2014 ASH Annual Meeting: Late But Certainly Not Least…

This year’s six late-breaking abstracts feature innovative research in preventing bleeding risk, better prediction tools in Hodgkin lymphoma, and new approaches for high-risk, difficult-to-treat malignancies.

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Targeting Factor XI: Preventing VTE Without Increasing Bleeding Risk
FXI-ASO, a novel factor XI inhibitor, significantly reduced the risk of post-operative venous thromboembolism (VTE) in patients undergoing knee surgery, according to results presented by Harry Roger Büller, MD, PhD. Three hundred patients were randomized to receive either 200 or 300 mg FXI-ASO (a second-generation antisense oligonucleotide) or the anticoagulant enoxaparin. Higher-dose FXI-ASO led to the lowest rates of VTE (4.2%, 3 of 71 patients), followed by lower-dose FXI-ASO (26.9%, 36 of 134 patients) and enoxaparin (30.4%, 21 of 69 patients). “Only three clots were present in the 300 mg group,” Dr. Büller said during his presentation of the results. “This rate, 4.2 percent, has never been seen in the setting of knee surgery, where the best evidence is around 10 or 15 percent.” Notably, the new agent exerted this effect without increasing bleeding rates: 2.6 and 2.8 percent in the high- and low-dose FXI-ASO groups, versus 8.3 percent in the enoxaparin group.

LBA-2
CATCH-ing Recurrent VTE in Cancer Patients with Tinzaparin
Tinzaparin, a low-molecular-weight heparin (LMWH), was more effective than warfarin in preventing recurrent VTE in cancer patients with symptomatic VTE, according to long-term results from the phase 3 CATCH study. During the six-month treatment period, recurrent VTE was less common in the 449 patients who were treated with 175 IU/kg once-daily with tinzaparin than in the 451 warfarin-treated patients (6.9% vs. 10.0%; p=0.07), amounting to a 35 percent relative risk reduction with tinzaparin. Tinzaparin was also safe, with approximately 90 percent of patients completing the study protocol and no differences in major bleeding events or mortality between the two study arms. Agnes Y.Y. Lee, MD, the study’s lead investigator, added, “This study reinforces clinical guidelines supporting the use of low molecular-weight heparins instead of warfarin to prevent recurrent blood clots.” Another factor working in tinzaparin’s favor: ease of use. Although it is self-injectable, it does not require extensive monitoring like warfarin.

LBA-3
More is Better in Terms of Anticoagulation and Pulmonary Embolism
In patients with previous unprovoked pulmonary embolism (another population at high risk for recurrent VTE), extended anticoagulation proved more effective in reducing VTE risk and major bleeding compared with shorter-term anticoagulation. In a study that included 371 patients who received 6 months of initial treatment with warfarin, patients were randomly assigned to an additional 18 months of warfarin (n=184) or placebo (n=187). Patients who received the additional 18 months of warfarin were significantly less likely to experience a primary endpoint event (recurrent VTE or major bleeding) compared to those randomized to the placebo arm (3.3% vs. 13.5%, HR=0.23; 95% CI 0.09-0.55). “Extending anticoagulation for 18 months was associated with a risk reduction of 77 percent of recurrent VTE or major bleeding during the treatment period,” lead author Francis Couturaud, MD, PhD, said during his presentation of the results, “but during follow-up after stopping treatment, the curves catch up and there is no significant difference at the end of the study.”

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Circulating Cell-Free DNA Sequencing Opens Up New Possibilities in Hodgkin Lymphoma
Using massive parallel sequencing of circulating cell-free DNA (ccfDNA) derived from Hodgkin/Reed-Sternberg (HRS) cells – the malignant cells in classic Hodgkin lymphoma (HL) – investigators have discovered a correlation between genetic imbalances in ccfDNA profiles and HRS cell burden in HL patients. ccfDNA was prospectively collected from nine patients with nodular sclerosis HL at first diagnosis or at relapse. FISH analysis strongly suggested that DNA derived from HRS cells caused the abnormal ccfDNA profile. All patients responded well to chemotherapy – paralleled by rapid normalization of ccfDNA profiles upon therapy initiation in all cases. Although these findings were from a small set of patients, researchers hope that the ability to interrogate the genomic status of HRS cells in ccfDNA will allow for better understanding of the biology of HL – as well as for the development of biomarkers and novel biological agents.

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Azacitidine Combination Regimens Fail to Improve Overall Response Rate in Higher-Risk MDS
The addition of lenalidomide or vorinostat to azacitidine did not improve overall response rates in patients with chronic myelomonocytic leukemia or higher-risk myelodysplastic syndromes, according to an analysis of 276 patients in the phase 2 North American Intergroup (SWOG S1117) study. Overall response rates were similar across all treatment arms: 36 percent in the monotherapy arm, 37 percent for azacitidine + lenalidomide (p=1.0 vs. monotherapy), and 22 percent for azacitidine + vorinostat (p=.07 vs. monotherapy). However, when patients remained on treatment for six months or longer, there was a trend toward greater relapse-free survival in the combination arms – raising questions about whether patients in these arms are remaining on treatment long enough to benefit from the additional therapy. More patients in the combination arms discontinued treatment due to toxicities, side effects, or complications, and had non-protocol defined dose reductions, though, Mikkael Sekeres, MD, MS, first author, noted during his presentation of the data. “We have to wonder if combination regimens in MDS are too toxic, and if we need to manage toxicities better,” Dr. Sekeres said.

LBA-6
Mixed Picture for Vosaroxin in Improving Overall Survival in Difficult-to-Treat AML
A combination of cytabarine and vosaroxin failed to improve survival for patients with relapsed or refractory acute myeloid leukemia (AML) – a setting in which viable treatment options are sorely lacking. In the phase 3 randomized VALOR trial, 711 adult AML patients with relapsed or refractory disease were randomized to receive cytarabine with either vosaroxin or placebo. Overall survival was similar in patients receiving the vosaroxin/cytabarine combination arm compared to those receiving cytarabine/placebo (7.5 months vs. 6.1 months with placebo; p=0.06). This was despite patients receiving vosaroxin being more likely to achieve complete response (30.1% vs. 16.3% with placebo). Survival was marginally improved in patients receiving vosaroxin when those undergoing bone marrow transplantation were censored from analyses (6.7 vs. 5.3 months, p=0.02). “The benefit was particularly visible in older patients, who experienced manageable added toxicity,” said lead study author Farhad Ravandi, MD.

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