ASH 2010 meeting report—Top 10 clinically oriented abstracts in coagulation medicine and platelet disorders

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The 2010 American Cancer Society of Hematology (ASH) annual meeting took place December 4-7, in Orlando, Florida, USA. There were over 20,000 attendees, with more than 4000 scientific presentations. There were many interesting presentations in the category of Basic and Clinical Science of Coagulation Medicine and Platelet Disorders. Of the numerous high quality presentations, herein, are summarized and discussed the top 10 abstracts in Coagulation Medicine and Platelet disorders that are likely to have a practical impact on patient care. All 10 abstracts are published in full in the November 19th, 2010 issue ofBlood(Volume 116, No. 21) and are identified here by their abstract numbers.

Outpatient management of deep vein thrombosis (DVT) with low molecular weight heparin (LMWH) has been shown to be safe and effective however data on outpatient management of pulmonary embolism (PE) are confined to retrospective analyses. In their report, Zondag et al. prospectively assigned patients who met the Hestia criteria to outpatient LMWH (nadroparin) and followed outcomes for three months. Eligible patients were hemodynamically stable, not needing thrombolysis, not pregnant, not at risk for bleeding or not hypoxic, not on therapeutic anticoagulation, not requiring narcotics for pain, had normal renal and liver function, had no history of heparin induced thrombocytopenia and no social or medical reasons for hospitalization. Of the 297 patients enrolled, 6 (2%) experienced recurrent VTE (5PE;1DVT), 3/297 patients died during follow up due to progressive malignancy ( n= 2) and intracerebral hemorrhage ( n= 1). One additional patient experienced major hemorrhage. The authors concluded that outpatient LMWH was safe and effective in management of PE.

Short- and long-term consequences of PE are not to be taken lightly. Mortality at one month is greater in patients presenting with a PE [1, 2] as is risk of recurrence. There are no published randomized trials of patients with PE, however, randomized trials of outpatient management of VTE included patients with PE [3, 4] and have demonstrated safety and efficacy of outpatient management in a carefully selected subset of patients. Thus, taken together, the data would suggest that selected patients with PE, who meet clinical and laboratory criteria, may be safely managed as outpatients.

In this randomized trial, treatment naïve patients ≥16 years of age with ITP [5] and platelet count ≤30 × 109/L received a single course of either dexamethasone (DEX) 40 mg daily d1-4 or prednisone (PRD) 1 mg/kg daily for four weeks. For patients receiving DEX, a second course was permitted for recurrent thrombocytopenia (<3 × 109/L). The primary objective was sustained response (SR) at six months and secondary objectives were response at four weeks, predictors of steroid response and toxicity. Fifteen patients received a single course of DEX. At the end of the study period, of the 151 enrolled patients (DEX:76;PRD:75) 117 (DEX:57;PRD:60) were evaluable. Response rates at four weeks were 68.2% and 81.2% and sustained responses were 25% and 36% in the DEX and PRD arms, respectively. Splenectomy was performed in 11 and 8 patients in the DEX and PRD arms respectively; median time to splenectomy was similar (∼152 days) in each arm. Median time to relapse (TTR) in pt achieving a SR was 1,320 (DEX) days and 1,140 (PRD) days. Toxicity included Grade 3 hyperglycemia in six patients (DEX) and five patients (PRD). Treatment was discontinued due to pneumonia, hyperglycemia and myalgia 1 patient each in the PRD arm. The authors concluded that DEX was not superior to PRD; there was a trend to increased toxicity in the PRD arm.

Corticosteroids are still considered the first line therapy for adults with ITP [5]; however, the optimal initial approach is evolving. In addition, varied criteria for assessment of response pose a challenge in comparing outcomes in different clinical trials [6]. A single course of DEX has been shown to result in high rates of initial (85%) and sustained (50%) response [7]; and although SR rates were increased to >70% with four to six cycles of DEX [8], details of ongoing randomized trials comparing DEX to PRD are in not published [8]. In this trial, there appeared to be no significant difference in the primary outcomes nor with rates of splenectomy between DXM or PRD arms. There was a trend towards increased toxicity requiring discontinuation of therapy in pts on the PRD arm. However, in those achieving a sustained response to DXM, there was a trend towards a longer time to relapse. Full publication of this and the GIMEMA clinical trial should provide us with more data on outcomes.

In this open-labeled, randomized, noninferiority study, patients with acute deep vein thrombosis (DVT) were randomized to either oral rivaroxaban alone (15 mg twice daily for three weeks, followed by 20 mg once daily) or subcutaneous therapeutic doses of enoxaparin followed by vitamin K antagonist (enox/VKA) for up to 12 months. After an initial 6–12 months of anticoagulation, a subset of patients were randomized, in a double blind fashion, to either ongoing rivaroxaban or placebo (extension study). Note: patients with symptomatic pulmonary embolism (PE) were excluded. Primary efficacy and safety outcomes were recurrent venous thromboembolism (VTE) and bleeding, respectively. In the initial phase of the study, 2.1% of rivaroxaban patients and 3% of enox/VKA patients experienced a recurrent VTE (HR,0.68;95%CI,0.44–1.04; P< 0.001); 8.1% of patients in each arm experienced hemorrhage. In the extension study, 1.3% of rivaroxaban patients, and 7.1% of placebo patients experienced recurrent VTE (HR,0.18;95%CI, 0.09–0.39; P< 0.001). The authors concluded that for acute management of DVT, rivaroxaban was noninferior compared with enox/VKA and for long term management of DVT, rivaroxaban was superior compared with placebo.

Standard approach to management of acute DVT consists of initial therapeutic doses of parenteral heparin or heparin derivative (low molecular weight heparin or fondaparinux) (administered as an inpatient or outpatient) followed by an oral VKA [9] for at least three months. This trial demonstrates that, in carefully selected patients, outpatient management of acute DVT with oral rivaroxaban is non-inferior to standard management. For long-term secondary prophylaxis, extended VKA therapy is superior to placebo in reducing the risk of recurrent VTE, [10]. In this trial, extending rivaroxaban treatment was superior in reducing recurrent VTE when compared with placebo. Although tempting, application of results this trial to patient management should be undertaken with caution. Given its renal excretion, long elimination half-life and lack of agents that reverse its anticoagulant effect, its use should be considered with caution. In addition, data on longer-term follow up are needed.

Prophylactic infusions of factor VIII (FVIII) reduces frequency of hemorrhage and resulting morbidity and mortality in patients with severe hemophilia A (HA) [11]. Up to 30% of patients with severe hemophilia A (HA), develop FVIII inhibitors resulting in increased frequency of hemorrhage and resulting morbidity and higher mortality compared to HA patients without inhibitors. In this prospective randomized cross over study, 34 subjects were randomized to either six months of prophylactic FEIBA (∼85 units/kg on three nonconsecutive days of the week) or on demand therapy (OD) therapy. After a three-month washout period, patients from one arm were crossed over into the other arm. The primary efficacy endpoint was assessment of total and joint bleeds. Of the 26 evaluable patients, 14 were initially randomized to prophylaxis and 12 to OD. While on the OD arm, subjects experienced a median of 12 (1-29) total bleeds and 11 (0–29) joint bleeds; once crossed over to the prophylactic therapy arm subjects experienced a statistically significant reduction in frequency of bleed: 4.5 (0–22) total bleeds and 3.0 (0–18) joint bleeds during the study period. No patient experienced thrombotic complications and one patient experienced an allergic reaction to FEIBA.

The benefits of prophylaxis in the bleeding disorders community has been accepted for many years and has been the standard of care; this benefit was recently documented in a randomized clinical trial [11]. Although similar benefits in HA patients with inhibitors has been recently recognized and documented in retrospective studies, results of this first randomized trial provide confirmatory data of a significant reduction in the frequency of hemorrhage in severe HA patients with prophylactic infusions of FEIBA compared with patients not on prophylaxis. Further studies into the effect of prophylaxis on other potential morbidity such as central venous catheter infections and effect on mortality are warranted.

In this prospective trial of elderly patients requiring initiation of warfarin anticoagulation, Moreau et al. analyzed the added value of warfarin sensitivity genotyping (VKORC1 and CYP2C9), over clinical (age, indication and INR) predictors in predicting warfarin dose requirements in a cohort of patients all of whom were managed in a uniform fashion [12, 13]. Their clinical model was tested in a cohort of 115 inpatients (mean age 86 years) and validated in a separate cohort of 55 patients. Prior to the initiation of warfarin, genotype was predictive of maintenance dose of warfarin; however, upon initiation of warfarin at a standard dose of 4 mg daily with measurement of INR of Days 3 and 6, genotyping was not predictive of maintenance dose of warfarin. The clinical algorithmic approach overestimated the warfarin dose by 1 mg in less than 2% of patients. The authors concluded that a simple dosing algorithm safely and accurately predicted warfarin maintenance dose without requiring genetic information.

Retrospective studies have found genotyping to be predictive of maintenance doses of warfarin, and in 2007, the US FDA added a black box warning to warfarin encouraging but not mandating warfarin sensitivity genotyping prior to its initiation [14]. On a practical basis, in real world patient management, testing is complex and not readily available as an in-house test for the large majority of hospitals, results typically are not available for up to a week and thus provide no utility for acute management. The data presented by Moreau et al. reinforce the utility of clinical predictors of warfarin dosing in initial patient management.

A subset of newly diagnosed multiple myeloma (MM) patients, receiving induction therapy with lenalidomide and low dose dexamethasone (DXM) followed by a randomization to receive consolidation therapy with melphalan, lenalidomide and DXM or high dose melphalan and stem cell transplant, were enrolled in this prophylaxis trial. Eligible patients received enoxaparin 40 mg daily or aspirin 100 mg daily. During the induction phase, Grades 3–4 thrombotic events occurred in 1% of enoxaparin arm and 2.4% in the aspirin arm ( P= 0.45). Minor bleeding occurred in 1% of patients in the enoxaparin arm.

When administered as a single agent, lenalidomide does not result in a high risk of thrombosis. However, when combined with DXM, the incidence of thrombosis increases

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up to 16% [15]. Guidelines for prevention and management of thrombosis in patients receiving thalidomide based regimens have been published [15]. In this randomized study, enoxaparin appeared to confer no increased protection from venous thrombosis over aspirin inpatients receiving lenalidomide and DXM therapy for MM. Given the multifactorial nature of venous thromboembolism, additional studies that stratify patients by risk will eventually permit individualized tailoring of VTE prophylaxis.

This abstract provides a final report on outcomes of 292 adult ITP patients who were enrolled on romiplostim studies. Of the 292 patients, 32.5% had undergone a splenectomy and romiplostim treatment was administered for a median of 78 weeks (range, 1–277) at a median weekly dose of 4 mcg/kg (2.2–7.3 mcg/kg). The large majority (94.5%) achieved a platelet count ≥50 × 109/L during the study with the target platelet count (50–200 × 109/L) being achieved and maintained after the first week of therapy. Of the patients on concurrent ITP medications prior to enrollment ( n= 37), 81% ( n= 30) were able to discontinue or reduce the dose by >25%. Mild adverse events included headache (38%), nasopharyngitis (34%), and fatigue (32%). In those that had a bone marrow biopsy, reticulin was present or increased in 11 patients. Neutralizing antibodies to romiplostim were detected in 2 patients; however, there was no cross-reactivity with thrombopoietin and the antibodies cleared after drug withdrawal. Of the 16 deaths, 2 were possibly attributable to treatment (unstable angina, myocardial infarction). During the study period, 25 thromboembolic events were reported.

This abstract provides us with long term data on efficacy of romiplostim in raising platelet counts in adults with ITP. More importantly, the large majority of patients were able to reduce concurrent medications compared with baseline. Additional studies and longer term follow up to demonstrate its utility as front line therapy and splenectomy sparing agent are needed.

This study evaluated the incidence of TEEs 446 ITP patients treated with eltrombopag on five clinical trials and compared the event rate to placebo. Twenty patients (4.5%) experienced 27 TEEs. (DVTn= 12; PEn= 6; MIn = 4; ischemic stroken= 3; suspected prolonged reversible ischemic neurologic deficitn= 1; TIAn= 1. This translated to an incidence of 3.14/100 PYs, 95% CI [1.92, 4.85]). No patients on placebo experienced a TEE. Events occurred at a median of 229 days (1–981 days) at a median platelet count of 143,000/μL ((14,000–482,000/μL) with 55% of patients having <150,000/μL platelets at the time of the TEE. In addition, all patients who experienced a TEE had at least one additional acquired risk factor for thrombosis.

Patients with ITP are known to be at increased risk for venous and arterial thrombosis [16]. The data presented herein add to previous observations of a lack of association between eltrombopag and TEE and in addition, provide evidence of lack of correlation between platelet count increases and the occurrence of TEEs in patients with chronic ITP on eltrombopag.

Data from an ongoing open-label, extension study in ITP patients on eltrombopag treatment are presented. Of 299 patients enrolled 41% withdrew due to adverse events (AEs, 11%), patient decision (11%), and lack of efficacy (10%); 38% of patients were splenectomized and 33% were receiving concomitant ITP medication. Median duration of eltrombopag treatment was 100 weeks (26–156). Overall, within 2 weeks, 87% (261/299) of patients achieved a platelet count ≥50,000/μL, the baseline platelet count, splenectomy status, or use of concomitant ITP medication did not influence the likelihood of achieving the target platelet count. This rise in platelet count was accompanied by a decrease in bleeding symptoms. Adverse events included headache (26%), nasopharyngitis (23%), and upper respiratory tract infection (21%) and led to withdrawal of 13% (38) of patients.

Sixteen patients (5%) experienced thromboembolic events (TEE), reflecting an incidence rate is 3.17/100 patient years (95% CI [1.81, 5.15]), and included DVT [8] and MI [4], and did not correlate with elevated platelet counts. Reversible liver function abnormalities occurred in 10% of patients. Of the >150 patients treated with eltrombopag for >1 year, no clinically relevant increase in reticulin fiber deposition was observed on bone marrow biopsies.

The increase in platelet count with eltrombopag was accompanied by a reduction in bleeding. However, longer-term follow up to monitor for hepatobiliary and bone marrow toxicities are warranted.

The role of a presence of residual vein thrombosis (RVT) in the long term management of anticoagulation with Low-Molecular Weight Heparin in cancer patients with acute DVT was analyzed. Over a period of 36 months, 347 patients with cacner and a first episode of DVT, received six months of full doses of LMWH followed by a 25% dose reduction for a further five months. Further management was based on presence or absence of RVT. Patients without RVT received no further anticoagulation ( n= 105) whereas patients with RVT were randomized to discontinue ( n= 123) or continue ( n= 119) LMWH for an additional six months, and all patients were followed for up to one year after discontinuation of LMWH.

Recurrent DVT occurred in 3 (2.8%) of patients without RVT, 27 (21.9%) of those randomized to discontinue and 17 (14.2%) of those who continued LMWH.

Overall, 89 (25.6%) patients died due to cancer progression after a median follow-up of 10.2 months after completion of LMWH.

Results of randomized trials have demonstrated the superiority of LMWH over vitamin K antagonists in management of patients with cancer and DVT and guidelines have been published [17]. In general, it is recommended that anticoagulation be continued as long as active cancer is present. However, in those with out active cancer the exact duration of anticoagulation remains indeterminate. Although the study by Siragusa et al. demonstrates that absence of RVT identifies a group of patients at a lower risk of recurrence, details on breakdown of patients with and without active cancer were not provided. Further details should be available with full publication of this interesting trial.

The clinical challenges in coagulation medicine include prevention and treatment of thrombosis while balancing the risks of type and duration anticoagulant therapy. On the other end of the spectrum, options for prevention and treatment of bleeding disorders need to be balanced with long-term toxicity. Clinical research efforts at defining the epidemiology of venous thromboembolism have led to development of guidelines which, with further clinical research, will continue to be refined. Availability of novel anticoagulants have the potential to further enhance the safety of long-term anticoagulation. Efforts at understanding the biology of thrombocytopenic disorders have led to significant advances in therapeutic options. Ultimately, these options need to be subjected to well-designed randomized trials with long-term follow-up in order to provide our patients with the best possible outcomes.

DOI

10.1002/ajh.22003

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