Page 313 - Haematologica March 2020

Eltrombopag in inherited thrombocytopenias
ble remission of mucosal hemorrhages and the remission persisted throughout the treatment period. In two patients, the reduction of spontaneous bleeding was asso- ciated with a very slight increase of platelet count (around 10x109/L). The same observation was previously made in a patient with WAS who was given long-term treatment with eltrombopag because of severe bleeding symptoms.17 Two patients achieved remission of bleeding with the dosage of 25 mg/day, suggesting that, in some patients with inherited thrombocytopenia, clinical benefit can be maintained with prolonged administration of relatively low doses of eltrombopag. Interestingly, the two patients with the greatest bleeding tendency at baseline experi- enced not only stable improvements of HR-QoL related to bleeding, but also an increase of the score measuring the subjective perception of fatigue.
The observation that some patients obtained a signifi- cant reduction of bleeding tendency following a very slight increase in platelet count suggests that eltrombopag may improve some discrete platelet functions in addition to raising platelet concentration. As mentioned, overall we did not observe any significant change in platelet GPIIb-IIIa activation or P-selectin expression in response to ADP and TRAP after eltrombopag treatment compared to that at baseline, in 12 investigated patients. However, we cannot exclude that the drug could have improved some other mechanisms of platelet function29 in some patients, and fur- ther investigations are required to explore this hypothesis.
Short-term treatment with eltrombopag was globally well tolerated, with 17% of patients reporting mild and transient headache and/or bone pain at the beginning of treatment. In one ANKRD26-RT patient, we observed a slight increase in plasma creatinine; clinical investigation of this subject suggested that a causal relationship between eltrombopag and this adverse event was unlike- ly. Regarding long-term treatment, the patient affected with WAS experienced worsening of a pre-existing cuta- neous eczema that required eltrombopag discontinuation after 14 weeks. This adverse event had never been described in the previous retrospective reports on WAS patients who received eltrombopag.17,18 No other adverse events were recorded with long-term therapy.
Eltrombopag has been associated with the occurrence of cataracts in patients with immune thrombocytopenia,30 and MYH9-RD is a syndromic disorder predisposing to cataracts.31 Thus, it is noteworthy that none of our MYH9- RD subjects showed development or progression of cataracts, not even the two patients who received long- term therapy and already had cataracts at baseline.
A previous study raised the suspicion that the TPO-RA romiplostim favors progression to myeloid leukemia in
patients with myelodysplastic syndromes.32 Subsequent trials of eltrombopag monotherapy in myelodysplastic syndromes did not reveal any safety issues in this regard:33- 35 however, a trend to an increased risk of disease progres- sion was reported in a study in which eltrombopag was tested in association with azacitidine in intermediate- or high-risk myelodysplastic syndromes.36 These observa- tions raise concerns about the safety of TPO-RA in ANKRD26-RT, a condition that increases the risk of myeloid malignancies.37 In the present study, short-term use of eltrombopag did not result in any changes of blood cell parameters or morphology (with the exception of platelet count) in ANKRD26-RT patients. However, fur- ther clinical data on this topic are needed, and caution should be used when treating individuals with ANKRD26- RT or other inherited thrombocytopenias predisposing to hematological malignancies38 with TPO-RA, especially with long-term administration.
In conclusion, this study shows that eltrombopag was effective in increasing platelet count in four different forms of inherited thrombocytopenia, which, taken together, affect more than 55% of patients with genetic thrombocy- topenias.28 In most patients, short-term administration of eltrombopag increased platelet count above the threshold for major surgery recommended by current guidelines,4,5 indicating that the drug can efficiently replace periopera- tive platelet transfusions in preparation for surgery or other invasive procedures. Although only four patients received long-term treatment, the results indicate that prolonged eltrombopag therapy can induce persistent remission of spontaneous bleeding. Both short- and long-term treat- ments were globally well tolerated. Although a greater amount of clinical data on the use of TPO-RA in inherited thrombocytopenias is certainly required, our results sug- gest that eltrombopag will probably have a central role in the treatment of thrombocytopenias of genetic origin.
Acknowledgments
The authors would like to thank all the patients and their fam- ilies. We thank the Clinical Trial Quality Team of the IRCCS Policlinico San Matteo Foundation for their continuing assistance and cooperation, Dr. Ruggero Panebianco (Novartis) for critically revising the study proposal, and Prof. Antonio Ruggiero (Department of Pediatrics, IRCCS Policlinico A. Gemelli Foundation) for his helpful collaboration.
This study was supported by grants from the IRCCS Policlinico San Matteo Foundation (to AP) and the Telethon Foundation (GGP17106 to AP and GGP10155 to PG).
Novartis made eltrombopag available for the study and par- tially supported the clinical and laboratory analyses required by the trial.
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