Standard Dose Rituximab and 3 4-Day Cycles of Dexamethasone (R+3D) Appears Curative in Females with ITP < 12 Months Duration

Background: Therapies in ITP primarily increase the platelet count while treatment continues: IVIG, steroids, IV RhIg, romiplostim, eltrombopag and others.  Curative effects of treatments other than splenectomy are uncertain; 2 recent studies with rituximab provided disappointing results. ITP in children often spontaneously improves but in children with chronic ITP and adults, this is much less common and management may be difficult. The aim of this study is to explore the efficacy and safety of R+3D.

Methods: ITP patients were managed with R+3D if appropriate. Forty-nine adults and 33 children with ITP (newly diagnosed, persistent, and chronic) were treated at Weill Cornell Medical College with the previously described R+3D treatment plan: weekly rituximab infusion 375mg/m² x 4 weeks + three 4-day cycles of 28mg/m² (max. 40mg) dexamethasone at 2-week intervals. Patients who came to the platelet disorders center were included even if they received all or part of their treatment elsewhere. Counts were obtained weekly, monthly, and 2-3x monthly thereafter for responders. Response was either partial (PR, plt count > 50,000-100,000) or complete (CR > 100,000). Analysis was descriptive and by Kaplan-Meier. Children and adults are presented separately.

Results: The overall estimated response (initial and long-term) in the 49 adults (22 men, 27 women) was associated with greater initial platelet response, female gender, and duration of ITP < 1 year. There was a significant difference in the projected 78% lasting response rate at 5 years in women with ITP of < 1 yr duration.  All other groups (men < or > 1 yr duration of ITP and women > 1 yr duration of ITP) had highly inferior results (<25%).

Ninety % of the 49 adults (44/49; 11 PRs and 33 CRs) initially responded to R+3Dex at 8 weeks. Children had lower initial responses at 45% (15/33; 2 PRs and 13 CRs). Four adults further improved from PR to CR and 2 children, 1 NR, 1 PR, to CR.  Kaplan Meier projected long-term treatment-free response for all adults treated with R+3Dex is 33.5%. Only 1 PR but 22/37 (59.5%) of CRs continue to maintain adequate platelet counts. Parallel projection of long-term response for children is 23.9%. In children, 10/16 (62.5%) responders continue to maintain their response at last follow-up., Female patients maintained a 44% long-term response at 5 years whereas male patients projected a rate of only 19% (p value = 0.009). In children, girls projected a 37% long-term response and boys projected 11% at 5 years.

Further divided by the duration of ITP, both adult and pediatric female patients with duration of ITP less than 12 months fared better than females with longer duration of disease (and males of any duration).

Conclusions: ITP does not typically display a large gender disparity compared to other autoimmune diseases such as systemic lupus erythematosus), (1.5F:1Mcompared to 9F:1M ). No gender differences were found in responses to first- and second-line treatments in a previous report (Andres et al., 2012). However, gender bias in especially long term response is dramatic and is shown separately in both children and adults; when combined with earlier treatment initiation, the difference in projected long-term, treatment-free remission is remarkable (Table 1). Studies in lymphoma and 2 other indications have also suggested a gender effect in response to rituximab, but attributed it to Pk in elderly women. The influence of gender on autoimmune diseases, ITP in particular, is complicated and warrants further study as to the mechanism of effect.

	Adults (n=49) Female: n=27 // Male: n=22	Children (n=33) Female: n=18 // Male: n=15
Initial Response	NR = 5 (10.2%)	NR = 18 (54.5%)
	PR = 11 (22.4%)	PR = 2 (6.1%)
	CR = 33 (67.4%)	CR = 13 (39.4%)
	Female: 26/27 (96.3%) Male: 18/22 (81.8%)	Female: 8/18 (44.4%) Male: 7/15 (46.7%)
Best Response	NR = 5 (10.2%)	NR = 17 (51.5%)
	PR = 7 (14.3%)	PR = 1 (3.0%)
	CR = 37 (75.5%)	CR = 15 (45.5%)
	Female: 26/27 (96.3%) Male: 18/22 (81.8%)	Female: 9/18 (50%) Male: 7/15 (46.7%)
Relapsed	21/44 (47.7%)	6/16 (37.5%)
	Female: 10/26 (38.5%) Male: 10/18 (55.5%)	Female: 2/9 (22.2%) Male: 4/7 (57.1%)
Ongoing	23/44 (52.3%)	10/16 (62.5%)
	Female: 16/26 (61.5%) Male: 8/18 (44.4%)	Female: 7/9 (77.7%) Male: 3/7 (42.9%)