Thrombopoietin mimetics are new treatment options for patients with immune throm-bocytopenia (ITP). Because of their mechanism of action, long-term administration was envisioned in order to maintain effective thrombopoiesis. We report on 30 romiplostim treated patients: 13/27 responders (48%) achieved stable platelet counts on a mean romiplostim dose of 2.43 µg/kg and were able to stop romiplostim after a mean of 44.3 weeks (range 12-122) on therapy with sustained response maintained at a mean of 26 months (range 12-52). No bleeding events occurred during the observational period. No specific patient’s features nor pattern of early response seemed to predict for sustained response. However, patients achieving safe platelet counts at lower dosages are probably worth a try of therapy tapering and discontinuation. Our observations support feasibility of romiplostim safe suspension in a relevant proportion of ITP patients.

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.

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, ptÕs 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 (WaldÕs test p=0.065). More than 2 lines of therapy determine a 72% decrease in the odds of achieving a response (WaldÕs test p=0.077). Either TPO-RA switch sequence was equally effective in yielding response (FisherÕs 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 ptÕs preference, 4/5 switched for side effects. Four pts (1 plt count instability, 3 ptÕs preference) underwent Òdouble switchÓ (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 Òdouble switchÓ 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. Table 1. 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 0 1 1 Rom->El 4 1 2 1 PtÕs preference 7 (12.3) 3 (42.9) 2 (28.6) 2 (28.6) El->Rom 0 0 0 0 Rom->El 7 3 2 2 Adverse event¡¡ 5 (8.8) 1 (20.0) 3 (60.0) 1 (20.0) El->Rom 5 1 3 1 Rom->El 0 0 0 0 CR: complete response; R: response; NR: no response (Rodeghiero et al, Blood 2009) *1 NR secondary to neutralizing antibodies development ¡¡1 hepatic enzyme increase, 1 CPK increase; 2 skin rash; 1 retinal thrombosis. 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.

Starting from 1980, 182 cases of primary extranodal non-Hodgkin’s lymphoma were diagnosed in our Division. Gastrointestinal NHL were the most frequent: 66 patients (36%), followed by head and neck (42 = 23%), skin(23 =13%), urogenital tract (16 = 9%), CNS (10 =5%), chest (9 = 5%), spleen (7 = 4%), bone (5 = 3%) soft tissues (4 = 2%). Median age was 55,4 (range 20–91); median age was lower in chest, bone and intestinal NHL. 77 patients had stage I disease (48,8%), 74 stage II (46,5%) and 8 patients stage III (5%). In the whole group, 134/182 (73.6%) patients achieved complete remission (CR); CRs were 81.8% in gastroenteric NHL, 75% in urogenital, 69.5% in skin, 66.6% in head and neck. Overall survival in the two most important groups are as follows: head and neck: 61% at 50 months and 55% at 100 months; gastrointestinal tract: at 50 months was 80%, at 100 months 75%. When prognostic factors were considered for the whole group, stage and modified I.P.I. (MIPI) were significantly associated with rate of complete remission and overall survival. Stage I pts had a significantly better rate of complete remission 83.1%, vs. 68.9% for stage II and 37.5% for stage III. Overall survival of stage I pts was significantly better than for patients with stage II or stage III disease (80% vs. 72.5% at 50 months; 80.1% vs. 62.7% at 100 months). Modified International Prognostic Index, MIPI is a score ranging from 0 to 5 according to age (>60), LDH (over normal values), ECOG P.S. (>1), Ann Arbor stage (II or III), extranodal sites (>1). Thirty six patients had a MIPI score of 0, 80 pts MIPI 1, 50 pts MIPI 2 and 16 had a MIPI score of 3 or more. A significant correlation between MIPI and achievement of CR was shown with 88.8% of pts with MIPI 0 achieving CR, 78.5% in MIPI 1, 28% in MIPI 2 and 25% in MIPI 3 or more. Overall survival for the four groups was as follows: 96%, 75%, 62%, 61% at 50 months; 96%, 70%, 54%, 24% at 100 months.

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