Page 310 - Haematologica March 2020

C. Zaninetti et al.
Platelet aggregation was normal in all the cases, except for two patients with MYH9-RD and one with mBSS who had slightly reduced responses to the lowest ADP dose (Online Supplementary Table S7). In 12 patients, platelet activation in response to ADP and TRAP was also assessed through flow cytometry as the induction of sur- face expression of P-selectin and of the activated form of GPIIb-IIIa.24 In these subjects, platelet activation at base- line was not significantly different from that of healthy controls. Overall, platelet responsiveness did not change significantly after eltrombopag treatment with respect to baseline in the investigated patients (Online Supplementary Figure S2).
The mean serum thrombopoietin level at baseline was 177.8 pg/mL [standard deviation (SD) 125]. Thrombopoietin levels were unchanged at the end of treatment both considering patients overall and stratifying them according to the different disorders or response to treatment (Online Supplementary Table S8).
Safety
We recorded seven adverse events in five patients (21%) (Table 4): all the adverse events were grade 1 (mild) accord- ing to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Four patients reported mild and tran- sient headache and/or diffuse bone pain during the first 2-3 days of treatment. One patient with ANKRD26-RT present- ed with increased plasma creatinine at the assessment after 3 weeks of treatment with 50 mg/day. Although this adverse event was grade 1 (creatinine 1.6 times above base- line), treatment was discontinued according to the study protocol. Further investigations showed that kidney dys- function was due to urinary retention because of pre-exist- ing benign prostatic hypertrophy and suggested that a causal relationship between eltrombopag administration and the adverse event was unlikely (see Table 4 for details). Results of an ophthalmic assessment at the end of therapy were unchanged in all cases, including the three patients with MYH9-RD who had cataracts at baseline.
Table 4. Adverse events recorded during part 1 of the study. All the adverse events were grade 1 according to the Common Terminology Criteria for Adverse Events, version 4.0.
Adverse event
Any adverse event
Headache
Bone pain
Increased plasma creatinine
N. of AE
7
4
2
1
N. of patients (%)
5 (21%)
4 (17%)
2 (8%)
1 (4%)
Description
Mild headache that resolved completely after 2 or 3 days. Some patients
took low doses of acetaminophen with benefit.
Mild diffuse bone pain that resolved completely after 3 or 4 days. Some patients took low doses of acetaminophen with benefit.
Increase 1.6-fold above baseline at the evaluation after 21 days of treatment. Treatment was stopped according to study protocol. Further investigations disclosed that the increased creatinine level was due to urinary retention because of concomitant benign prostatic hypertrophy. Creatinine level continued to increase progressively for 2 months after eltrombopag discontinuation and then completely resolved after specific urologic treatment. Worsening of prostatic hypertrophy has never been reported as an adverse reaction of eltrombopag treatment.1 Based on the clinical course of the disorder and data from literature, the investigators suggest that a causal relationship between eltrombopag administration and the AE was unlikely.
1Eltrombopag(Revolade®)Productinformationavailableat https://www.ema.europa.eu/en/medicines/human/. N:number;AE:adverseevent.
Table 5. Response in part 2 of the study in the four patients enrolled.
Patient ID (patient/family)1
Gender/age, years
Diagnosis
Treatment duration, weeks WHO bleeding score - baseline
Bleeding symptoms - baseline
1/1
F/49
MYH9-RD
16
3
Easy bruising Petechiae Gum bleeding Epistaxis
12/10
F/45
MYH9-RD
16
3
Easy bruising Gum bleeding Menorrhagia
17/13
F/45
ITGB3-RT
16
2
Easy bruising Menorrhagia
22/16
M/24 WAS 8 2
Easy bruising Epistaxis Hematochezia
Platelet count - baseline, x109/L
WHObleedingscore-endofpart22 1 1 1 0
Bleeding symptoms - end of part 2 Platelet count - end of part 2,3 x109/L Eltrombopag dose - end of part 2, mg/day
Response in part 24
14
Easy bruising 75
50 Minor
38
Easy bruising 76
25 Minor
62
Easy bruising None 70 19 25 50
Minor Major
9
1See Online Supplementary Table S4. 2Spontaneous bleeding during the 2 weeks preceding the last on-treatment visit according to the World Health Organization bleeding scale. 3Asevaluatedatthelaston-treatmentvisitbyphase-contrastmicroscopyinacountingchamber.4Accordingtopredefinedstudycriteria.ID:identity;MYH9-RD:MYH9-relateddis- ease; ITGB3-RT: ITGB3-related thrombocytopenia;WAS:Wiskott-Aldrich syndrome;WHO:World Health Organization.
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