What is the next step after failure of steroids in ITP? Splenectomy & Rituximab Dr. Roberto Stasi Department of Haematology St George's Hospital and Medical School London
Factors that contribute to ITP management decisions The goal of treatment in chronic ITP is not well defined and depends on balancing efficacy against the adverse effects of a given treatment 1 Compliance Tolerance of side effects The extent of bleeding Complications of specific therapies Management decision factors 2,3 Accessibility of care Patient expectations Activity and lifestyle Potential interventions that may cause bleeding Comorbidities predisposing to bleeding 1. Rodeghiero F, et al. Blood 2009; 113: 2386 93; 2. Neunert C, et al. Blood 2011; 117: 4190 207; 3. Provan D, et al. Blood 2010; 115: 168 86
Available second-line treatments One-off treatments Splenectomy Rituximab Continued administration Further corticosteroids (e.g. high-dose DXM) Immunosuppressive agents (e.g. azathioprine) Continued administration TPO-R agonists (eltrombopag or romiplostim)
In favour of splenectomy Consolidated experience Historical 2 nd line treatment for ITP Efficacy Rapid response Compliance(one-off treatment) Safety Cost-effective 1. Hitzrot J et al. Ann Surg 1923;78:185 190; 2. Dameshek W et al. An New York Acad Sci 1960;82:924 938
Initial responses to splenectomy 85-90% Outcome after splenectomy patients (%) 100 90 80 70 60 50 40 30 20 10 0 66 47 adults-only case series (N = 2623) 22 CR PR Refractory to splenectomy 12 CR, complete response platelet count 150 x 10 9 /L at least one month after treatment in the absence of steroid therapy PR, partial response platelet count 50 x 10 9 /L at least one month after treatment in the absence of steroid therapy Kojouri K et al. Blood 2004;104:2623 2634
Probability of maintaining response for 5 years after surgery is 75% 1.0 0.9 0.8 Probability (%) 0.7 0.6 0.5 0.4 0.3 0.2 402 patients (137 males, 265 females) who underwent splenectomy for ITP between 1959 and 2002 in 22 different Italian Haematology Centres 0.1 0 0 48 96 144 192 240 Months Vianelli N et al. Haematologica 2005;90:72 77
Rapid response and compliance The immediate postoperative response ~80% 1 Issues of acceptance but no issues of compliance (one off treatment) 1. Schwartz et al. Am. J. Hematol. 72:94 98, 2003
Complication rates and mortality are further decreased with advances in surgical practice Death Laparotomy Articles 81 29 Mortality rate, % (no. patients who died/total no. patients evaluable) Complications Laparoscopy 1 (48/4955) 0.2 (3/1301) Articles 35 19 Complication rate, % (no. patients with complications/total no. patients evaluable) 12.9 (318/2465) 9.6 (88/921) Advances in surgical practice have led to a significant decrease in mortality and complication rates (p=0.008) Kojouri K et al. Blood 2004;104:2623 2634
Long-term complications have not been widely reported Life long risk of overwhelming post-splenectomy infection for splenectomized patients ~5% 1 Italian experience of fatal sepsis: Vianelli N et al. reported no cases of fatal sepsis (n=402) 2 Stasi R et al. reported no cases of fatal sepsis (n=208) 3 1. Davidson et al. Clin Microbiol Infect 2001; 7: 657 660 2.Vianelli N et al. Haematologica 2005;90:72 77 3. Stasi R et al. Am J Med 1995;98:436 442
Splenectomy is not financially toxic Splenectomy $8,034 (~ 5,000). Price is for a 4 day admission. More days charged at $1800 per day. 1 1 http://healthcarebluebook.com/page_results.aspx?id=25&dataset=hosp 2 http://www.scottishmedicines.org.uk/files/romiplostim_nplate FINAL_May_2009_Amended_1_Sept_2009_for_website.pdf
Against splenectomy Irreversible effects Immunological (can not put back the spleen) cosmetic Lack of validated predictive factors Site of splenic platelet sequestration Pre-splenectomy response to corticosteroids Younger age Higher platelet count after splenectomy Response to IVIG Not all patients are candidates to surgery Comorbidities, patient refusal
In favour of rituximab 10+ year experience Medical therapy: better accepted than splenectomy Good response rate It can avoid splenectomy Safety Costs
Rituximab systematic review: Efficacy 80,0 19 reports for efficacy (n = 313) Pooled estimate for response (%) 70,0 60,0 50,0 40,0 30,0 20,0 10,0 46,3 24,0 62,5 0,0 150 x 10E9/L 50-150 x 10E9/L >50 x 10E9/L Arnold DM et al. Ann Intern Med. 2007;146:25-33
Low vs. standard dose Rituximab Low dose 1 Standard dose 2 Patients 28 57 Dose 100 mg x 4 375 mg/m 2 x 4 CR CCR 12 (43%) (>100 x 10 9 /l) 9 (32%) (11 months) 18 (32%) (>150 x 10 9 /l) 16 (28%) (17 months) Time to response 44 days 21-56 days 1 Zaja Haematologica 2008;93:930 2 Cooper Br J Haem 2004; 125: 232
The use of rituximab can avoid splenectomy Godeau et al. Blood. 2008;112(4):999-1004
Adverse events associated with Rituximab Arnold et al. Ann Intern Med. 2007;146(1):25-33
Against rituximab Low long term response rate Viral reactivation JCV (PML) 1 HBV HZV Avoid pregnancy for 12 months 2 1 Carson KR et al. Blood. 2009;113(20):4834-4840 2 Chakravarty et al. Blood. 2011;117(5):1499-1506
Long term response to rituximab Total Initial response 1 year 2 years 5 years 100% 100% 57% 57% 38% 38% 30% 30% 21% 26% Children Adults Patel et al. Blood. 2012 Jun 21;119(25):5989-95
Summary There is no reason to delay splenectomy after other treatments have failed When splenectomy is contraindicated, rituximab provides a good alternative Both splenectomy and rituximab are tolerated well They may be the definitive treatment for chronic ITP and are much cheaper than TPO-R agonists