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Letters to the Editor
Dual pyroptotic biomarkers predict erythroid response in lower-risk non-del(5q) myelodysplastic syndromes treated with lenalidomide and recombinant erythropoietin
Symptomatic anemia is the most common manifesta- tion in patients with lower-risk myelodysplastic syn- drome (MDS) that requires treatment. Although both recombinant erythropoietin and lenalidomide are modest- ly effective as single agents, combined treatment yields a significantly higher and durable erythroid response.1,2 However, less than 50% of patients respond, therefore predictive biomarkers may assist in treatment selection for these patients. NLRP3 inflammasome-directed pyrop- tosis, irrespective of the functional classes of underlying somatic mutations, drives ineffective erythropoiesis, the common phenotype of lower-risk MDS.3 Although how MDS-related somatic mutations of disparate functional
classes (e.g., RNA splicing and epigenetic regulation) acti- vate the NLRP3 inflammasome remains elusive, they are linked to genomic instability with excessive reactive oxy- gen species production.4,5 Furthermore, NLRP3 can also be activated by aberrantly elevated proinflammatory cytokines, such as S100A9, in the bone marrow microen- vironment of MDS.4 Apoptosis-associated speck-like pro- tein containing a CARD (ASC) is the adapter molecule that binds NLRP3 in response to activating signals, which then polymerizes to generate docking sites for the cas- pase-1 effector that instructs a number of cellular process- es, including interleukin-1β production and lytic cell death, i.e., pyroptosis.6 ASC filaments cluster into a soli- tary signal complex referred to as a speck, which is released upon cytolysis and circulates for extended peri- ods because of its inherent resistance to proteolytic degra- dation.7 Circulating ASC speck is a measurable biomarker of pyroptosis, and elevated levels have previously been found in patients with known NLRP3 inflammasome acti-
Table 1. Characteristics of patients. Median (range) or N (%)
Demographics
Age (years)
Male (%)
Clinical features
Hemoglobin (g/dL)
ANC (x109/L)
Platelet (x109/L)
Serum EPO > 200 mU/mL (%) Bone marrow blast > 2% (%) Bone marrow erythroblast (%) RARS (%)
Favorable karyotype (%) Splicing gene mutations
SF3B1 (%) U2AF (%) SRSF2 (%) ZRSR2 (%)
Epigenetic mutation TET2 (%)
IDH (%) DNMT3A (%) ASXL1 (%)
EZH2 (%)
Number of mutations IPSS low risk (%) Biomarker
ASC specks > median (%) Treatment
Prior responder to recombinant
erythropoietin (%)
Lenalidomide (%)
Lenalidomideplusepoetin (%)
All (n=69)
73 (46-86) 48 (69.6)
8.1 (6.3-10.0)
2.1 (0.15-10.06) (n=67) 235 (58-587) (n=67) 27 (48.2) (n=56)
27 (39.1)
28.9 (1.0-79.0) (n=67) 38 (55.1)
59 (86.8) (n=68)
52 (75.4) 0 (0.0) 6 (8.7) 5 (7.2)
34 (49.3)
2 (2.9)
13 (18.8)
12 (17.4)
2 (2.9)
2 (0-6)
33 (48.5) (n=68)
34 (49.3)
24 (35.8) (n=67)
31 (44.9) 38(55.1)
Responder (n=28)
74 (46-86) 21 (75.0)
8.1 (6.3-10.0) 1.56 (0.40-5.70) 241 (58-417)
6 (28.6) (n=21)
11 (39.3)
28.5 (4.4-79.0) (n=27) 12 (42.9)
24 (88.9) (n=27)
21 (75.0) 0 (0.0) 2 (7.1) 2 (7.1)
17 (60.7)
0 (0.0)
8 (28.6)
3 (10.7)
2 (7.1)
3 (0-6)
10 (37.0) (n=27)
20 (71.4)
11 (40.7) (n=27)
7 (25.0) 21(75.0)
Non-responder (n=41)
73 (54-85) 27 (65.9)
8.0 (6.8-9.7)
2.43 (0.15-10.06) (n=39) 231 (68-587) (n=39) 21 (60.0) (n=35)
16 (39.0)
30.5 (1.0-65.0) (n=40) 26 (63.4)
35 (85.4)
31 (75.6) 0 (0.0) 4 (9.8) 3 (7.3)
17 (41.5) 2 (4.9) 5 (12.2) 9 (22.0) 0 (0.0) 2 (0-6) 23 (56.1)
14 (34.1)
13 (32.5) (n=40)
24 (58.5) 17(41.5)
P*
0.250 0.418
0.815 0.075 0.598 0.029 0.983 0.618 0.092 0.733
0.954 1.000 1.000 1.000
0.116 0.511 0.120 0.335 0.161 0.291 0.124
0.002 0.490 0.006
*Continuous variables were compared by the Mann-Whitney test, and categorical variables were compared using the Fisher exact test or c2 test, as appropriate. ANC: absolute neutrophil count; EPO: erythropoietin; RARS: refractory anemia with ring sideroblasts; IPSS: International Prognostic Score System; ASC: apoptosis-associated speck-like protein containing a CARD.
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