Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: Myelaxat, a phase 2 pilot study
Funding information: Celgene Company
Abstract
The risk of venous thromboembolism (VTE) is higher in myeloma patients receiving immunomodulatory compounds. A VTE prophylaxis using low-molecular-weight heparin or aspirin is therefore proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficacy and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective phase 2 pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with immunomodulatory compounds lenalidomide (len) or thalidomide (thal), using apixaban in a preventive scheme. Myeloma patients requiring Melphalan-Prednisone-Thalidomide in the first line, or Lenalidomide-Dexamethasone in the relapse setting received apixaban, 2.5 mg x 2/day for 6 months. Venous (pulmonary embolism—PE, or symptomatic proximal or distal deep vein thrombosis—DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. One hundred and four patients were enrolled (mean age 69.8 ± 7.8 years), 11 in first line and 93 in relapse. Two venous thrombotic events were observed, for example, an asymptomatic proximal DVT and a symptomatic distal DVT, in the context of apixaban stopped 14 days before, due to lenalidomide-induced thrombocytopenia. No PE or arterial cardiovascular events were reported. Only one major and 11 CRNM hemorrhages were reported. These data must now be confirmed on a randomized large study.
1 INTRODUCTION
Cancer is a well-recognized risk factor for venous thromboembolism (VTE),1 deep vein thrombosis (DVT), or pulmonary embolism (PE). Among oncologic diseases, multiple myeloma (MM) is the second most common hemopathy and accounts for 10% of hematologic cancers. The incidence of VTE among patients with MM is high, ranging from 3.9% to 11%, even upon thromboprophylaxis, in randomized studies using MPT or lenalidomide-dexamethasone.2-5 The risk of VTE in myeloma patients was reported as higher at induction therapy (26%–67%) than at relapse (11%–15%).6, 7 The median event occurrence rate varies from 1 to 6 months depending on the studies.8 Moreover, besides VTE, arterial cardiovascular events were also reported although at a lower incidence rate.9
The incidence of thromboembolic events observed in myeloma treated with thalidomide/lenalidomide (thal/len) combined with dexamethasone or chemotherapy is identical to that observed in populations at high risk of venous thromboembolism, that is, orthopedic surgery, for which anticoagulant prophylaxis is systematically recommended. Although thromboprophylaxis is largely used in treated-myeloma patients, the type and duration of treatment are debatable.10 A VTE primary prophylaxis strategy using low molecular weight heparin (LMWH) or aspirin according to a risk assessment model based on treatment received and level of risk was proposed by the International Myeloma Working Group.8
Although LMWH seem to be more suitable in terms of prevention efficacy in high-risk patients,11 their cost and injectable formulation affecting quality of life are brakes on their long-term use. Therefore, it seems appropriate to consider the use of oral anticoagulants that are currently used in the prevention and treatment of VTE. Among the available direct oral anticoagulants (DOACs), apixaban, a direct anti-Xa, was shown to be equivalent or superior to standard enoxaparin 4000 U/d prophylaxis in the reduction of major VTE in surgical (total knee and hip prosthesis) and medical patients, without any increase in bleeding.12-14
Because the profile of apixaban seems compatible with its use in thromboprophylaxis in myeloma treated with immunomodulatory compounds thal/len, we conducted a pilot prospective study to assess the safety and efficiency of apixaban for VTE prophylaxis in myeloma patients receiving thal/len.
2 METHODS
2.1 Design
The Myelaxat (anti-Xa anticoagulant in myeloma) study was a prospective multicenter non randomized phase 2 pilot study conducted in France between June 2014 and June 2016. The protocol was approved by the institutional ethics committee (University Hospital, Grenoble-Alpes, France). The trial was registered at ClinicalTrials.gov (NCT01309334). All patients provided informed consent.
2.2 Patients
Twenty-one centers enrolled consecutive patients with myeloma, who were asymptomatic for VTE at inclusion, and requiring melphalan-thalidomide-prednisone (patients in first line),15 or lenalidomide-dexamethasone (patients in relapse).7 All patients were over 18 years of age, with an Eastern cooperative Oncology Group performance status of 0 to 2.
Patients had to have an AST or ALT level less than three times the upper limit of normal, a bilirubin level less than 1.5 times the upper limit of normal, a platelet count of more than 75 G/L and a creatinine clearance (Cockcroft) of more than 30 mL/min. Medical practitioner was asked to specify the level of estimated thrombotic risk at study entry (high vs. low, according to IMWG).8
Patients needing curative anticoagulant treatment (heparin, LMWH, vitamin K antagonists, dabigatran, rivaroxaban, apixaban) or absolutely needing antiplatelet treatment for an associated disorder (atrial fibrillation, mechanical valves, proximal deep vein thrombosis, pulmonary embolism, acute coronary syndrom documented in less than the last 6 months), or preventive treatment with an anticoagulant in a postoperative context, were excluded; also patients receiving medication that might interact with apixaban, that is, azole antimycotic agents and inhibitors of HIV protease, and patients included in previous or upcoming chemotherapy myeloma trials.
Patients with active bleeding or at high hemorrhagic risk, or with the discovery of proximal DVT on the screening ultrasound were also excluded.
2.3 Study interventions
All patients received apixaban, 2.5 mg x 2/day for 6 months, and were monitored monthly for 7 months (clinical parameters—pulse, blood pressure, biochemistry—blood count, renal function, hepatic parameters). At the end of the study period, thromboprophylaxis was at the practitioners' discretion.
Systematic proximal bilateral compression ultrasound (CUS) was performed at screening, on day 10-15, and at months 1, 3, and 6.
Venous (PE, symptomatic proximal or distal DVT, or all proximal asymptomatic DVT) or arterial (myocardial infarction, cerebral ischemic event) and bleeding events according to ISTH 2005 (major or clinically relevant nonmajor [CRNM] bleeding event) were registered at each study visit.16
Apixaban had to be stopped in case of VTE or major/CRNM bleeding, thrombocytopenia less than 50 G/L, renal insufficiency defined by Cockcroft clearance less than 30 mL/min, or hepatopathy grade 2. In case of VTE or major bleeding, apixaban was definitively stopped.
2.4 Outcomes
The primary objective was to evaluate the incidence of venous thromboembolic event and the incidence of hemorrhagic complications.
The main outcomes were total VTE (fatal or nonfatal PE, symptomatic distal or proximal DVT of lower limbs, asymptomatic proximal DVT detected by bilateral compression ultrasound and VTE-related death) and major or clinically relevant nonmajor bleeding. Secondary objectives included the incidence of VTE complications according to the type of myeloma treatment (diagnosis or relapse), and the incidence of arterial cardiovascular events.
Efficacy and safety data were reviewed by an independent data monitoring committee.
2.5 Total patient sample size and statistical analysis
The incidence of VTE and bleeding events was calculated over the period of apixaban treatment and reported per 100 patient-months (% pt-mths). Because this was a pilot study, and taking into account the lack of data in the literature, the alpha risk was impossible to determine and the calculation of the required number of subjects was done according to data from the ADOPT study (for hemorrhages),14 and Carrier's meta-analysis (for VTE events).11
In the ADOPT study on medical conditions regarding hemorrhages, the rate of major and clinically relevant nonmajor bleeding was comparable in the 2 arms apixaban—enoxaparin over the period of exposure to the two drugs.14 The rate of major hemorrhagic events over 1 month of treatment with apixaban was 0.47% (95% CI 0.28–0.79). Considering a linear incidence of major hemorrhagic events over a 6 month period of treatment (as described in AVEROES),17 the expected median was 2.82% at the end of a 6-month period. With a sample size of 105 patients, we would be able to detect such events with a 95% confidence interval (0%–6%).
Based on Carrier's meta-analysis regarding VTE incidence,11 the lower incidence of symptomatic VTE events expected during the treatment period was <0.7 (95% CI 0.5–1.1) % pt-mths, as observed in patients in relapse receiving any prophylaxis.
Based on the results from the ADOPT study,14 the incidence was <0.47 (95% CI 0–1.9) % pt-mths for severe bleeding, and <2.2 (95% CI 0-5.32) % pt-mths for clinically relevant nonmajor bleeding.
All included patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional ethics committee (University Hospital, Grenoble-Alpes, France). The trial was registered at ClinicalTrials.gov (NCT01309334).
3 RESULTS
3.1 Patients
In total, 108 patients were assessed for eligibility between June 2014 and June 2016. After exclusion of four patients (Thrombocytopenia n = 2, long term anticoagulant n = 1, DVT at inclusion n = 1), 104 patients (89.4% in relapse) were enrolled. The main characteristics of the patients and the underlying diseases are shown in Table 1.
| Mean age (y) ± SD | 69.8 ± 7.8 |
| Gender | Male 56 (51.8%)/Female 52 (48.2%) |
| Creatinine clearance (Cockcroft, ml/min) | |
| <30 | 0 |
| 30-50 | 14 (13.5%) |
| >50 | 87 (83.6%) |
| NA | 3 |
| BMI (mean, SD) | 26.2 (4.8) |
| Myeloma | |
| IgG | 61.5% |
| IgA | 21.1% |
| IgD | 0.01% |
| Light chain | 16.3% |
| First line | 10.6% |
| Relapse | 89.4% |
| First relapse | 76.3% |
| Thrombotic assessment | |
| High risk | 14% |
| Low risk | 86% |
- Thrombotic assessment was based on IMWG criteria.
Fifteen patients had a previous VTE, five had a deep venous catheter. The thrombotic risk assessment according to IMWG criteria was classified as 14% high-risk and 86% low-risk patients.
The median duration of apixaban treatment per patient was 168 days (ranged 163–171). All patients treated with MPT (n = 11) received apixaban for the entire period (6 months). In contrast, for patients receiving lenalidomide-dexamethasone, apixaban had to be prematurely stopped because of myeloma progression (n = 9), or chemotherapy toxicity (n = 3). No patients received aspirin or LMWH during exposition to apixaban.
3.2 Thromboembolic outcome
The main clinical outcomes are depicted in Table 2. Neither arterial cardiovascular event, nor pulmonary embolism, and no death due to VTE was observed. Two VTE events were reported (incidence of VTE related to the entire Myelaxat population 0.38 (95% CI 0.05–1.4) % pt-mths, that is, 4.5% (95% CI 0.6–15.5) pt-year), both in patients in relapse receiving lenalidomide-dexamethasone treatment (Table 3). The symptomatic distal DVT was diagnosed in a high VTE risk patient during the sixth cycle of lenalidomide-dexamethasone, although apixaban had been stopped 14 days before due to Lenalidomide-induced thrombocytopenia grade 4. No VTE was reported in patients in first line.
| Outcomes | Number of patients (n = 104) | VTE risk assessment according to IMWG |
|---|---|---|
| Efficacy | ||
| VTE event | 2 | |
| VTE related death | 0 | |
| Type of VTE event | ||
| Asymptomatic proximal DVT | 1 | Low risk |
| Symptomatic distal DVT | 1 | High riska |
| Safety | ||
| Major bleeding | 1 | Low |
| Fatal bleeding | 0 | |
| Intracranial | 0 | |
| Nonfatal major bleeding (epistaxis) | 1 | |
| Clinically relevant nonmajor bleeding | 10 | |
| Epistaxis | 2 | Low |
| Gastrointestinal | 4 | Low |
| Genito-urinary | 3 | Low |
| Hematoma | 1 | Higha |
- Abbreviations: VTE, venous thromboembolic disease; DVT, deep vein thrombosis. The asymptomatic proximal DVT was discovered on CUS at month 3, while patient was responder to Lenalidomide-Dexamethasone.
- a Denotes the both outcome in a same patient.
| Carrier first line LMWH prophylaxis | Carrier relapse any prophylaxis | Myelaxat total (N = 104) | Myelaxat relapse (N = 93) |
|---|---|---|---|
| 2.1 (1.1-3.6) | 0.7 (0.5–1.1) | 0.38 (0.05-1.40) | 0.43 (0.05-1.45) |
- Abbreviation: VTE, venous thromboembolic disease.
- Incidence (95% CI) of VTE events was calculated for the entire population and for the patients in relapse because they represent the main population.
- Incidence of VTE depicted in Carrier's meta-analysis was also reported for first line and relapse.
3.3 Bleeding outcome
Eleven hemorrhagic events were observed during the period of apixaban treatment. One major hemorrhagic event was notified (incidence: 0.19% (95% CI 0.04–1.1) pt-mths, that is, 2.27% (95% CI 0.06–12.0) pt-year) consisting of severe epistaxis requiring blood transfusion at cycle 1. The platelets count was 100G/l. Ten clinically relevant nonmajor hemorrhagic events were observed (incidence: 1.9% (95% CI 0.9–3.5) pt-mths, that is, 22.7% (95% CI 11.5–37.8) pt-year): Two epistaxis occurring during cycles 1 and 6, four gastrointestinal bleeds concerning two patients and occurring during cycles 2, 2, 3, and 4, one gynecologic hemorrhagic event (cycle 4), two macroscopic hematuria (cycles 1, 2), and one subcutaneous hematoma (cycle 2) although patient had thrombocytopenia grade 3, 45 G/L.
One CRNM hemorrhagic event (epistaxis) occurred during the additional observation period (cycle 7) although apixaban was stopped at the end of cycle 6 and the patient was treated with aspirin.
The incidence was the same for lenalidomide-dexamethasone and melphalan-thalidomide-prednisone. Bleeding events occurred although platelet count was higher than 100 G/L except in one case (thrombocytopenia grade 3). No concomitant treatment at hemorrhagic risk was identified.
4 DISCUSSION
Patients with immunomodulatory compounds thal/len-treated multiple myeloma, especially when used in combination with dexamethasone and/or chemotherapy, are at high risk of VTE.11 The risk is higher in patients treated in the first line compared to patients treated in relapse. Because VTE is a multifactorial disease, an expert panel proposed stratifying the thrombotic risk to identify patients at high risk versus low risk of VTE. Based on this stratification, they proposed using thromboprophylaxis with LMWH in high risk and aspirin in low risk patients.8 Although the optimum prophylaxis remains debatable,11 LMWH seems to be the best primary care option.18-20 However, as LMWH requires daily intravenous injection, new oral alternatives, as efficient and safe as heparin, might be evaluated as prophylactic drugs.
DOACs offer the convenience of oral administration without routine laboratory monitoring, obviously improve quality of life (QOL), and provide similar results compared to LMWH in VTE prophylaxis. In this one arm pilot analysis using apixaban, a direct oral anti-Xa anticoagulant at a dose of 2.5 mg bid for thromboprophylaxis, we observed no arterial cardiovascular event, no pulmonary embolism event, no death due to VTE, and an incidence of VTE inferior or close to the ones reported by Carrier's meta-analysis, either patients in first line or in relapse (Table 3).11 Regarding safety, the incidence of major and clinically relevant nonmajor hemorrhagic events was close to the ones reported in high VTE risk medical patient treated with apixaban.14
To the best of our knowledge, this is the first prospective controlled study conducted with DOACs specifically in myeloma, with a systematic evaluation of thrombosis events by CUS. In a recent retrospective study regarding only 25 patients who benefited from thromboprophylaxis by DOACs for immunomodulatory compounds-treated myeloma, Man et al reported an incidence of 16% for nonmajor bleeding events, 4% for arterial thrombotic events and no VTE.21 In another recent retrospective cohort of 70 patients, the authors reported no VTE events, two arterial thrombosis events, and one (1.4%) major bleeding.22 The interest of this study was the great number of patients in first line myeloma treatment. However, the systematic detection of VTE was not performed, and therefore the exact incidence of VTE events cannot really be evaluated, and the incidence of CRNM bleeding was not mentioned. Finally, the recent AVERT study evaluating prevention by apixaban 2.5 mg bid compared to placebo in cancer patients showed a decrease in VTE events combined with an increase in major bleeding.23 Unfortunately, myeloma was poorly represented (n = 7, 2.4%), and due to the sample size, there is limited ability to make definitive conclusions about outcomes associated with individual tumor types or individual chemotherapy regimens.
The strength of our study was the prospective design, systematic evaluation of VTE events, and the collection of type of bleeding. However, it suffered from several limitations, in particular the small size of the sample and the absence of a comparative arm. Enrollment of patients was quite limited and many patients suffering from myeloma were not included in this study because they already participated in another chemotherapy clinical trials, raising the possibility of selection bias, As an exploratory approach, we chose to perform indirect comparisons in terms of efficacy and safety based on previously published data. The duration of the treatment was limited to the first 6 months, which was based on the higher incidence of VTE found during this period. Finally, 89.4% of patients were in relapse and only 10.6% in first line. This is due to the fact that, during this study in France, treatment with lenalidomide-dexamethasone was only allowed in relapse, with the MPT scheme not frequently used in first line. This might introduce bias because relapse patients were known to be at a lower risk of VTE events, which should make the benefit-risk analysis cautious.
In conclusion, our study provides event rates that will inform the design of a future larger randomized controlled trial.
ACKNOWLEDGMENTS
We thank IFM staff, IFM centers, study coordinators, and nurses participating in Myelaxat study, and also patients, and their family.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
AVAILABILITY OF DATA AND MATERIALS
The data set supporting the conclusions of this article are available in the Department of Biostatistics, University Hospital Grenoble-Alpes, CS 10217 F-38043 GRENOBLE CEDEX.
AUTHOR CONTRIBUTIONS
Performed research: Pegourie, Karlin, Benboubker, Orsini-Piocelle, Tiab, Auger-Quittet, Rodon, Royer, Leleu, Bareau, Cliquennois, Fuzibet, Voog, Belhadj-Merzoug, Decaux, Rey, Slama, Leyronnas, Zarnitsky, Boyle
Patients enrollment: Pegourie, Karlin, Benboubker, Orsini-Piocelle, Tiab, Auger-Quittet, Rodon, Royer, Leleu, Bareau, Cliquennois, Fuzibet, Voog, Belhadj-Merzoug, Decaux, Rey, Slama, Leyronnas, Zarnitsky, Boyle
Data analysis: Pegourie, Leleu, Pernod
Manuscript writing: Pegourie, Pernod
Manuscript review: Karlin, Benboubker, Orsini-Piocelle, Tiab, Auger-Quittet, Rodon, Royer, Leleu, Bareau, Cliquennois, Fuzibet, Voog, Belhadj-Merzoug, Decaux, Rey, Slama, Leyronnas, Zarnitsky, Boyle
