Case Presentation. A Case from the Clinic. Additional Data. Examination and Data 10/27/2013

Transcription

1 Northwestern University Feinberg School of Medicine Treatment of Severe Thrombocytopenia in Systemic Lupus Erythematosus: The Role of New Agents Disclosures: Advisory Board: Incyte Corporation Speaker s Bureau: Incyte Corporation Brady L. Stein, MD MHS Assistant Professor of Medicine Division of Hematology/Oncology and Developmental Therapeutics Institute October 28, 2013 Case Presentation A Case from the Clinic 33 year-old woman with SLE referred after experiencing 7 days of excessive bruising and epistaxis; otherwise asymptomatic SLE since 1998, well controlled, on hydroxychloroquine No fevers, NS, or weight loss; no rash or joint pain New herbal supplement (weight loss product) No other new medications Examination and Data Healthy appearing, no distress Oral mucosal and LE petechiae No lymphadenopathy or splenomegaly Laboratories: WBC: 3.7 x 10 9 /L (mild) Hemoglobin: 11.5 g/dl (mild) Platelets: 2 x 10 9 /L Previously normal Additional Data Negative anti-ds DNA antibody and Normal ESR and CRP Normal anti-phospholipid antibody levels HIV, Hepatitis C and H.pylori negative LDH normal Blood smear notable for severe thrombocytopenia Clinical Diagnosis Acute immune thrombocytopenia, underlying SLE 1

2 Early course Stop herbal supplements *IVIG and Dexamethasone 40mg daily x 4 days Complete response within 7 days ( 146 x 10 9 /L) Rapid decline in platelets, requiring 3 additional courses of pulse Dexamethasone No change in SLE activity (remains quiescent) Steroid-associated long term consequences unacceptable What is the ideal next treatment strategy? Overview: Thrombocytopenia in SLE Epidemiology Differential Diagnosis Pathogenesis Management strategies *Steroids and/or IVIG typical 1 st line approaches to ITP per American Society of Hematology Guidelines (ASH) 2011 Epidemiology: Thrombocytopenia in SLE Definition: Platelets < 100 x 10 9 /L on 2 occasions Prevalence: Complicates course of between 7-30% of SLE patients Precedes official diagnosis of SLE in up to 16% Particularly women with high-titer ANA or other autoantibodies Acute, severe TCP more associated with SLE activity Chronic, moderate TCP less associated with SLE activity Relevance: May associate with increased morbidity, end-organ damage and mortality Diagnostic Evaluation Reviewed by Hepburn, AL et al, Rheumatology 2010 Ziakas, PD Ann Rheum Dis 2005 Zhao Platelets 2010 Thrombocytopenia in SLE: Differential Dx and workup Other Immunemediated processes Evan s syndrome: DAT and hemolysis labs (retic, LDH, etc) TTP: Blood smear, hemolysis labs, ADAMTS 13 testing Macrophage Activation syndrome: Ferritin, triglycerides, LDH Immune thrombocytopenia Anti-plt testing? Anti-phospholipid s? Platelet parameters? (MPV, reticulated plts) Thrombocytopenia in SLE patient Consumption: DIC: D-dimer, PT/PTT fibrinogen Blood loss (NSAIDs/Steroids): Occult stool testing Other vitamin/mineral deficiency: B12 and folate levels Pathogenesis: Immune thrombocytopenia Marrow disorders: MDS/Lymphoma Autoimmune fibrosis: Blood smear/marrow Infection: Typical and atypical Blood and urine cultures, imaging, etc Medication effects: Hold MMF, Azathioprine, MTX, Cyclophosphamide 2

3 Impairments in production and/or survival Impairment in platelet production TPO GP-Ib/IX Increased platelet destruction *GP-IIb/IIIa Management strategies: Older and Newer Splenic clearance Indications and considerations for treatment Age Co-morbidities Cost Lifestyle SLE activity Bleeding history Menorrhagia Platelet count Typical trigger is a platelet count of < x 10 9 /L Need for anticoagulation Anti-phospholipid Antibody Syndrome Platelet goal of 50 or more if requiring anticoagulation or reduced dose of LMWH Need for procedures Older treatments: Splenectomy Splenectomy Decrease in antibody production and platelet clearance Largest series: 25 pts ( ) 88% with immediate response, 64% with sustained responses at 6 yrs Recent series: 20 patients ( ) 85% response rate with lap splenectomy, with disease activity (SLEDAI) scores and decreased steroid dosing -Concerns for poor efficacy and disease activity not confirmed in practice -*Recommended after failure of steroids in primary ITP in eligible candidates Dameshek 1960 Annals of Internal Medicine Hall, et al 1985 Annals of Internal Medicine You, et al 2004 Annals of Surgery *ASH ITP Guidelines 2011 Zhou 2013, Clinical Rheumatology Rituximab: Suppression of antibody production B cell TPO B cells result in polyclonal production, T cell, and dendritic cell activation Anti-CD20 antibody used for B cell depletion in autoimmune and neoplastic diseases Efficacy in Primary ITP Single agent: 40% with platelets > 50 x 10 9 /L at 1 year In Combination: 58-63% response rate with Dexamethasone at 6 months After splenectomy Unlabeled use for primary ITP, optimal dosing unknown, *typically used after failure of steroids/ivig, or splenectomy Godeau Blood 2008 Zaja Blood 2010 Gudbrandsdottir Blood 2013 *ASH ITP Guidelines 2011 Rituximab in SLE-thrombocytopenia Study Design Patients Response rates Jovancevic et al Lupus 2013 Jovancevic et al Lupus 2013 Tew et al Lupus 2010 Terrier et al Art Rheum 2010 Garcia-Carrasco et al Lupus 2010 Case series responders (9 complete) Review of literature Post-hoc analysis from *RCT As reviewed in Jovancevic et al Lupus 2013 *Merrill JT, et al. Art Rheum (10 with TTP) 57 responders (51 complete) Durability 7 long term responders Relapse in 13% 16 Normalized Not reported Prospective 13 evaluable 12 responders (10 complete) Prospective 7 evaluable 6 complete responders Not reported Not reported 3

4 Conclusions: Rituximab in SLE-thrombocytopenia Theoretical rationale given contribution from B cells to SLE/SLE-ITP pathogenesis Efficacy in SLE-ITP likely comparable to that of primary ITP Evidence from smaller, lower quality studies Unclear impact on underlying SLE disease activity Adverse reactions typically infusion-related PML in 2 SLE patients treated with Rituximab Previously on steroids and alkylating agent chemotherapy ACR estimate 2 cases per 8000 patients receiving Rituximab in 2008 Carson, KR et al. Blood 2009 Kavanaugh A, Matteson E Hotline: Rituximab and Progressive Multifocal Leukoencephalopathy. American College of Rheumatology TPO-agonists: Eltrombopag Romiplostim Thrombopoietin Agonists Bussel Lancet 2009; Cheng Lancet 2011 Kuter, Lancet 2008; Kuter, NEJM 2010 Platelet production not maximized in setting of peripheral destruction Insufficient increase in TPO levels Four phase 3 studies support efficacy Romiplostim (SC): Response rates in splenectomized (79%) and nonsplenectomized (88%) patients; lower rates of bleeding, treatment failure, improved quality of life Eltrombopag (PO): Increased (59%) and sustained responses compared to *SOC/placebo; less need for rescue, and allowed for DC other meds *SOC standard of care TPO Agonists Long term therapy usually required Durable response, but platelets decline upon discontinuation Safety concerns/adverse Effects Headache Bone marrow fibrosis Hepatotoxicity (Eltrombopag) Thrombosis, typically in those with additional risk factors? Concern in SLE patients with APLS Portal vein thrombosis in patients with liver disease Saleh, M et al. Blood yr f/u Eltrombopag Kuter, D et al. Br J Haematology year f/u Romiplostim SLE and TPO agonists-limited Evidence Potential Benefit Pregnant SLE patient with Evan s syndrome (plts 3 x 10 9 /L, refractory to steroids, IVIG, Rituxan, Cytoxan Responded to Romisplostim by 3 rd week, induced at 34 weeks 44 yo male SLE/APS patient with Evan s syndrome, developed severe thrombocytopenia (plts 3 x 10 9 /L) Responded to Romiplostim by 4 th week, allowing for splenectomy Alkaabi et al, Lupus 2012 Gonzalez-Nieto, I Lupus 2011 Possible Harm 19 yo with SLE, prior splenic and renal infarct with chronic thrombocytopenia, unresponsive to Rituxan/IVIG, developed renal limited thrombotic microangiopathy (TMA) 6 weeks after Romiplostim 19 yo with APL s and no thrombosis, but severe ITP developed renal TMA after 1 week of Eltrombopag Tomov et al, Lupus 2013 Jansen, et al. NEJM 2011 Other Potential Options Belimumab theoretical rationale, decrease in autoantibody production noted, and fewer hematological flares reported Epratuzumab effect on cytopenias unknown *Azathioprine *Mycophenolate Mofetil *Cyclosporine *Cyclophosphamide Stohl, et al Arthritis and Rheum 2012 Manzi et al Arthritis and Rheum 2010 *These agents can exacerbate thrombocytopenia as well, evidence typically limited Case resolution: Treating Our Patient Age and Co-morbidities Young, no co-morbidities Lifestyle No risky behaviors or occupation SLE activity Quiescent Immunosuppressive therapies not strongly indicated Platelet count Goal at least x 10 9 /L in this case Evidence not strong enough to recommend rituximab over splenectomy Individualized decision making: Splenectomy favored as her most durable option, but have to consider bleeding, infection (early and late), thrombosis Newer therapies not suitable in her case Deferred for now, tolerating prednisone 5mg daily with plts of 60 x 10 9 /L 4

5 Thank you for your attention 5