Page 90 - Haematologica June

S. Bertoli et al.
continued from the previous page
Characteristics
Albumin - g/dL Median (IQR) <3.5 – n. (%) ≥3.50 – n. (%)
Ferritin - ng/mL Median (IQR) ≤1000 – n. (%) >1000 – n. (%)
Lactate dehydrogenase – IU/L Median (IQR)
≤1550 – n. (%)
>1550 – n. (%)
Fibrinogen – g/L Median (IQR) ≤1.5 – n. (%) >1.5 – n. (%)
Study period – n. (%) 2004-2009
2010-2015
Hydroxyurea – n. (%) No
Yes
Chemotherapy – n. (%) Daunorubicin-cytarabine Idarubicin-cytarabine Idarubicin-cytarabine-lomustine Time sequential induction Other
Allo-SCT – n. (%) No
Yes
No dexamethasone n=100 (62.5%)
3.50 (3.30-3.90) 41 (41.4)
58 (58.6)
928.5 (570.0-1342.0) 24 (52.2)
22 (47.8)
1618.0 (913.0-2506.0) 48 (48.0)
52 (52.0)
4.0 (2.8-4.8) 8 (8.0) 92 (92.0)
67 (67.0) 33 (33.0)*
41 (41.0)
59 (59.0)
32 (32.0) 15 (15.0) 45 (45.0) 5 (5.0)
3 (3.0)
75 (75.0)
25 (25.0)
Dexamethasone n=60 (37.5%)
3.50 (3.20-4.00) 29 (49.2)
30 (50.8)
1103.0 (606.0-2249.0) 25 (46.3)
29 (53.7)
1498.5 (790.0-2369.0) 32 (53.3)
28 (46.7)
3.7 (2.6-4.7) 7 (11.7) 53 (88.3)
0 (0.0) 60 (100.0)
11 (18.3)
49 (81.7)
16 (26.7) 13 (21.7) 21 (35.0) 5 (8.3)
5 (8.3)
41 (68.3)
19 (31.7)
P
0.500 0.344
0.287
0.558
0.455 0.514
0.197
0.441
<0.001 93 (58.1)
0.003
0.281
0.361
All patients n=160 (100%)
3.50 (3.20-4.00) 70 (44.3)
88 (55.7)
1064.0 (599.5-1904.0) 49 (49.0)
51 (51.0)
1551.5 (840.5-2476.0) 80 (50.0)
80 (50.0)
3.9 (2.7-4.8) 15 (9.4) 145 (90.6)
67 (41.9)
52 (32.5)
108 (67.5)
48 (30.0) 28 (17.5) 66 (41.3) 10 (6.3) 8 (5.0)
116 (72.5)
44 (27.5)
992
IQR: interquartile range; ECOG: Eastern Cooperative Oncology Group; ELN: European LeukemiaNet; Allo-SCT: allogeneic stem cell transplantation (16 from sibling and 28 from HLA 9/10 or 10/10 matched unrelated donors). $ELN is unknown if FLT3-ITD or NPM1 mutation was missing for normal karyotypes or if karyotype is missing. ¶NPM1 and FLT3- ITD mutations in patients with intermediate-risk cytogenetics. * Among the 33 patients who did not receive dexamethasone, only 3 patients had symptoms of pulmonary leukostasis and more than 100 x109/L white blood cell count (WBC), whereas 3 additional patients had more than 100 x109/L WBC without leukostasis.
P<0.001) (Online Supplementary Table S3), and overall sur- vival (adjusted HR: 0.41; 95% CI: 0.22-0.79; P=0.007) (Table 3). Of note, when put in the multivariate model, FLT3-ITD mutations had no significant impact. Among patients who had undergone allogeneic stem cell trans- plantation in first complete response, the outcome of the dexamethasone group was still better than that of the no dexamethasone group (Online Supplementary Figure S1).
Impact of dexamethasone on leukemia-initiating cells in a co-culture system
The use of dexamethasone was unexpectedly associat- ed with a lower relapse rate suggesting that this drug could display potent antileukemic activity against AML cells at the origin of relapse and/or by enhancing the cyto- toxicity of chemotherapy. Leukemic long-term culture ini- tiating cells have been shown to be a reliable functional readout for monitoring the activity of leukemia-initiating cells, an AML subpopulation of cells thought to be at the origin of relapse.15,16 Using an optimized niche-like co-cul- ture system capable of maintaining leukemia-initiating cells ex vivo, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38±14% as
compared to untreated primary AML cells (Figure 3A). Interestingly, primary AML cells treated with dexametha- sone presented a higher expression profile of the CD38 marker after one week, and a higher percentage of myeloid and lymphoid lineage positive cells as well as monocytic CD11b/CD14-positive cells within the long- term culture weeks suggesting that dexamethasone may have a differentiation effect on AML (Figure 3B and C).
Impact of dexamethasone on chemoresistance
We next sought to determine whether dexamethasone could improve the cytotoxicity of genotoxic drugs used in AML. In liquid culture, short-term dexamethasone treat- ment with or without cytarabine or doxorubicin did not show synergy or an additive effect in a panel of genetically diverse AML cell lines (Online Supplementary Figure S2 and Online Supplementary Table S4). However, in a co-culture system, one week of exposure to dexamethasone signifi- cantly enhanced cytarabine activity in most AML cell lines (Figure 3D). Recently, it has been shown that cytarabine resistance of AML cells is associated with increased sensi- tivity to glucocorticoids.17,18 We thus wondered whether AML cells resistant to cytarabine display specific tran-
haematologica | 2018; 103(6)