Page 312 - Haematologica March 2020

C. Zaninetti et al.
was discontinued after 8 weeks of part 2 of the study. The adverse event was grade 2 according to CTCAE version 3.0. The patient described a similar exacerbation of the eczema before enrollment into this study, which occurred without any apparent causes. However, the eczema improved some weeks after eltrombopag discontinuation, supporting a causal relationship with the treatment. No additional adverse events were observed during part 2 therapy. In particular, no occurrence or worsening of cataracts was observed, even in the two patients with MYH9-RD who had cataracts at baseline.
Post-treatment assessments
Twenty patients were re-evaluated 30 days after the end of part 1 or 2 (3 patients refused the visit). Post-treatment assessments did not identify any adverse events. The mean platelet count was 47.0x109/L (SD 26), similar to that at baseline in the same patients (40.9x109/L, SD 23). The bleeding tendency returned to that recorded at baseline in all the cases.
Discussion
TPO-RA represent an appealing hypothesized treat- ment for the majority of patients with thrombocytopenias of genetic origin. In fact, in most forms of inherited throm- bocytopenia, the megakaryocyte response to thrombopoi- etin is totally or partially preserved:25,26 TPO-RA can there- fore potentially increase platelet production in many of these disorders. Moreover, in most patients with inherited thrombocytopenia platelet function is normal or only par- tially impaired, so that increasing platelet count is expect- ed to improve hemostasis.25,27 Patients with an inherited thrombocytopenia may benefit from short-term courses of TPO-RA as well as prolonged treatment. Short-term courses may be given in preparation for elective surgery or other invasive procedures whenever the platelet count is below the safe threshold for the specific procedure. In this context, TPO-RA can replace perioperative platelet trans- fusions, thus preventing alloimmunization and the other risks of blood derivatives, and provide an option to increase platelet count even in patients refractory to platelet transfusions.10-12,14,15 On the other hand, patients with clinically significant spontaneous bleeding may ben- efit from long-term TPO-RA administration to achieve an enduring remission of bleeding symptoms and reduce the risk of major hemorrhages. Despite these premises, clini- cal evidence on the efficacy and safety of TPO-RA in inherited thrombocytopenias is very scarce.28
The only previous prospective study investigated the short-term use of eltrombopag in patients with MYH9-RD and showed that most patients responded to treatment without major side effects.9 The present trial investigates the response to short-term eltrombopag in a wider range of inherited thrombocytopenias, and provides information on the effects of prolonged treatment in those patients with clinically significant spontaneous hemorrhages.
We gave a short-term course of eltrombopag to patients affected with five different disorders: the large majority of them (91.3%) responded to the drug and the mean platelet count at the end of therapy was increased by 64.5x109/L compared to baseline (P<0.001). However, we observed some differences in the degree of platelet response between the patients with the different forms of inherited
thrombocytopenia. Eltrombopag was highly effective in MYH9-RD, thus confirming and extending the results of the previous trial.9 All the MYH9-RD patients responded, most of them (78%) reached a platelet count >100x109/L, and the mean increase in platelet count compared to base- line was 98.1x109/L. The two individuals with mBSS also achieved major responses with an increase in platelet count close to that of MYH9-RD subjects (80.5x109/L). Although seven of the eight evaluable patients with ANKRD26-RT responded to eltrombopag, the extent of platelet response was globally lower than that in MYH9- RD and mBSS patients: in fact, most ANKRD26-RT sub- jects obtained minor responses and the mean increase in platelet count in responders was 41.8x109/L. In the three XLT/WAS patients, results appeared similar to those of ANKRD26-RT: these patients reached a minor response with an average rise in platelet count of 41.4x109/L. In spite of these differences, we believe that in all the above disorders the response to eltrombopag is highly relevant with regards to the use of the drug in preparation for sur- gery in clinical practice. In fact, current guidelines define a platelet count of 50x109/L as the threshold level recom- mended for major surgery, with the exception of neuro- surgery and posterior eye surgery that require a platelet count of 100x109/L.4,5 In this view, while the response observed in MYH9-RD and mBSS appears a very good result, even the extent of the increase in platelet count obtained in ANKRD26-RT and XLT/WAS appears suffi- cient to avoid the use of platelet transfusions to prepare most patients for most surgical procedures.
Finally, we treated only one patient with ITGB3-RT, who failed to achieve a platelet response according to the study criteria.
All the patients who responded in part 1 of the study, even those achieving a minor response, had complete remission of bleeding symptoms whenever these were present at baseline. Even one of the two patients classified as non-responders according to the study criteria, experi- enced the remission of mucosal bleeding following a slight increase in platelet count. Remission of bleeding is consis- tent with the results of platelet function studies during eltrombopag treatment: since platelet responses to differ- ent agonists were normal or only slightly impaired, increasing platelet count was effective in improving hemostasis. Consistent with previous findings in XLT/WAS patients,18 flow cytometry showed that platelet responsiveness to ADP and TRAP does not change signif- icantly with eltrombopag administration.
Concerning the dosage of eltrombopag, ten of the 11 patients who achieved a major response obtained this result with a dose of 50 mg/day, while one patient required a dose of 75 mg/day. Overall, ten of the 13 patients who were switched from 50 to 75 mg/day obtained a further increase of platelet count with the high- er dose: four subjects reached a better response according to the study criteria, while six patients achieved only slightly higher platelet counts. All the patients with ANKRD26-RT or XLT/WAS, but one, required the switch to the higher dose, which resulted in a higher platelet count in most cases. These data suggest that 75 mg/day is the most reasonable starting dose for preoperative eltrom- bopag in patients with either of these two disorders.
Effects of long-term eltrombopag administration were investigated in four patients who had frequent episodes of spontaneous mucosal bleeding. All of them achieved a sta-
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haematologica | 2020; 105(3)