Early combination treatment of immune thrombocytopenia: Is this the way?
Authors: James B. Bussel
Journal: American Journal of Hematology (2020)

A hypothesis long-held by some is that more intense treatment of ITP at diagnosis will result in a higher cure rate. A limitation of designing studies in this area is that some or even many patients will improve on their own and not require "curative" treatment.5 Since it is currently not possible to distinguish those patients who will improve with or without treatment from those who will have long-standing chronic disease, treatment studies with long-term outcomes as important endpoints have been difficult to perform in early stage patients.6 This dilemma points out how very limited we are in our ability to forecast at diagnosis initial response rates to individual agents, which complications will develop, for example, bleeding or thrombosis, or who can be cured and, if so, by which treatment. Laboratory-based prediction models (primarily involving molecular studies) of chronic ITP are still in an early state even in children.7 Large additional studies are needed to better define this area, likely with novel approaches given there has been a surprising lack of enlightenment thus far. Another virtue of this study is that the treatments chosen are not too toxic to be used upfront in essentially all adult ITP patients. This contrasts with splenectomy which would not be equally acceptable in this very early setting (8, 9). Rituximab and high dose dexamethasone have not proven to be effective in providing a cure except in women of child-bearing age including adolescents.10-12 Furthermore, infusion of rituximab prevents response to vaccines for a minimum of 4-6 months which assumes added importance in the era of the SARS-CoV-2 pandemic. The randomized controlled trial reported here shows that combining two agents (dexamethasone and recombinant human thrombopoetin) appears to increase the rate of sustained remissions compared to that seen with dexamethasone alone. Approximately half or more of adults with ITP treated at diagnosis with dexamethasone and rhTPO with up to two cycles of dexamethasone and 2 weeks of rhTPO required no further treatment. The difference between the two treatment groups in the several analyses of sustained response was 10%-15% of patients in favor of combining dexamethasone and rhTPO. This was statistically significant at the .05 level in some, but not all, of the analyses. Several features of the patients relevant to outcome bear mentioning. First, all patients were treatment naïve. Second, the platelet counts in both arms were a median of only 7000/μL. In previous ITP studies, for example, of TPO agents13, 14 patients with platelet counts of >15 000/μL responded significantly and substantially better than did those with platelet counts of <15 000/μL. It needs to be determined whether more impressive results would be seen in a "more typical" presenting population in which half of the patients would have platelet counts of 15-30 000/μL. To the extent that the addition of rhTPO to dexamethasone apparently increased the "curative," "long-term" effects of treatment, this would be the first clear demonstration of such a long-term effect of a TPO agent. It is natural to believe that if an effect of rhTPO is found, other TPO agents like romiplostim, eltrombopag, and avatrombopag would have a similar effect; however, clearly this would need to be substantiated. There is an ongoing study by the ICON group exploring early use of eltrombopag in children with newly diagnosed ITP. Third, it is worth remarking that many of the recent large randomized studies in adults with ITP have come from groups in China. For example, a study comparing rituximab alone to rituximab and TPO together enrolled well over 100 patients.15 It demonstrated more rapid onset of efficacy in the rhTPO + rituximab arm although no significant difference in long-term outcome was observed. Another large study explored the addition of danazol to all-trans retinoic acid (ATRA, or tretinoin, INN) in comparison to danazol alone.16 The combination was more effective in increasing and maintaining the platelet count. Finally, the first (only prospective) study of a thrombopoietic agent in pregnant women with ITP was conducted in 31 women in China in 2015.17 These and several other studies highlight the role of China in developing new treatments for ITP given their often sophisticated practice of hematology and their large number of patients. In summary this study demonstrates that the combination of rhTPO and dexamethasone likely increases the long-term cure rate of treatment naïve adults with ITP at diagnosis. These results are in tune with recommendations of the recent ASH ITP guidelines and the International Consensus report, both of which advocate strongly to shorten the period of steroid use and, as such, to initiate second-line treatment earlier. While this study starts before "earlier", that is,. at the time of diagnosis, it looks to provide a cure with treatment completed by the first two weeks of ITP. Certainly there are patients who do not respond to the dexamethasone-rhTPO combination, either at all or who relapse after initially responding. However having half of them achieving clinical remission and being finished with all treatment is very encouraging and certainly a goal worth confirming in future randomized studies in other populations. The authors declare no conflict of interest. Data sharing not applicable to this article as no new data were created or analyzed in this study.