6/168)	5.6 (3/54)	4.2 (2/48)	0.0 (0/12)	0.0 (0/7)	0.0 (0/11)	8.1 (3/37)	1.4 (1/72)	11.1 (1/9)	5.9 (1/17)
Serious ADR rate	0.0 (0/24)	1.9 (1/52)	3.0 (4/133)	2.4 (4/168)	3.7 (2/54)	4.2 (2/48)	0.0 (0/12)	0.0 (0/7)	0.0 (0/11)	8.1 (3/37)	1.4 (1/72)	11.1 (1/9)	0.0 (0/17)
Serious bleeding-related ADR rate	0.0 (0/24)	1.9 (1/52)	3.0 (4/133)	1.8 (3/168)	3.7 (2/54)	4.2 (2/48)	0.0 (0/12)	0.0 (0/7)	0.0 (0/11)	8.1 (3/37)	1.4 (1/72)	11.1 (1/9)	0.0 (0/17)
TM-α, thrombomodulin alfa; DIC, disseminated intravascular coagulation; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; ALL, acute lymphoblastic leukemia; Ph+, Philadelphia-positive.

Efficacy

Efficacy outcomes are shown in Table 3. JMHW DIC resolution rates ranged from 45.5–94.7%. The DIC resolution rate was > 70% for L1 (94.4%) and Ph + ALL (88.9%), and < 50% for M1 (45.5%). The 28-day survival rate was > 80% for L3 (100%), Ph + ALL (88.2%), M3 (86.9%), L2 (86.1%), L1 (83.3%), and M1 (82.7%), and < 60% for MDS-overt AML (54.5%) and M7 (57.1%). The improvement rate of the underlying disease was > 60% for L3 (77.8%), M6 (75%), M3 (74.9%), L2 (68.1%), M1 (67.3%), M4 (66.7%), and L1 (62.2%), and < 40% for MDS-overt AML (18.2%). In M3 and M7, in which the frequency of pre-existing bleeding was high (at 56.5% and 57.1%, respectively, Table 1), the ratios of disappeared, improved, or unchanged symptoms in the clinical course of bleeding symptoms after administration of TM-α were 94.7% and 100%, respectively. The ratio of disappeared, improved, or unchanged symptoms in the clinical course of bleeding symptoms after administration of TM-α was > 70% for all subtypes. The ratio of exacerbated symptoms was > 20% for M5 (28.6%) and M4 (21.4%) (Table 3).

Table 3

Efficacy outcomes of TM-α in DIC patients associated with hematological malignancy by subtypes.
Subtype		AML									ALL
Subtype		M0	M1	M2	M3	M4	M5	M6	M7	MDS overt AML	L1	L2	L3	Ph + ALL
JMHW DIC resolution rate		66.7 (12/18)	45.5 (15/33)	57.0 (45/79)	57.7 (75/130)	58.8 (20/34)	60.7 (17/28)	50.0 (3/6)	50.0 (2/4)	50.0 (4/8)	94.4 (17/18)	65.3 (32/49)	66.7 (4/6)	88.9 (8/9)
28-day survival rate		70.8 (17/24)	82.7 (43/52)	78.2 (104/133)	86.9 (146/168)	72.2 (39/54)	63.8 (30/47)	66.7 (8/12)	57.1 (4/7)	54.5 (6/11)	83.8 (31/37)	86.1 (62/72)	100 (9/9)	88.2 (15/17)
Clinical improvement rate of understanding diseases		45.8 (11/24)	67.3 (35/52)	56.4 (75/133)	74.9 (125/167)	66.7 (36/54)	47.9 (23/48)	75.0 (9/12)	42.9 (3/7)	18.2 (2/11)	62.2 (23/37)	68.1 (49/72)	77.8 (7/9)	58.8 (10/17)
Clinical course of bleeding symptoms	(i) Disappeared	28.6 (2/7)	38.9 (7/18)	40.0 (14/35)	57.4 (54/94)	64.3 (9/14)	35.7 (5/14)	0.0 (0/4)	25.0 (1/4)	0.0 (0/1)	33.3 (3/9)	52.0 (13/25)	0.0 (0/1)	66.7 (2/3)
	(ii) Improved	0.0 (0/7)	22.2 (4/18)	8.6 (3/35)	13.8 (13/94)	7.1 (1/14)	0.0 (0/14)	0.0 (0/4)	0.0 (0/4)	0.0 (0/1)	22.2 (2/9)	12.0 (3/25)	100 (1/1)	0.0 (0/3)
	(iii) Unchanged	57.1 (4/7)	22.2 (4/18)	42.9 (15/35)	23.4 (22/94)	7.1 (1/14)	35.7 (5/14)	100 (4/4)	75.0 (3/4)	100 (1/1)	22.2 (2/9)	24.0 (6/25)	0.0 (0/1)	33.3 (1/3)
	(i) + (ii) + (iii)	85.7 (6/7)	83.3 (15/18)	91.4 (32/35)	94.7 (89/94)	78.6 (11/14)	71.4 (10/14)	100 (4/4)	100 (4/4)	100 (1/1)	77.8 (7/9)	88.0 (22/25)	100 (1/1)	100 (3/3)
	(iv) Exacerbated	14.3 (1/7)	16.7 (3/18)	8.6 (3/35)	5.3 (5/94)	21.4 (3/14)	28.6 (4/14)	0.0 (0/4)	0.0 (0/4)	0.0 (0/1)	22.2 (2/9)	12.0 (3/25)	0.0 (0/1)	0.0 (0/3)
TM-α, thrombomodulin alfa; DIC, disseminated intravascular coagulation; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; ALL, acute lymphoblastic leukemia; Ph+, Philadelphia-positive; JMHW, Japanese Ministry of Health and Welfare.

Changes in coagulation and fibrinolysis markers

Changes in DIC score during TM-α administration are shown in Fig. 2. Although median JMHW DIC score at baseline was higher for M1, M3, and M5, the post-administration DIC scores for each subtype were significantly improved compared with those pre-administration, except in M6, M7, and MDS-overt AML. A comparison of changes in coagulation and fibrinolysis markers that could be measured both before and after TM-α treatment by subtype is presented in Table S2 (see Additional file 2). High median values of FDP before TM-α administration was 67.2 µg/mL, 62.9 µg/mL, and 61.4 µg/mL for M3, M5, and L3, respectively, improving to 8.6 µg/mL, 10.6 µg/mL, and 8.5 µg/mL, respectively, after TM-α administration. High median values of DD before TM-α administration was 34.1 µg/mL, 32.2 µg/mL, 30.0 µg/mL, 26.9 µg/mL, and 37.9 µg/mL for L3, Ph + ALL, M1, M3, and M5, respectively, improving to 11.9 µg/mL, 4.7 µg/mL, 5.2 µg/mL, 4.0 µg/mL, and 7.2 µg/mL after TM-α administration. Abnormal fibrinogen before TM-α administration was 125 mg/dL for M3, but normalized to 243 mg/dL after TM-α administration. High median values of PT ratio before TM-α administration was 1.32 for M5, respectively, improving to 1.11 after TM-α administration. The low median values of AT before TM-α administration was 66.8% for L3, improving to 90.4% after TM-α administration. High median values of TAT before TM-α administration was 37.6 ng/mL and 31.4 ng/mL for M1 and M3, respectively, but improved to 8.5 ng/mL and 4.8 ng/mL after TM-α administration. High median values of PIC before TM-α administration was 16.4 µg/mL, 13.2 µg/mL, and 12.5 µg/mL for L1, M1, and M3, respectively, improving to 0.6 µg/mL, 2.6 µg/mL, and 2.1 µg/mL after TM-α administration.

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 [3].

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 [5], and Fenaux et al. reported that lethal bleeding due to DIC associated with APL was a major cause of remission failure [11]. 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 [12]. 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 [13]. 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 [14]. 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 [17]. Bleeding was often severe in adults with L2 and L1 [18]. 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 [8]. 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% [8].

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.

This study showed the clinical features of DIC associated with acute leukemia according to FAB classifications, and also provided safety and efficacy profiles of TM-α by detailed classifications based on the FAB classification in clinical practice.

DIC, disseminated intravascular coagulation; FAB, French-American-British; TM-α, thrombomodulin alfa; AML, acute myeloid leukemia; ALL, acute lymphoid leukemia; Ph+, Philadelphia-positive; APL, acute promyelocytic leukemia; PMS, post-marketing surveillance; MDS, myelodysplastic syndromes; ADR, adverse drug reaction; JMHW, Japanese Ministry of Health and Welfare; ISTH, International Society of Thrombosis and Haemostasis; FDP, fibrin and fibrinogen degradation products; PT, prothrombin time; APTT, activated partial thromboplastin time; TAT, thrombin-antithrombin complex; PIC, plasmin-α2 plasmin inhibitor complex; AT, antithrombin

Ethics approval and consent to participate:

Approval for this study (No. 30-019) was obtained from the appropriate ethics committees and institutional review boards of Uonuma Institute of Community Medicine.

Consent for publication:

Not applicable.

Availability of data and materials:

The data that support the findings of this study are available from Asahi Kasei Pharma Corporation but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.

Competing interests:

Yoshinobu Seki, Toshimasa Uchiyama, Seiji Madoiwa, and Naoki Takezako received personal fees from Asahi Kasei Pharma Corporation outside the present work. Kazuo Kawasugi and Takayuki Ikezoe received grants and personal fees from Asahi Kasei Pharma Corporation outside the present work. Noriaki Kawano has not received any grants or personal fees. Hideo Wada received grants and personal fees from Asahi Kasei Pharma Corporation and Japan Blood Products Organization outside the present work. Goichi Honda is an employee of Asahi Kasei Pharma Corporation.

Funding:

This work was supported by Asahi Kasei Pharma Corporation, which funded the analysis and English editing of the manuscript.

Authors' contributions:

YS planned the study design, interpreted the data and wrote the manuscript. YS provided oversight and supervised the current study. NK, TU, KK, SM, NT, TI, and HW advised on study design and interpretation of the data, and reviewed the manuscript. GH planned the study design.

Acknowledgments:

We would like to thank all investigators who participated in this PMS study. We express our sincere appreciation to Ms. Hideyo Ohshige and Ms. Fumiyo Komatsu for their helpful suggestions.

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Additionalfile1.doc
Table S1 Diagnostic criteria for DIC defined in this study.
Additionalfile2.doc
Table S2 Changes in coagulation and fibrinolysis markers during treatment by subtype.

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Clinical Features of DIC According to the French-american-british (FAB) Classification in Patients With Acute Leukemia and Thrombomodulin Alfa Treatment – Cross-sectional Analysis of a Post-marketing Surveillance Study Cohort –

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Clinical features at baseline

Safety

Efficacy

Changes in coagulation and fibrinolysis markers

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