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J. Greiner et al.
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Total (n=949) UFH (n=312) Enoxaparin (n=317) Antithrombin (n=320) N(%) N(%) N(%) N(%)
Genetics
t(12;21) / TEL-AML1 Negative
Positive
No information
t(9;22) / BCR-ABL Negative Positive
No information
t(4;11) / MLL-AF4 Negative Positive
No information
Peripheral blast count on day 8 (prednisone response)
< 1x109/L (PGR) ≥ 1x109/L (PPR) No information
Risk group Standard Medium High
MRD at end of induction Negative
<5x10-4
≥5x10-3
No information
MRD at week 12 Negative <5x10-4 ≥5x10-3
No information
Randomized in induction in AIEOP-BFM ALL 2000*
Randomized
assigned to prednisone assigned to dexamethasone
Not randomized
722 (76.1) 199 (21.0) 28 (3.0)
924 (97.4) 25 (2.6) 0 (0.0)
942 (99.3) 7 (0.7) 0 (0.0)
880 (92.7) 65 (6.8) 4 (0.4)
301 (31.7) 512 (54.0) 136 (14.3)
303 (31.9) 316 (33.3) 184 (19.4) 146 (15.4)
579 (61.0) 146 (15.4) 43 (4.5) 181 (19.1)
125 (13.2) 136 (14.3) 688 (72.5)
235 (75.3) 65 (20.8) 12 (3.8)
303 (97.1) 9 (2.9) 0 (0.0)
311 (99.7) 1 (0.3) 0 (0.0)
291 (93.3) 19 (6.1) 2 (0.6)
97 (31.1) 171 (54.8) 44 (14.1)
103 (33.0) 107 (34.2) 57 (18.3) 45 (14.4)
187 (59.9) 53 (17.0) 16 (5.1) 56 (17.9)
39 (12.5) 45 (14.4) 228 (73.1)
245 (77.3) 63 (19.9) 9 (2.8)
309 (97.5) 8 (2.5) 0 (0.0)
314 (99.1) 3 (0.9) 0 (0.0)
295 (93.1) 22 (6.9) 0 (0.0)
101 (32.1) 169 (53.7) 45 (14.3)
104 (32.8) 113 (35.6) 58 (18.3) 42 (13.2)
202 (63.7) 47 (14.8) 12 (3.8) 56 (17.7)
41 (12.9) 45 (14.2) 231 (72.9)
242 (75.6) 71 (22.2) 7 (2.2)
312 (97.5) 8 (2.5) 0 (0.0)
317 (99.1) 3 (0.9) 0 (0.0)
294 (91.9) 24 (7.5) 2 (0.6)
101 (31.8) 170 (53.5) 47 (14.8)
96 (30.0) 96 (30.0) 69 (21.6) 59 (18.4)
190 (59.4) 46 (14.4) 15 (4.7) 69 (21.6)
45 (14.1) 46 (14.4) 229 (71.6)
*For details see Figure S2 in the Online Supplementary Appendix and Möricke et al., Blood (2016).19 CNS: central nervous system; CVC: central venous catheter; MRD: minimal residual disease; PGR: prednisone good-response; PPR: prednisone poor-response; UFH: unfractionated heparin; WBC: white blood cell count.
Thromboembolic events
Among the 949 randomized patients, 42 thromboem- bolic events were observed (4.4%; 95% CI: 3.2 to 5.9). Of these events, 20 (47.6%) occurred in the upper deep venous system, seven (16.7) in the lower deep venous system, and 13 (30.9%) in cerebral sinus veins; two patients (4.8%) had a cerebral arterial stroke. Eight of the 42 thromboembolic events (19%) were distant to the site of the CVC. Thirty-three events occurred between treat- ment day 9 and 36 during induction therapy, the other nine events occurred between treatment day 37 and 52 of induction consolidation.
Children below 6 years of age had a significantly lower risk of thromboembolism (14/512, 2.7%) than those aged 6 to 9 years (11/188, 5.9%) or 10 years and older (17/249, 6.8%; P=0.018). Other patients’ characteristics and fea- tures, such as gender, initial white blood cell count,
immunophenotype or treatment response did not influ- ence the incidence of thromboembolism (data not shown). The incidence of thromboembolism was significantly higher among patients randomized to UFH (25/312; 8.0%) than in the enoxaparin (11/317; 3.5%; P=0.011) or antithrombin group (6/320; 1.9%; P<0.001). The as-treat- ed analysis revealed an incidence of 6.7% in the UFH group (25/372) compared to 3.2% in the enoxaparin (7/216; P=0.089) and 2.6% in the antithrombin group (9/341; P=0.013). The respective cumulative incidences are depicted in Figure 2A,B. The difference between the incidence of thromboembolism in the enoxaparin and antithrombin groups as treated was -0.6%; the lower and upper limits of the 95% CI were -3.5% and +2.3%, respectively (P-values for the corresponding one-sided tests were P=0.01 and P=0.001). Thus, antithrombin and
enoxaparin were equally effective.
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haematologica | 2019; 104(4)