Chronic immune thrombocytopenia (ITP) may represent the epiphenomenon of a complex immune-dysregulation process. Not all patients respond with equal effectiveness to different therapies as immunosuppressant (MMF and Sirolimus) or TPO-agonists, and no specific indicators at diagnosis are available to predict response.
To identify a group of clinical and immunological variables predictive of response to a specific second-line therapy.
Lymphocytes subsets including ALPS panel (double-negative T-lymphocytes—DNTs-, B220+DNTs, CD27+B cells, and CD3+CD25+/HLADR+ ratio), ALPS biomarkers (IL10, IL18, and sFAS), Ig serum levels, autoantibody screening, and Coombs test were analyzed at diagnosis, after at least 6 months, and after response to a second-line therapy.
72 consecutive patients with persistent/chronic ITP have been retrospectively studied. 17/72 (24%) responded to first-line therapy consisting of steroids and/or IVIG. Thirty-three of the remaining 55 responded to immunosuppressants (28) or TPO-agonists (5) given as second-line treatment. The remaining 22 patients underwent treatment with TPO-agonist after immunosuppressant failure (20) or immunosuppressant after TPO-agonist failure (2). Overall, 17 (24%) patients responded to first-line therapy, 31 (43%) and 16 (22%) patients responded to immunosuppressant and TPO-agonists, respectively, and 8 (11%) patients did not respond to any treatment. Table 1 shows patients’ demographic/clinical characteristics according to the response. Signs of immune-dysregulation in the acute phase such as DNT>1.5%, reduced in CD4 (p = 0.05) and NK cells (p = 0.05), and the simultaneous presence of ¾ positive parameters of the ALPS panel (p < 0.05) predicted a better response to immunosuppressant than to TPO-agonists. Furthermore, 51 patients were studied after the response to the treatment: in addition to platelets count, patients responding to immunosuppressants showed a statistically significant reduction of lymphoproliferation (p 0.025) and normalization of CD4+ (p 0.01), NK cells (p 0.08), (p 0.016), B220+DNTs (p 0.001), CD25/HLADR+ ratio (p 0.035), IL-18 (p 0.02), and ANA positivity compared with the others.
Demographic and clinical characteristics of the 72 patients according to the response
| Total n=72 | First-line th response n=17 | IS response n=31 | TPO-A response n=16 | Non responder n=8 | Overall response (P-value) | IS vs tpo-A (P-value) | |
|---|---|---|---|---|---|---|---|
| Female, n (%) | 39 (54) | 11 (65) | 16 (52) | 9 (52) | 3 (37) | 0.666 | 0.763 |
| Age at onset, yrs, median (IQR) | 9.1 (5.2-12.4) | 9.9 (6.8-13.5) | 9 (5.5-12.3) | 10 (6.5-14.3) | 4.2 (3.1-6) | 0.017 | 0.296 |
| Age at onset >9.1 yrs, n (%) | 36 (50) | 10 (59) | 15 (48) | 11 (69) | 0 | 0.009 | 0.183 |
| Cutaneous/mucosal diathesis, yes, n (%) | 651 (90) | 14 (82) | 28 (90) | 15 (94) | 8 (100.0) | 0.670 | 1.000 |
| Family history,2 yes, n(%) | 17 (24) | 6 (35) | 9 (29) | 2 (12) | 0 | 0.149 | 0.287 |
| Splenomegaly3/Lymphofoproliferation4, n (%) | 9 (12.5) | 0 | 9 (29) | 0 | 0 | 0.004 | 0.019 |
| Low IgA, n (%) | 13 (18.1) | 1 (5.9) | 9 (29) | 2 (12.5) | 1 (12.5) | 0.220 | 0.287 |
| Low IgG n (%) | 7/66 (11) | 0/16 | 4/31 (13) | 3/16 (19) | 0/3 | 0.347 | 0.676 |
| Low IgM n (%) | 3/70 (4.3) | 0/17 | 3/30 (10) | 0/16 | 0/7 | 0.514 | 0.542 |
| IgG subclasses abnormalities, n (%) | 8/60 (13) | 4/16 (25) | 3/29 (10) | 1/12 (8) | 0/3 | 0.515 | 1.000 |
| Reduced response to vaccines | 6/32 (19) | 0/9 | 6/19 (32) | 0/2 | 0/2 | 0.231 | 1.000 |
| Antinuclear antibodies, yes, n (%) | 17/70 (24) | 4/16 (25) | 10/31 (32) | 2/16 (12) | 1/7 (14) | 0.519 | 0.176 |
| Antithyroid antibodies, yes, n (%) | 5/70 (7) | 1/16 (6) | 2/31 (6) | 2/15 (13) | 0/8 | 0.768 | 0.587 |
| Anti-red blood cells antibodies, yes, n (%) | 8/70 (11) | 0/16 | 8/31 (26) | 0/16 | 0/7 | 0.013 | 0.038 |
| Anti-transglutaminase antibodies, yes, n (%) | 1/71 (1) | 1/16 (6) | 0 | 0 | 0 | 0.563 |
| Total n=72 | First-line th response n=17 | IS response n=31 | TPO-A response n=16 | Non responder n=8 | Overall response (P-value) | IS vs tpo-A (P-value) | |
|---|---|---|---|---|---|---|---|
| Female, n (%) | 39 (54) | 11 (65) | 16 (52) | 9 (52) | 3 (37) | 0.666 | 0.763 |
| Age at onset, yrs, median (IQR) | 9.1 (5.2-12.4) | 9.9 (6.8-13.5) | 9 (5.5-12.3) | 10 (6.5-14.3) | 4.2 (3.1-6) | 0.017 | 0.296 |
| Age at onset >9.1 yrs, n (%) | 36 (50) | 10 (59) | 15 (48) | 11 (69) | 0 | 0.009 | 0.183 |
| Cutaneous/mucosal diathesis, yes, n (%) | 651 (90) | 14 (82) | 28 (90) | 15 (94) | 8 (100.0) | 0.670 | 1.000 |
| Family history,2 yes, n(%) | 17 (24) | 6 (35) | 9 (29) | 2 (12) | 0 | 0.149 | 0.287 |
| Splenomegaly3/Lymphofoproliferation4, n (%) | 9 (12.5) | 0 | 9 (29) | 0 | 0 | 0.004 | 0.019 |
| Low IgA, n (%) | 13 (18.1) | 1 (5.9) | 9 (29) | 2 (12.5) | 1 (12.5) | 0.220 | 0.287 |
| Low IgG n (%) | 7/66 (11) | 0/16 | 4/31 (13) | 3/16 (19) | 0/3 | 0.347 | 0.676 |
| Low IgM n (%) | 3/70 (4.3) | 0/17 | 3/30 (10) | 0/16 | 0/7 | 0.514 | 0.542 |
| IgG subclasses abnormalities, n (%) | 8/60 (13) | 4/16 (25) | 3/29 (10) | 1/12 (8) | 0/3 | 0.515 | 1.000 |
| Reduced response to vaccines | 6/32 (19) | 0/9 | 6/19 (32) | 0/2 | 0/2 | 0.231 | 1.000 |
| Antinuclear antibodies, yes, n (%) | 17/70 (24) | 4/16 (25) | 10/31 (32) | 2/16 (12) | 1/7 (14) | 0.519 | 0.176 |
| Antithyroid antibodies, yes, n (%) | 5/70 (7) | 1/16 (6) | 2/31 (6) | 2/15 (13) | 0/8 | 0.768 | 0.587 |
| Anti-red blood cells antibodies, yes, n (%) | 8/70 (11) | 0/16 | 8/31 (26) | 0/16 | 0/7 | 0.013 | 0.038 |
| Anti-transglutaminase antibodies, yes, n (%) | 1/71 (1) | 1/16 (6) | 0 | 0 | 0 | 0.563 |
Exclusively cutaneous involvement, n=33;
family history of autoimmune diseases in first-degree relatives;
defined based on age-specific values of longitudinal spleen diameter, measured by abdominal ultrasound;
defined based on the presence of persistent lateral cervical and/or axillary and/or inguinal and/or intra-abdominal adenopathies identified by clinical examination or targeted ultrasound, lasting for more than 6 months and without an alternative diagnosis.
An early immunophenotypic characterization at diagnosis represents a useful tool in the choice of second-line therapy and an indicator to perform early genetic studies for a potential target therapy.
