Venous Thromboembolism in Hematopoietic Stem Cell Transplant Recipients

REVIEW Venous thromboembolism in hematopoietic stem cell transplant recipients

S Chaturvedi1, A Neff2, A Nagler3, U Savani4, M Mohty5 and BN Savani1

Venous thromboembolism (VTE) is an increasingly recognized problem in the post-hematopoietic stem cell transplantation (HSCT) setting, with a lack of high-quality evidence-based data to recommend best practices. Few patients with hematologic malignancies and even fewer post-HSCT patients were included in randomized trials of VTE prophylaxis and treatment. Prior VTE, GVHD, infections and indwelling venous catheters are risk factors for thrombosis. The increasing use of post-transplant maintenance therapy with lenalidomide in patients with multiple myeloma adds to this risk after autologous HSCT. These patients are also at high risk of bleeding complications because of prolonged thrombocytopenia and managing the competing risks of bleeding and thrombosis can be challenging. This review aims to provide a practical, clinician-focused approach to the prevention and treatment of VTE in the post-HSCT setting.

Bone Marrow Transplantation (2016) 51, 473–478; doi:10.1038/bmt.2015.308; published online 21 December 2015

INTRODUCTION INCIDENCE AND RISK FACTORS FOR VTE AFTER HSCT The association between malignancy and thromboembolic disease is Retrospective studies of venous thromboembolic complications in well established.1–2 In addition to increased prevalence in patients HSCT recipients report a high incidence of VTE, as well as bleeding with cancer, venous thromboembolism (VTE) has been identified as complications.17–19,30,31 In an analysis of 1514 patients undergoing an independent predictor of reduced survival in these patients.3–5 HSCT as inpatients and followed for 180 days, Gerber et al.17 Although most commonly associated with solid malignancies, VTE is reported a 4.6% incidence of VTE, the majority of which were increasingly recognized as a complication in patients with hemato- catheter related and all of which occurred after engraftment. logic malignancies and various studies have reported rates of VTE as Another retrospective series of 447 patients undergoing bone high as 6% in patients with lymphoma,6,7 5–20% in patients with marrow transplantation reported a 5.7% incidence of VTE in the acute leukemia8,9 and 5–10% in multiple myeloma (MM) that can first 100 days following transplant despite being on heparin increase to as high as 23–75% in patients treated with chemotherapy, prophylaxis (100 U/kg IV daily) for hepatic sinusoidal obstruction thalidomide or lenalidomide, and dexamethasone.10,11 Alarge syndrome.18 A retrospective study by O’Hara et al.31 from Indiana number of patients with hematologic malignancies undergo hema- University found a 2.5% incidence of VTE in patients undergoing topoietic stem cell transplantation (HSCT); however, there is limited autologous HSCT, however, large proportion of patients in this information regarding the incidence, risk factors, and the optimal study underwent HSCT for germ cell tumors and not hematologic approach to prevention and treatment of VTE in these patients. A conditions. Finally, Gonsalves et al.30 investigated the incidence of 3.7% 1-year incidence of VTE, and 8–20% incidence of catheter-related symptomatic VTE after HSCT in an ambulatory care setting and thrombosis (CRT) have been reported in autologous stem cell found a 1-year incidence of 3.7%. These studies reported that VTE transplant recipients.12 HSCT recipients have several identifiable risk occurred more frequently following allogenic HSCT, in patients factors for thrombosis including malignancy, high-dose myeloablative with a history of previous VTE or those with GVHD.19,31 chemotherapy and immune-modulatory drugs,13–16 graft versus host Most episodes of VTE in these studies were catheter related. disease (GVHD),17–19 infections,14,20 indwelling vascular catheters and Cortolezzi et al.32 have previously reported that there was a 12% prolonged immobilization.14 HSCT is also associated with an ‘acquired incidence of catheter-related thromboembolic complications hypercoagulable state’ characterized by inflammation, endothelial in a cohort of 416 patients with hematologic malignancies. damage and activation of endothelium-dependent coagulation Twenty-one percent of these patients were HSCT recipients factors, increase in von Willebrand factor and platelet adhesion, and 81.2% had platelet counts o50 000/μL. There was a increased thrombin generation, decreased anti-thrombin levels and non-statistically significant trend toward lower rates of thrombotic decreased levels of anticoagulant proteins such as protein C.21–27 graft complications with thrombocytopenia.32 GVHD has also been versus host disease (GVHD) is associated with inflammation that leads identified as a risk factor for VTE,17–19 which has been attributed to to endothelial damage and activation.28 TNF alpha, an essential the inflammatory milieu and endothelial activation.28,29 In mediator in the pathogenesis of GVHD, has been shown to enhance addition, some patients with GVH are treated with extracorporeal pro-thrombotic alterations on the endothelial cell surface.29 photopheresis that necessitates placement of a central venous

1Hematology and Stem Cell Transplantation Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, TN, USA; 2Benign Hematology Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, OH, USA; 3Hematology Division, Department of Medicine, Chaim Sheba Medical Center, Tel Hahomer, Israel; 4University of Michigan, Ann Arbor, MI, USA and 5Department of Haematology, Saint Antoine Hospital, Paris, France. Correspondence: Dr BN Savani, Hematology and Stem Cell Transplantation Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, 1301 Medical Center Drive, 3927 TVC, Nashville, TN 37232, USA. E-mail: [email protected] Received 22 July 2015; revised 22 October 2015; accepted 23 October 2015; published online 21 December 2015 Thromboembolism after stem cell transplantation S Chaturvedi et al 474 catheter (CVC) for prolonged periods. This is a potential risk factor contraindicated. In a prospective study of 78 patients with CRT for thrombosis which has been reported as a reason for treated with full-dose dalteparin bridged to warfarin, there were discontinuation of therapy.33,34 no new thrombotic events at 3 months and 57% of catheters were In addition to a risk of thrombosis, HSCT recipients also have an still functional.49 The optimum duration of anticoagulation has not increased risk of bleeding because of prolonged and severe been evaluated in prospective studies. Current American College thrombocytopenia. In the studies mentioned above, the rate of of Chest Physicians (ACCP) guidelines recommend anticoagulation bleeding in HSCT recipients ranges from 15.2 to 27.1%, and for 3 months or until the catheter is removed, whichever is life-threatening or fatal bleeding occurred in 1.1–3.6% longer.48 Several clinicians prefer to continue anticoagulation for – patients.17 19 Gerber et al.17 reported that the initiation of 1–2 weeks after the catheter is removed.41 therapeutic anticoagulation during days 1–180 after HSCT was the strongest predictor of bleeding (odds ratio (OR) 3.1 [95% confidence interval (CI) 1.8–5.5)]. Furthermore, GVHD VTE PROPHYLAXIS [OR 2.4 (95% CI 1.1–3.3)] increased the risk of bleeding, There are currently no studies of empiric prophylactic whereas auto-transplantation (versus allotransplant) was anticoagulation in HSCT recipients. In the absence of protective [OR 0.46 (95% CI 0.33–0.64)].17 Given the competing HSCT-specific studies, studies in patients with cancer provide the risks of bleeding and thrombosis, identifying patients at high risk next best evidence that can be extrapolated. Two large studies of for these outcomes can be used to optimize strategies for VTE prophylactic anticoagulation in patients with cancer undergoing prophylaxis. Previous VTE is a well-recognized risk factor for VTE chemotherapy, the PROTECHT (nadroparin vs placebo) and that may help target prophylaxis.35,36 GVHD, although associated SAVE-ONCO (semuloparin vs placebo) trials showed a significant with thrombosis, is less useful as it is also associated with an reduction in the relative risk of VTE with anticoagulation, however, increased risk of bleeding. The timing of hemostatic complications the absolute risk reduction is small and no survival benefit is also an important consideration as bleeding events are more has been demonstrated.50,51 The American Society of Clinical likely to occur early in the post-transplant course when patients Oncology (ASCO) and National Comprehensive Cancer Network are profoundly thrombocytopenic, whereas thrombotic events (NCCN) guidelines advise against the use of routine prophylactic 17,19 occur more frequently after hematopoietic recovery. anticoagulation in ambulatory patients with cancer.47,52 An It must be noted that prolonged hospitalization, common in the exception is made for patients with MM receiving treatment with 37 HSCT setting, is a known risk factor for VTE. This association has thalidomide, lenalidomide or pomalidomide. Hospitalized patients not been extensively studied in the HSCT population; however, and those with CVCs are also at higher risk of thrombosis.53 These one study comparing outcomes of brief (o5 days) and prolonged special situations are addressed below. (45 days) in patients undergoing autologous HSCT for MM noted a non-statistically significant increased rate of thrombosis in Multiple myeloma patients with prolonged hospitalizations (3.7% vs 4.6%).38 Inherited thombophilias (for example, factor V Leiden, Patients with MM have a high baseline risk of thrombosis of – – prothrombin gene mutation, protein C or S deficiency) are 5 10% that increases to 23 75% in patients being treated with the immunomodulators thalidomide and lenalidomide with dexa- associated with an increased risk of thrombosis in the general 10,11 population.37 In the HSCT population, one prospective study of methasone or chemotherapy. Consolidation therapy with the 171 patients suggested that there is a disproportionate prevalence thalidomide or lenalidomide after HSCT has been shown to improve complete respose rates and prolong event-free survival of inherited thrombophilia in patients with central line-associated 54,55 thrombosis,39 while a second study found no correlation and is thus rapidly becoming standard of care. In patients between inherited thrombophilias and thrombotic events in HSCT receiving thalidomide consolidation after autologous stem cell 54 recipients.40 An inherited thrombophilia may add some risk in transplantation for MM, Barlogie et al. reported that rate of VTE patients who already have an underlying malignancy, indwelling was 24% and 6% in the induction and consolidation periods, catheters and often prolonged hospitalizations. respectively, despite thromboprophylaxis with LMWH. McCarthy et al.55 reported that there were no episodes of VTE in patients receiving consolidation therapy with lenalidomide, however, these CATHETER-RELATED THROMBOSIS patients were also getting prophylactic anticoagulation. Although CRT is a common problem with asymptomatic thrombosis pomalidomide has not been evaluated in the setting of consolida- occurring in 19–41%, and symptomatic thrombosis in 1–4% of tion after autologous HSCT, a 2% to 4% rate of VTE with patients.41 CRT can lead to significant discomfort from symptoms, thromboprophylaxis has been reported in the setting of relapsed/ 56–58 catheter dysfunction, increased risk for infections and long-term refractory myeloma. Thromboprophylaxis strategies have not risk for venous stenosis.41 Although CRT clearly contributes to been specifically evaluated in patients on maintenance therapy morbidity and catheter dysfunction, the majority of CRT are with novel immune-modulatory agents after transplant, however, asymptomatic and there is little evidence that CRT is associated studies in patients with newly diagnosed MM receiving lenalido- with an increased rate of pulmonary embolism or increased mide or thalidomide-based treatments show a significant benefitof mortality.42 The primary objectives of treatment of CRT are to thromboprophylaxis.59,60 Palumbo et al.59 randomly assigned 659 reduce symptoms, prevent extension into more central veins, patients receiving thalidomide-based regimens to low-dose aspirin, preserve access and to prevent chronic venous stenosis. There is warfarin or enoxaparin. The rate of VTE, serious cardiovascular no evidence that removal of the catheter improves outcomes.43,44 events or sudden cardiac death in the first 6 months was 6.4% in Therefore, it is reasonable to not remove the catheter unless it is the aspirin group, 8.2% in the warfarin group and 5% in the non-functional, no longer needed or may be infected. There are enoxaparin group, whereas there were three major bleeding no prospective randomized studies of thrombolysis for CRT, episodes, all in the aspirin group. The risk of VTE in the aspirin however, thrombus reduction by catheter-directed thrombolysis is and enoxaparin groups was not different. In a second study relatively safe and effective and may be tried in an attempt to evaluating aspirin vs LMWH prophylaxis, 342 patients on preserve the catheter.45,46 Anticoagulation is required in patients lenalidomide-based regimens were randomized to low-dose aspirin with acute CRT regardless of whether the catheter is removed.47,48 or prophylactic LMWH. No major hemorrhagic complications were We prefer low molecular weight heparin (LMWH) as there is reported. Symptomatic VTE was reported in 2.3% patients in the evidence of its effectiveness in other patients with cancer-related aspirin group and 1.2% in the LMWH group. Compared with LMWH, VTE. Vitamin K antagonists may be used if LMWH is the absolute difference in the proportion of VTE was 1.07% (95% CI,

Bone Marrow Transplantation (2016) 473 – 478 © 2016 Macmillan Publishers Limited Thromboembolism after stem cell transplantation S Chaturvedi et al 475 − 1.69 to 3.83; P = 0.452) in the ASA group.60 Therefore, ASA may be more traditional model where patients remained hospitalized for an effective and less-expensive alternative to LMWH thrombopro- most of the post-transplant course. Ambulatory HSCT patients phylaxis in low-risk patients. The International Myeloma Working frequently have indwelling vascular catheters with the potential group and ASCO recommend prophylaxis with either aspirin or for developing CRT. Incidence of symptomatic CRT ranges from 4 LMWH for lower risk patients, and LMWH for higher risk patients to 14% in different studies.41 Despite multiple randomized and receiving thalidomide or lenalidomide.47,61 observational studies, thromboprophylaxis for the prevention of CRT in patients with cancer remains controversial. A randomized Hospitalized patients control trial of enoxaparin 40 mg SC daily for 6 weeks vs placebo Based on randomized clinical trials of thromboprophylaxis in daily for 6 weeks in patients with cancer undergoing CVC insertion 62,63 found that enoxaparin was safe, but did not reduce the rate medically ill hospitalized patients, and a meta-analysis 45 that demonstrated 40% lower rates of VTE with pharmacologic of CVC-related thrombosis. The largest study of thromboprophylaxis versus placebo,64 the current ACCP52 and prophylaxis in CVC randomized 1590 cancer patients undergoing 47 chemotherapy to adjusted-dose warfarin (international ASCO guidelines strongly recommend thromboprophylaxis in normalized ratio, 1.5–2.0), fixed-dose warfarin (1 mg/d) and no hospitalized medically ill and cancer patients, respectively. prophylaxis.65 Symptomatic CRT was less frequent in the patients However, trials of thromboprophylaxis did not include given adjusted-dose warfarin than in those who received no HSCT patients who are not specifically included in these prophylaxis (2.7% vs 5.9%, P = 0.019), but major bleeding recommendations. The potential benefit from VTE prophylaxis is was more common (3.4% vs 0.2%, Po0.001). Warfarin 1 mg/d proportional to VTE risk and therefore this is particularly important was not protective but was still associated with increased risk of in patients with reduced mobility, and with a history of VTE (if not major bleeding.65 Three recent meta-analyses of randomized on long-term anticoagulation) because of an even higher risk trials concluded that prophylactic warfarin and LMWH do not of thrombosis. Our practice is to start prophylactic anticoagulation – significantly reduce symptomatic CRT in patients with cancer.66 68 for hospitalized patients in the post-transplant period once the Based on the available evidence, prophylactic anticoagulation to platelet count is 450 000/μL, and there is no active bleeding. For prevent CRT is not routinely recommended.41 very high-risk patients, anticoagulation can be considered if the platelet count is 430 000/μL, however, this must be balanced with the risk of bleeding. VTE TREATMENT Venous duplex ultrasonography should be performed in patients Central venous catheters presenting with extremity swelling, redness or tenderness; or There is an emerging trend toward increasing ambulatory care pulmonary angiography in patients with chest pain, dyspnea or and 'outpatient transplants' in HSCT patients, in contrast with a unexplained tachycardia. A clinical assessment of bleeding risk is

Table 1. Risk factors, prevention and treatment of venous thromboembolism in HSCT recipients

Risk factors Underlying malignancy (MM, leukemia, lymphoma) Indwelling vascular catheters IMiDs (lenalidomide, thalidomide, pomalidomide) in patients with MM Prolonged hospitalization GVHD Infections Prior history of venous thromboembolism Other inherited or acquired thrombophilia

Prophylaxis Indications for prophylaxis Patients with MM receiving IMiDs. During hospitalization or post-operatively, as long as platelet count is 450 000/μL. Prophylaxis is not recommended in outpatients with indwelling vascular catheters. Suggested prophylactic strategy Aspirin in low-risk patients with MM receiving IMiDs. LMWH (prophylactic dose of 40 mg SC daily) for higher risk (4 1 risk factor) patients with MM receiving IMiDs. Prophylactic doses of UFH or LMWH in hospitalized patients. Treatment General principles Start therapeutic doses of LMWH or IV UFH in patients who have platelet count 450 000/μL and no active bleeding. UFH is preferred in case of renal impairment (GFR o30 mL/min) or high bleeding risk. Continue LMWH or transition to warfarin (if LMWH is contraindicated) for maintenance therapy. DOACs are not recommended in patients with cancer. Duration of anticoagulation General: 3–6 months or as long as malignancy or use of IMiDs persists, whichever is longer. Catheter-related thrombosis: 3 months or as long as catheter is in place. Inferior vena cava ﬁlters Restrict use to patients in whom anticoagulation is contraindicated, or those who develop pulmonary embolism on anticoagulation. Remove as soon as anticoagulation can be started. Abbreviations: DOACs = direct oral anticoagulants; IMiDs = immunomodulatory drugs; LMWH = low molecular weight heparin; MM = multiple myeloma; UFH = unfractionated heparin.

© 2016 Macmillan Publishers Limited Bone Marrow Transplantation (2016) 473 – 478 Thromboembolism after stem cell transplantation S Chaturvedi et al 476 necessary in patients who are diagnosed with VTE. Patients with contraindicated) may be used. We do not recommend treating no increased risk based on bleeding history and platelet count patients with active cancer with direct oral anticoagulants outside 450 000/μL, should be started on therapeutic anticoagulation of a clinical trial. with either LMWH or unfractionated heparin. The use of LMWH is restricted to patients with glomerular filtration rate 430 mL/min, whereas unfractionated heparin is used in patients with impaired CONCLUSIONS renal function (glomerular filtration rate o30 mL/min) or those VTE is an increasingly recognized problem in patients with with high bleeding risk. Following initiation of anticoagulation hematologic malignancies, including HSCT patients, however, with LMWH or unfractionated heparin, patients may be continued these patients are also at risk of potentially life-threatening on LMWH or transitioned to warfarin with a standard international bleeding complications complicating VTE prevention and normalized ratio target of 2–3. LMWH is preferred in patients with treatment strategies. Pharmacologic prophylaxis is indicated in evidence of relapsed malignancy. The newer, direct oral antic- patients on lenalidomide (or other immunomodulatory agent) oagulants have not been evaluated in patients with cancer or consolidation therapy after HSCT, and should be considered in HSCT recipients. A recent meta-analysis of phase 3 trials of direct patients with a history of VTE. We recommend treating sympto- oral anticoagulants for treatment of VTE noted that in the subset matic or incidental VTE with full-dose anticoagulation for at least of 973 patients with cancer, the rate of recurrent VTE was 4.1% 3 months or longer in the presence of active cancer. Central compared with 6.1% with warfarin, and rates of bleeding were 69 venous CRT may be treated with full-dose anticoagulation and similar. There is a need for trials evaluating the use of direct oral does not always necessitate removal of the catheter (Table 1). anticoagulants in patients with cancer and HSCT. Based on current There is an urgent need for well-designed clinical studies of VTE evidence, their use cannot be recommended outside of a research prevention and treatment in HSCT patients. setting. The use of inferior vena cava filters should be restricted to patients with acute deep vein thrombosis and a contraindication CONFLICT OF INTEREST to anticoagulation, and possibly patients who develop pulmonary The authors declare no conflict of interest. embolism while on therapeutic anticoagulation.48 Filters should not be used for primary prophylaxis of pulmonary embolism.70–72 Retrievable filters should be removed as soon as risk of pulmonary REFERENCES embolism resolves or when anticoagulation can be resumed. 1 Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous throm- These recommendations are in keeping with the 2012 boembolism and its effect on survival among patients with common cancers. 47,72 ACCP guidelines and the ASH choosing wisely campaign. In Arch Intern Med 2006; 166:458–464. patients with large, symptomatic thrombosis and severe 2 Khorana AA. 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