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Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts resulting from both immune-mediated platelet destruction and inappropriate bone marrow platelet production. Therefore, in patients with ITP failing immunosuppressants/splenectomy, an alternative approach is to enhance platelet production stimulating thrombopoiesis. Studies on the development of recombinant thrombopoietins (rhTPO) were halted as a minority of patients developed an autoantibody that neutralized pegylated rhTPO and also cross-reacted with and neutralized endogenous TPO resulting in thrombocytopenia. Clinical use of romiplostim, a second-generation TPO-RAs, has shown that during long-term treatment, it may elicit the development of neutralizing antibodies to this agent resulting in acute thrombocytopenia. In our case series of 47 primary adult patients with ITP treated with romiplostim, 28 of 47 are evaluable for response loss. Among these, we observed eight patients who either progressively (3 of 8) or abruptly (5 of 8) lost response which accounts for a prevalence of 28.5%. Neutralizing antibody testing could be performed in 4 of 8 patients and 3 of 4 tested positive. These antibodies did not cross-react with endogenous TPO and retesting of 2 patients at 9 and 7 months yielded a negative result. At follow-up, 5 of 8 patients - including the 3 patients with neutralizing antibodies - went into long-term complete response when switched to a different therapy while 3 of 8 patients never regained a response on subsequent lines of therapy. Response loss does not seem to be so rare an event during romiplostim administration (28.5% in our series) and in a minority of patients, it can be associated with development of drug neutralizing antibodies. Although recognized by the manufacturer as a possible adverse event ensuing during romiplostim administration, development of neutralizing antibody in everyday clinical practice has so far not been specifically addressed in reports on romiplostim use outside controlled studies. Unfortunately, testing for these antibodies requires adhesion to strict procedures which is not easily accomplished in everyday clinical practice. This complexity represents a significant drawback in extending antibody testing to all patients who lose response to romiplostim.

[Graphic][1] Introduction . Availability of the 2 TPO-RAs Romiplostim (Rom) and Eltrombopag (El) offers an effective treatment option for primary ITP patients (pts). However, some pts are either not responsive or lose response - i.e. desired platelet (plt) count achieved but not sustained over time, or experience wide fluctuations in plt count with either TPO-RA. Adverse events may cause treatment discontinuation. Finally, ptOs preference may be an important issue considering the different route and timing of administration of the two agents. Availability of two TPO-RAs for clinical use, with different molecular structure and site of binding within the TPO receptor, makes it appealing to try switching with the aim of overcoming treatment limitations of either agent. The present survey offers insight into outcome of TPO-RA switching in a group of ITP pts treated at 8 Centers representative of the Italian territory. Patients. Charts of ITP pts on treatment who underwent TPO-RA switch were retrospectively reviewed. Results . Between Jan 2009 and Feb 2015, 57 of 249 pts on TPO-RA (22,9%) underwent switch: El ˆ Rom 26/57 (45.6%), Rom ˆEl 31/57 (54.4%). Median age at 1st TPO-RA administration was 55 yrs (range 16-81); M/F = 23/34. Median disease duration prior to 1st TPO: 58 mos (range 2-648). Median lines of previous therapy 3 (range 1-6; splenectomy: 23/57, 40.4%). Overall 42/57 pts (73,7%) had received maximum product dose as per prescribing information prior to switch. Table 1 summarizes reasons for TPO-RA switch and outcome. Overall, 32/57 pts (56.1%) achieved, regained or maintained a response upon switching. The majority of pts (39/57, 68.5%) were switched for efficacy issues, i.e. failure to respond to 1st TPO (27 pts) or response loss (12 pts); among these 39 pts, 48.7% responded to the 2nd TPO-RA. One pt lost response to Rom because of development of neutralizing antibodies; response was regained upon switching to El. In this subgroup of pts, disease duration and lines of previous therapy (but not splenectomy status) seem to have an impact on response to switching. Each one month increase in disease duration determines a 0.7% decrease in the odds of achieving a response (WaldOs test p=0.065). More than 2 lines of therapy determine a 72% decrease in the odds of achieving a response (WaldOs test p=0.077). Either TPO-RA switch sequence was equally effective in yielding response (FisherOs exact test p=0.752) and age at 1st TPO-RA had no impact on response. Of the 18 pts switched for reasons other than efficacy, 13 (72.2%) maintained a response on the 2nd TPO-RA: 5/6 switched for plt count instability (counts stabilized = 2/5 responding pts), 4/7 switched for ptOs preference, 4/5 switched for side effects. Four pts (1 plt count instability, 3 ptOs preference) underwent Odouble switchO (i.e. Rom ˆ El ˆ Rom): re-exposure to Rom was not associated with response loss. Discussion . Switching enables approximately 56% of pts to achieve, regain or maintain a plt response; switching for inefficacy yields lower response rates (48.7%) compared to switching for reasons other than efficacy (72.2%) Plt counts fluctuation stabilized in 40% of pts. Re-exposure to R in the 4 pts who underwent Odouble switchO was not associated with response loss, confirming absence of tachyphylaxis with this TPO-RA. Our results are in line with those reported by Khellaf (Haematologica 2013) and Gonzales-Porras (BJH 2014): TPO-RA switch can be a safe and appealing treatment option for ITP pts who experience suboptimal results with either agent. | REASON for SWITCHING | n (%) | NR (%) | R (%) | CR (%) | | | --------------------- | --------- | --------- | --------- | --------- | | | All | 57 (100) | 25 (43.9) | 14 (24.6) | 18 (31.5) | | | El->Rom | 26 (45.6) | 10 (38) | 8 (31) | 8 (31) | | | Rom->El | 31 (54.4) | 10 (48.4) | 6 (19.4) | 10 (32.3) | | | 1st TPO-RA failure | 27 (47.4) | 16 (59) | 4 (15) | 7 (26) | | | El->Rom | 15 | 7 (47) | 3 (20) | 5* (33) | | | Rom->El | 12 | 9 (75) | 1 (8) | 2 (17) | | | Loss of response | 12 (21.1) | 4 (33) | 2 (17) | 6 (50) | | | El->Rom | 4 | 2 (50) | 1 (25) | 1 (25) | | | Rom->El | 8 | 2 (25) | 1 (12.5) | 5 (62.5) | | | Plt count fluctuation | 6 (10.5) | 1 (17) | 3 (50) | 2 (33) | | | El->Rom | 2 | | 1 | 1 | | | Rom->El | 4 | 1 | 2 | 1 | | | PtOs preference | 7 (12.3) | 3 (42.9) | 2 (28.6) | 2 (28.6) | | | El->Rom | | | | | | | Rom->El | 7 | 3 | 2 | 2 | | | Adverse eventii | 5 (8.8) | 1 (20.0) | 3 (60.0) | 1 (20.0) | | | El->Rom | 5 | 1 | 3 | 1 | | | Rom->El | | | | | | * CR: complete response; R: response; NR: no response (Rodeghiero et al, Blood 2009) * *1 NR secondary to neutralizing antibodies development * ii1 hepatic enzyme increase, 1 CPK increase; 2 skin rash; 1 retinal thrombosis. Table 1. Disclosures De Stefano: Janssen Cilag: Research Funding; Shire: Speakers Bureau; Amgen: Speakers Bureau; Bruno Farmaceutici: Research Funding; Novartis: Research Funding, Speakers Bureau; Roche: Research Funding; Celgene: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. [1]: /embed/inline-graphic-2.gif