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The American Society of Hematology’s annual meeting in December was an outstanding opportunity to learn about and discuss the latest research results in our specialty. With more than 4,500 abstracts presented, narrowing them down to a list of a few standouts isn’t easy. Nevertheless, here is my list of the Top 5 ASH takeaways. My choices are clinically focused, and begin with two exciting studies in classical Hodgkin lymphoma.
Background: Several ASH abstracts (Nos. 289, 290 and 291) provide preliminary data showing outstanding response rates in patients with refractory Hodgkin lymphoma using checkpoint blocking antibodies. Monoclonal programmed cell death-1 (PD-1)-blocking antibodies have shown efficacy in a variety of cancer types, including melanoma and lung cancer. Recent studies suggest that Hodgkin Reed-Sternberg cells have developed mechanisms that exploit the PD-1 pathway to evade immune detection. This is the rationale for trying monoclonal PD-1-blocking antibodies in Hodgkin lymphoma.
Abstract No. 289 is a multi-institutional phase I study describing the efficacy of Nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Nivolumab is a fully human IgG4 monoclonal PD-1-blocking antibody.
This report details 23 patients with refractory or relapsed classical Hodgkin lymphoma treated with Nivolumab. Seventy-eight percent had prior autologous stem cell transplant, and 78 percent had prior treatment with brentiximab vedotin. Drug-related adverse events were modest, with the most common being rash. Eighty-seven percent (20 of 23) had an objective response rate, with 17 percent achieving a complete response. Among the 18 patients who previously failed brentiximab vedotin, the overall response rate was 89 percent. The study’s conclusions were that these responses were striking, with a tolerable safety profile. Based on these results, the Food and Drug Administration has granted Nivolumab breakthrough status in relapsed classical Hodgkin lymphoma and a large multinational phase 2 trial of this therapy is underway.
My commentary of this study is this: While most patients with Hodgkin lymphoma do quite well – with the majority cured with standard chemotherapy, radiation therapy, or both – those that relapse do poorly. Autologous stem cell transplant can salvage 40 to 50 percent of such patients, but the remainder die of their disease. Brentiximab vedotin is a new drug that has shown promising results in relapsed Hodgkin lymphoma patients, but results are rarely curative. Nivolumab and other checkpoint inhibitors may significantly improve disease responses and survival in this challenging patient population. It is not often that a new class of drugs exhibits such striking activity in any disease. These data, therefore, are a significant development.
Background: This abstract describes the Aethera Trial, which is a randomized double-blind placebo-controlled phase 3 study of brentiximab vedotin in the treatment of patients with relapsed refractory Hodgkin lymphoma undergoing autologous stem cell transplant (ASCT). For two decades ASCT has been the standard of care for patients with chemosensitive relapsed refractory Hodgkin lymphoma. Between 40 and 50 percent are cured but the remainder have poor prognosis. This is a study of post-transplant maintenance therapy that attempts to improve prognosis. The study randomized patients to brentiximab vedotin versus placebo following ASCT. A total of 329 patients were randomized at 78 sites in the United States and Europe. The most common adverse event was peripheral sensory neuropathy (36 percent) and upper respiratory tract infection (25 percent). Patients were treated every three weeks for as long as one year. The study had a crossover design. At a median follow-up of two years, 65 percent of patients treated with brentiximab vedotin had disease- free survival compared to 45 percent in the placebo group, representing a 25 percent absolute improvement. This improvement was sustained across all subgroups.
This is a potentially practice-changing study. If these results are confirmed, adding brentiximab vedotin after ASCT could become standard of practice and result in more cures. It is another major development in Hodgkin lymphoma treatments.
Background: Several ASH abstracts offer promising data about a novel way of treating multiple myeloma. Abstracts 83, 84 and 176 describe early-phase studies investigating the use of an anti-CD38 monoclonal antibody in combination with other effective multiple myeloma drugs. Abstract No. 83 is a multi-institutional study of patients with refractory multiple myeloma treated with an anti-CD38 monoclonal antibody in combination with lenalidomide and dexamethasone. A total of 31 patients were studied. They were a heavily pretreated group, with a median of six prior treatments. More than 95 percent of patients previously received lenalidomide or pomalidomide, and more than 85 percent of these patients were refractory to at least one prior IMiD-based therapy. No dose-limiting toxicities were reported. Infusion-associated reactions, generally mild, occurred in 39 percent. With a median follow-up of six months, the response rate was 65 percent, with a clinical benefit seen in 71 percent of patients. The study’s conclusion was that this was strikingly effective therapy in a heavily pretreated population.
I believe these data are important. Multiple myeloma therapy has been revolutionized with the addition of bortezamib, and lenalidomide (and more recently pomalidomide). An effective agent that appears to synergize with lenalidomide is a significant advance.
Background: The fourth study I would like to highlight is a late- breaking abstract whose senior author is Alok Khorana, MD, of our Taussig Cancer Institute. The abstract reports on a randomized trial of low molecular weight heparin versus warfarin for the treatment of acute venous thromboembolism (VTE) in cancer patients. Only one prior study, which is more than 10 years old, has compared low molecular weight heparin with warfarin for the prevention of recurrent VTE in cancer patients. Warfarin is still often used for this indication in cancer patients worldwide. This was a very large trial of 900 patients from 165 sites in 32 countries across five continents examining the use of low molecular weight heparin or warfarin in patients with proven symptomatic proximal deep vein thrombosis and/or pulmonary embolism. Mean age of participants was 59; 59 percent were female. The most common primary tumor sites were gynecologic (23 percent), colorectal (13 percent) and lung (12 percent). Symptomatic nonfatal deep vein thrombosis (DVT) occurred in 2.7 percent in the low molecular weight heparin arm and in 5.3 percent in the warfarin arm (p = 0.04). There was no difference in the incidence of severe bleeding events in either arm, but significantly fewer patients experienced clinically relevant non-major bleeding in the low molecular weight heparin arm. The conclusion was that low molecular weight heparin lowered the risk of recurrent VTE compared with warfarin, and significantly reduced the incidence of clinically relevant non-major bleeding.
This study is important because it decisively establishes that low molecular weight heparin is the standard of care for patients with cancer who have suffered an acute DVT or pulmonary embolism.
Background: This final study is a long-term analysis of an Italian trial called HD 2000 that compared doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus the combination of cyclophosphamide, vincristine, procarbazine, prednisone (COPP) with epidoxorubicin, bleomycin, vinblastine (EBV), and lomustine, doxorubicin, and vindesine (CAD) (i.e., COPP/EBV/CAD) in patients with newly diagnosed advanced Hodgkin lymphoma. ABVD has been the standard treatment for Hodgkin lymphoma for approximately 30 years. Many single-institution studies have suggested that other chemotherapeutic regimens might be superior, but randomized trials have always shown that ABVD remains the standard of care. This study compared two newer regimens with ABVD. A total of 305 eligible patients with stage 2, 3, or 4 Hodgkin lymphoma were randomly assigned to one of the three treatment arms. Median follow-up was 119 months, or 10 years. The 10-year overall survival rates were 84 percent, 84 percent and 86 percent for the three treatment arms, which was statistically non-significant. A total of 11 second malignancies were documented. The risk of secondary malignancies at 10 years were 6.7, 4.4, and 0.9 for BEACOPP, CEC, and ABVD respectively, with a statistically significant difference between BEACOPP and ABVD. The study concluded that ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.
I believe this study is important for several reasons. The first is that it highlights the importance of long-term follow-up. Far too many studies of hematologic malignancies have relatively short follow-up times. In Hodgkin lymphoma, long-term follow-up is vital to adequately assess treatment efficacy. Second, the risk of secondary malignancies remains a major therapeutic concern for these patients. They are generally younger, and secondary malignancies may have devastating effects. A key advantage of ABVD is the very low incidence of secondary malignancies. This study definitely shows the importance of secondary malignancies in the treatment of patients with Hodgkin lymphoma and reminds us that when treating a younger patient for any disease for which there is curative intent, long-term toxicities must be part of the overall decision analysis.
There were many other important scientific presentations at ASH 2014. It is an excellent meeting and I strongly encourage you to attend next year’s event in Orlando, Florida. The studies I have discussed here are exciting as we continue to advance our scientific knowledge and translate that into better treatments for our patients.
Dr. Bolwell is Chairman of Cleveland Clinic’s Taussig Cancer Institute.
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