Venous Thromboembolism (VTE) in Myeloma. Christine Chen May 2017

Transcription

1 Venous Thromboembolism (VTE) in Myeloma Christine Chen May 2017

2 Objectives 1. Review the magnitude of the problem and why myeloma patients are at risk of VTE 2. Discuss thromboprophylaxis approaches in myeloma 3. Provide guidance for the treatment of cancerrelated VTE Choice of therapeutic agent Dosing Duration of therapy Monitoring

3 Disclosures n None applicable to this presentation

4 Case 1 n 75 year old male with newly diagnosed myeloma is started on Rd therapy n He develops a DVT in the left leg at the beginning of cycle 2 n He was supposed to take ASA 81 mg as prophylaxis but didn t like it due to excess bruising n He is otherwise quite fit

5 What would you do? 1. LMWH x 5 days, then warfarin x 6 mos 2. LMWH x 6 mos 3. LMWH indefinitely 4. Apixaban or other DOAC x 6 mos 5. Apixaban or other DOAC indefinitely

6 Facts - VTE in Cancer n Cancer patients: Have a 4-7-fold increased risk of VTE than noncancer patients Comprise 20% of all VTE pts Have a 3-fold increased risk of VTE recurrence Have a 4-fold higher risk of death over cancer patients without VTE Streiff. ASH Education book 2016, pp

7 Type of cancer and risk of VTE Characteristic VTE Risk (95% CI) Cancer site - All cancers IRR, 3.96 ( ) - Pancreas IRR, ( ) - Hematologic IRR, ( ) - Brain IRR, ( ) - Lung IRR, 7.27 ( ) - Colorectal IRR, 3.93 ( ) - Prostate IRR, 3.25 ( ) - Breast IRR, 2.87 ( ) Higher risk with advanced stage, high grade, active cancer Streiff ASH Education Book 2016

8 VTE risks in myeloma Disease-related Patient-related Treatmentrelated hyperviscosity, renal failure, chrom 11 abnorms, light chain disease Prior VTE, immobility, advanced age, obesity, paraplegia, thrombophilia, infection CVC line, high-dose DEX, ESAs, surgery, IMiD therapy (particularly in combination) Proposed mechanisms: Increased FVIII, VWF, P-selectin, and fibrinogen M-protein associated TF activity Cytokine-mediated increased APCR, decreased PS Increased cathepsin G (platelet agonist) à ASA prophylaxis

9 Risk-adapted model for thromboprophylaxis with IMiDs (IMWG) Larocca et al: n=342 NDMM treated with Rd + MPR consolidation Low risk for VTE and bleeding ASA 100mg po OD (VTE 2.27%) vs Enoxaparin 40mg SC OD (VTE 1.2%) P=0.452 Palumbo et al. Leukemia 2008;22:414 Larocca et al. Blood 2012;119:933

10 Princess Margaret Policy for Thromboprophylaxis with IMiDs n Low risk for VTE No prior VTE, nonsedentary, no thrombophilia ASA 81mg daily (even with maintenance) n High risk for VTE Prior VTE, sedentary, thrombophilia Full dose LMWH (no data for dosing) Could consider warfarin or DOACs if LMWH contraindicated or compliance is an issue

11 Treatment of VTE in Cancer n Standard approach for VTE in non-cancer patients à heparin (either LMWH or UFH) x 5-10 days overlapping with warfarin to continue x 3-6 months Prandoni et al. Blood 2002;100:

12 The CLOT Trial Dalteparin 200 IU/kg SC x 5-7 days followed by Warfarin PO daily x 6 mos (target INR 2.5) Dalteparin 200 IU/kg SC x 1 mo, then dropped to 75 80% of full dose for months % 9% HR 0.48 Lee et al. NEJM 2003;349:146

13 LMWH versus LMWH + warfarin for short-term VTE therapy No.of pts LMWH Dose and duration CLOT (Lee 2003) 672 Dalteparin 200IU/kg OD x 1 mo, 150IU/kg OD x 5 mos CANTHANOX (Meyer 2002) 146 Enoxaparin 1.5 mg/kg OD x 3 mos LITE (Hull 2006) 200 Tinzaparin 175 IU/kg OD x 3 mos ONCENOX (Deitcher 2006) 122 Enoxaparin 1mg/kg BID x 6 days, 1 mg/kg or 1.5mg/kg OD x 6 mos CATCH (Lee 2015) 900 Tinzaparin 175 IU/kg OD x 6 mos LMWH consistently leads to lower VTE recurrence rates than LMWH + warfarin

14 Can we do better? n Longer duration of therapy n Use of newer direct oral anticoagulants (DOACs) n Predictive tools

15 Longer duration of anticoagulation DALTECAN study assessing efficacy/safety of LMWH x 12mos Dalteparin 200 IU/kg x 1mo, then reduced dose 150 IU/kg mos 2-12 (N=334) LMWH for 12 months appears effective and safe Indefinite anticoagulation may be appropriate if ongoing active cancer or therapy (ACCP, NCCN, ASCO) Francis et al. J Thromb Haemost 2015;13:1028

16 Use of newer DOACs in cancer DOACs vs warfarin: 6 RCTs with and without cancer meta-analysis including 1132 cancer patients showed DOACs have a lower VTE recurrence (OR 0.63) with comparable safety (OR 0.77) DOACs vs LMWH: No head to head comparisons in cancer thrombosis Indirect network comparison showed comparable efficacy (RR 1.08) and nonsignificant improved safety with DOAC (RR 0.67) Awaiting results of RCTs: CANVAS, CASTA DIVA, HOKUSAI CA pts N=940 DOAC (edoxaban, apixaban, or rivaroxaban) LMWH (dalteparin, enoxaparin, fondaparinux) Vedovati et al. Chest 2015;147:475 Posch et al. Thromb Res 2015;136:582

17 Direct Oral Anticoagulants (DOACs)

18 Can predictive tools help? Event Recurrent VTE by 1 yr Major bleed Death due to CA A1 n=119 A2 n=123 B N=105 P value 18.5% 21.9% 2.8% < % 6.5% 4.8% % 15.4% 10.5% Patients with active cancer and VTE treated x 6 mos with LMWH Residual clot assessed on repeat ultrasound (69% positive) Randomized based on results Absence of residual clot identifies a low risk group for recurrent VTE P value comparing A1 to B Napolitano JCO 2014;32:3607

19 Other tips: VTE in Cancer n n Avoid use of IVC filters no data showing reduction in mortality or hospitalization Refractory VTE: If on warfarin, switch to LMWH If on LMWH, consider empiric increase of dose by 20-50% No evidence that DOACs are more effective n Chemotherapy-induced thrombocytopenia (ISTH 2013) Acute VTE full dose LMWH + platelet transfusion to keep platelets >50 Non-acute VTE For platelets 50, full-dose LMWH without transfusion For platelets 25-50, reduce dose to 50% For platelets <20-25, withhold dose

20 Catheter-associated DVT Cancer patients: 2-fold increased risk at 4.3% incidence 0.3/1000 CVC days in cancer patients 2-3 fold increased risk of recurrence Risk of recurrence decreased by 77% if anticoagulated >90 days (OR 0.23) consider anticoagulation for duration of line (if longer than 90days) No need to remove line Thrombolyse for limb-threatening clots or massive PE Lee JCO 2006;24:1404 Bleker 2016 Thromb Res;140(suppl1):S81 Baumann J Vasc Surg Venous Lmphat Disord 2015;3:243

21 Conclusions n Management of VTE in cancer is challenging and myeloma patients have particular risks à IMiDs, sedentary, hyperviscosity, ESAs n LMWH has been standard therapeutic therapy for over a decade à DOACs emerging as new standard of care

22 Supplemental slides

23 VTE risks in myeloma Leleu et al. Thromb Haemost 2013; 110:

24 Active therapy is the major risk for VTE in cancer Characteristic VTE Risk (95% CI) Chemotherapy (in general) - During chemo 69.4 per 1000 person-years - 1 mo after chemo 48 per 1000 person-years - 2 mos after chemo 22.3 per 1000 person-years - 3 mos after chemo 14.6 per 1000 person-years In myeloma, the following have been associated with increased VTE risk: - multi-agent chemo (vs monotherapy) - high-dose DEX - anthracyclines - erythroid-stimulating agents (ESA) - ImmunoModulatory Drugs (IMiDs)

25 VTE with IMiDs (no prophylaxis) Empiric observation that ASA decreases VTE risk IMiDs downregulate PU.1 à increased cathepsin G, a platelet aggregation agonist Palumbo et al. Leukemia 2008;22:414 Pal et al. Blood 2010;15:605