Top 10 ASH Abstracts from Cleveland Clinic’s Hematology/Medical Oncology Staff

Which of the more than 4,500 research abstracts from the 2014 American Society of Hematology’s Annual Meeting is likely to have the biggest healthcare impact in 2015? That is the topic of discussion at the 2014 ASH Review hosted by Cleveland Clinic and the Case Comprehensive Cancer Center.

At Cleveland Clinic’s Taussig Cancer Institute, our quest to provide the most innovative and effective care for our patients means we constantly assess new developments. Many of our clinicians and researchers attended and presented findings at ASH’s December session. We’ve had lots of discussions (and debates) since then about which results we think are the most intriguing, the most clinically relevant, or have the greatest potential to change the practice of hematology in the next 12 months.

While many of the studies deserve merit, here is our inaugural Top 10 list of the ASH abstracts we believe best match those criteria, as selected by our Cancer Institute’s Department of Hematology and Medical Oncology staff.

Lymphoid Cancers

289: Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma – Preliminary Safety, Efficacy and Biomarker Results of a Phase I Study
Nivolumab targets the PD1/PDL1 system that normally functions to turn off immune responses, thus allowing the immune system to attack Hodgkin lymphoma (HL) cells. In a group of 23 patients with relapsed HL, 87 percent responded to this immunotherapy and many of those have ongoing responses, although the follow-up period is short. HL seems particularly sensitive to this PD1/PDL1 attack, which is explained in part by the presence of genetic abnormalities in these genes. Other lymphoid diseases may not be as sensitive (ASH abstract 291). Another presentation (abstract 290) reported the efficacy of pembrolizumab, another drug that targets the same PD1-PDL1 system. The FDA recently approved both of these drugs for other indications, so they will be available. Although HL is relatively uncommon, and fortunately most patients are cured with current therapies, having this treatment is important for those who relapse. Its efficacy also raises the possibility of incorporating it earlier, in combination with current standard therapy, to improve outcomes with less toxicity. This is an example of how are increasing understanding of the biology of specific cancers leads to effective targeted treatments.

79: Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase 3 Study
This is a large (792 patients) international randomized trial for patients with relapsed (1 to 3 prior regimens) multiple myeloma (MM). It is clear that combining an immunomodulatory drug and a proteasome inhibitor is an effective strategy against MM, so the results of this trial are not that surprising: Longer progression-free survival of 26 months with three drugs vs. 18 months with two drugs, although two-thirds of the patients had prior treatment with the proteasome inhibitor bortezomib, which might be expected to lessen the carfilzomib benefit. In addition, quality of life was better, and toxicity was not significantly different. The strengths of this presentation are that it represents real-world experience with a large number of patients, and that not all proteasome inhibitors are cross-resistant. The results support moving this regimen into the front-line setting, as we are doing at Cleveland Clinic, but using an oral proteasome inhibitor so that the entire treatment consists of pills, not intravenous infusions. For patients whose disease has returned after initial treatment, we have several trials of carfilzomib with other novel agents.

24: Vemurafenib Has Potent Antitumor Activity in Patients with Relapsed/Refractory BRAF Mutant Hairy Cell Leukemia
Hairy cell leukemia (HCL) is a rare subtype of B cell lymphoma for which we already have effective therapy. Nonetheless, some patients have recurrent disease resistant to these usual treatments. A specific molecular abnormality — mutation in the B-RAF gene that signals cells to grow — was identified in HCL. Fortunately, B-RAF mutation had already been identified in other cancers and a specific drug targeting this mutation exists. This report and a similar one from Italy (abstract 150) show high response rates in these patients, although it is still too early to know how long these will last. Since vemurafenib is approved for use in other indications, we can use it in this situation. This is another excellent example of how understanding the mutations in cancer leads to effective targeted treatment approaches.

Benign Hematology

229: Caplacizumab, Anti-vWF Nanobody Potentially Changing the Treatment Paradigm in Thrombotic Thrombocytopenic Purpura: Results of the TITAN Trial
The TITAN trial was a randomized, placebo-controlled trial of a new nanobody, caplicizumab, directed against the A1 domain of Von Willebrand factor (vWF) in acute thrombocytopenic purpura (TTP). Caplicizumab inhibits the interaction between vWF and platelet GP1b, and hence platelet aggregation in the presence of large vWF multimers. Caplicizumab given either before or after the first plasma exchange shortened the time to a platelet response in patients with TTP by almost two days. Patients receiving caplicizumab also required fewer days of plasma exchange and had a lower incidence of exacerbation within the first 30 days. Toxicity was minimal, with only a slight increase in bleeding. This study suggests that caplicizumab will be a valuable agent in the treatment of acute TTP.

344: Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects
Dabigatran is an oral direct thrombin inhibitor used for stroke prophylaxis in patients with atrial fibrillation. Presently, there is no antidote for patients who develop bleeding complication while being treated with dabigatran. Idarucizumab is a fully humanized antibody fragment directed against dabigatran. Previous studies have demonstrated that it immediately reduces prolonged clotting assays in healthy volunteers receiving dabigatran. In this study, 46 volunteers, some with impaired renal function were treated with idarucizumab in a dose-escalation trial. Idarucizumab normalized prolonged clotting times immediately after infusion. While clotting times increased again within two to four hours after administration of the 1 gm dose of idarucizumab, administration of larger doses (5 gm or 2.5 gm) caused sustained reversal. Dabigatran could be restarted 24 hours after idarucizumab administration.

4829: Mortality from Cancer-Associated Venous Thromboembolism
Venous thromboembolism (VTE) is a common morbidity associated with cancer, although the percentage of cancer deaths directly attributable to VTE is uncertain. In this retrospective study researchers examined the charts of 99,288 patients at the University of Texas MD Anderson Cancer Center who died between 2000 and 2010. VTE was present in 11,032 patients. Electronic health records from 9,000 of these individuals were examined, and a cause of death could be assigned to 1,459 patients who harbored various malignancies. VTE was determined to be the direct cause of death in 13.6 percent of patients, with arterial thromboembolism causing death in an additional 3.5 percent. In the 203 patients whose immediate cause of death was attributed to VTE, 51 had hematological malignancies and 152 had solid tumors. One hundred sixty-two of the 203 patients were receiving anticoagulation at the time of their fatal VTE. This research demonstrate that VTE is a significant cause of mortality in patients with a wide variety of malignancies, both hematologic and solid. Moreover, it reinforces that better therapies for cancer-associated thrombosis are needed.

Myeloid Cancers

115: AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a Phase I Study in Patients with IDH2 Mutation Positive Advanced Hematologic Malignancies
IDH2 mutations occur in approximately 10 percent of myeloid malignancies. AG-221 is a first-in-class IDH-2 inhibitor that has gained much attention recently, and was prominently mentioned in a recent report in the New Yorker. In this phase I study of 73 patients, 55 of whom had relapsed/refractory AML, 11 of the 45 patients evaluable for a response had a complete remission (CR) or CR with incomplete count recovery after receiving AG-221 as a single agent; an additional 10 patients had a partial remission.

4: Lenalidomide Induces Ubiquitination and Degradation of CSNK1A1 in MDS with Del(5q)
In this plenary presentation, for the first time since lenalidomide’s FDA approval 10 years ago, investigators uncovered the drug’s likely mechanism of action in myelodysplastic syndrome, through a similar pathway as its activity in multiple myeloma. Through their experiments, the researchers also discovered why lenalidomide’s predecessor, thalidomide, was not identified as teratogenic prior to being marketed for morning sickness associated with pregnancy.

823: In Analogy to AML, MDS Can be Sub-Classified By Ancestral Mutations
In this work from the Maciejewski lab at Cleveland Clinic, for the first time investigators identified the true complexity of the myelodysplastic syndromes, with an average of nine distinct genetic events occurring prior to diagnosis. The researchers also for the first time identified the order in which those genetic abnormalities occurred.

Blood and Marrow Transplant

673: The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma
Approximately half of patients with relapsed/refractory Hodgkin lymphoma have disease progression after autologous stem cell transplantation (ASCT). The AETHERA trial investigated brentuximab vedotin as consolidation post-ASCT for patients at high risk for relapse or progression (primary refractory disease, relapse within 12 months after frontline therapy or relapse ≥ 12 months with extranodal disease). Patients received brentuximab vedotin 1.8 mg/kg q3 weeks or placebo x 16 cycles (~1 year). Consolidation with brentuximab vedotin significantly improved progression-free survival compared to placebo and was generally well tolerated.