The 10 Most Compelling Abstracts from ASH 2015

The American Society of Hematology’s annual meeting is an excellent opportunity to learn about and assess new developments in the treatment of blood and marrow disorders. The staff of Cleveland Clinic Cancer Center’s Department of Hematology and Medical Oncology has compiled the following list of the 10 abstracts from ASH 2015 that our physicians consider to be the most intriguing, the most clinically relevant, or that have the greatest potential to change the practice of hematology in the near future.

1) Late-Breaking Abstract No. 6: Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High-Risk Relapsed/Refractory CLL with 17p Deletion: Results of the Pivotal International Phase 2 Study

Comment: Venetoclax belongs to a new class of drugs that target the pathway preventing cells from dying. It is a well-tolerated oral agent that has impressive activity in this very difficult population of patients who do not respond to standard chemotherapy agents. We have participated in trials using this drug. It works so well that the main problem with it is risk of tumor lysis in the first few weeks of therapy, requiring extremely careful attention during that time.

2) Abstract No. 0812: A Prospective Randomized Trial of Targeted Therapy for Diffuse Large B-Cell Lymphoma (DLBCL) Based upon Real-Time Gene Expression Profiling: The Remodl-B Study of the UK NCRI and SAKK Lymphoma Groups (and No. 0811: Randomized Phase 2 Open-Label Study of R-CHOP ± Bortezomib in Patients with Untreated Non-Germinal Center B-Cell-like Subtype Diffuse Large Cell Lymphoma: Results from the Pyramid Trial)

Comment: These papers demonstrate the lack of efficacy of adding the proteasome inhibitor bortezomib to R-CHOP for DLBCL. One interesting finding was that the expected worse outcomes for activated peripheral blood B-cell (ABC)-subtype DLBCL, compared with germinal center (GC)-subtype DLBCL, treated with R-CHOP were not observed. These studies indicate the need for caution before adding agents to R-CHOP outside of a clinical trial. Cleveland Clinic Cancer Center has an active clinical trial in which we treat patient with DLBCL with R-CHOP with the addition of the more potent proteasome inhibitor carfilzomib and using a more rational schedule.

3) Abstract No. 0099: Allogeneic T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor Cause Remissions of B-Cell Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation Without Causing Graft-Versus-Host Disease.

Comment: T-cells engineered to attack CD19, a protein expressed on the surface of almost all B-cells, are under investigation as a lymphoma therapy. To date, the patient’s own T-cells have served as the basis of this immunotherapy. Cleveland Clinic Cancer Center is about to begin clinical trials in which anti-CD19 chimeric antigen receptor (CAR) T-cells will be used to treat patients with relapsed DLBCL and mantle cell lymphoma. In this study, however, patients whose disease recurred after an allogeneic transplant and donor lymphocyte infusion — a group with extremely poor prognosis — were infused with CD19 CAR T-cells made from donor T-cells. A single infusion of these cells, without any additional chemotherapy, induced responses in eight of 20 patients (with six complete remissions).

4) Late-Breaking Abstract No. 1: Remissions of Multiple Myeloma During a First-in-Humans Clinical Trial of T-Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor

Comment: T-cells engineered to attack B-cell maturation antigen (BCMA) proteins, which are expressed on almost all malignant plasma cells, are under investigation as a myeloma therapy. This report provides the first evidence that such a strategy can generate deep and sustained remissions for these patients.

5) Late-Breaking Abstract No. 8: Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High- Versus Reduced-Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network

Comment: For younger patients with AML and MDS in remission, this trial demonstrates that full- intensity conditioning treatment produces better outcomes than does reduced-intensity conditioning.

6) Plenary Abstract No. 3: The Multi-Kinase Inhibitor Midostaurin Prolongs Survival Compared with Placebo in Combination with Daunorubicin/Cytarabine (C) Induction, High-Dose C Consolidation, and as Maintenance Therapy in Newly Diagnosed Acute Myeloid Leukemia Patients Age 18-60 with FLT3 Mutations: An International Prospective Randomized P-Controlled Double-Blind Trial

Comment: This is the second prospective randomized trial demonstrating a benefit for the addition of tyrosine kinase inhibitors to the standard AML treatment. Younger patients with FLT-3 mutations experienced an overall survival benefit, which suggests a new standard of care.

7) Abstract No. 92: Luspatercept Treatment Leads to Long- Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from the Phase 2 PACE-MDS Extension Study

Comment: Luspatercept inhibits Smad2/3 signaling, which is increased in patients with MDS and contributes to ineffective erythropoiesis. This phase 2 trial from Europe provides evidence that luspatercept is well-tolerated and that 77 percent of patients experience a sustained reduction in transfusion requirements. Confirmation of this study likely will result in regulatory approval of luspatercept for use in this otherwise transfusion-dependent patient population.

8) Abstract No. 103: Modified Ham Test Distinguishes aHUS from TTP and Predicts Response to Eculizumab

Comment: A modified Ham test developed by these investigators measures cell viability of a PIGA mutant cell line after exposure to patient serum. Sera from patients with atypical hemolytic uremic syndrome (aHUS), a disease of excessive alternative pathway of complement activation, show increased cell death in this assay, as previously published by this group. In this study of results from 29 patients with thrombotic microangiopathies (TMA), aHUS was defined by platelet count < 100 x 109/L, serum creatinine > 2.25 mg/dL and ADAMTS13 activity > 10 percent; thrombocytopenic purpura (TTP) was defined as TMA with ADAMTS13 activity < 10 percent. Response to eculizumab was defined as TMA event-free status for > 12 weeks and normalized blood counts.

A cutoff of 20.5 percent cell-killing in the modified Ham test suggested an aHUS diagnosis with 100 percent specificity and 94.1 percent sensitivity. One patient with TMA but without lab values of aHUS showed low cell-killing in the modified Ham test and relapsed after eight weeks of eculizumab. Twelve aHUS patients responded to eculizumab, and six of those patients whose eculizumab dosage was discontinued remained in remission after eight months off-drug. The researchers concluded that the modified test not only can distinguish between TTP and aHUS, but may also predict response to therapy with eculizumab.

This innovative test may help clinicians distinguish between these two similar syndromes, which will also help guide appropriate therapy.

9) Abstract No. 5: Source of Factor VIII Replacement (Plasmatic or Recombinant) and Incidence of Inhibitory Alloantibodies in Previously Untreated Patients with Severe Hemophilia A: The Multicenter Randomized Sippet Study

Comment: In this study of treatment-naïve patients with Hemophilia A, inhibitors developed in 35.4 percent of patients over time (cumulative incidence). Of the patients who received plasma-derived concentrates, the cumulative inhibitor incidence was 26.7 percent. For those who received recombinant Factor VIII, the cumulative incidence was 44.5 percent. For high-titer inhibitors, the cumulative incidence was 18.5 percent for plasma-derived; for recombinant, 28.4 percent. Patients receiving recombinant products had a 1.87-fold higher incidence of inhibitors, a major complication of hemophilia therapy and a cause of morbidity and even mortality. This study confirms previous reports that plasmatic Factor VIII replacement is preferable for most patients with inhibitors.

10) Abstract No. 431: Safe and Effective Use of Rivaroxaban for the Treatment of Cancer-Associated Venous Thromboembolic Disease: A Quality Improvement Initiative

Comment: This report of the first 200 patients with cancer enrolled to receive rivaroxaban to treat cancer-associated venous thromboembolism (VTE) examined primary endpoints that included new or recurrent pulmonary embolism (PE), symptomatic proximal lower-extremity deep vein thrombosis, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of drug, or death. Patients with active gastrointestinal or genitourinary lesions or gastric resection were excluded — a group that comprised < 5 percent of otherwise eligible patients. Seventy percent of the study cohort had PEs. Of the patients with solid tumors, 65.6 percent had metastatic disease. The researchers performed an outcome analysis of the first 100 patients treated for at least six months or who had reached an endpoint. At six months, cumulative incidence of death was 14.4 percent, new/recurrent VTE was 4.3 percent, major bleeding was 1.1 percent and clinically relevant non-major bleeding was 7.9 percent. These outcomes are comparable to published results using low-molecular weight heparin, where new/recurrent VTE rates were ~9 percent and major bleeding was 6 to 9.5 percent. These preliminary results suggest that, for this selected population, rivaroxaban may be a safe and effective choice, but further randomized studies are desired before declaring a new standard of care.

Cleveland Clinic Cancer Center’s Department of Hematology and Medical Oncology staff also compiled the following list of the 10 most compelling benign hematology-related abstracts from ASH 2015.

1) Abstract No. 5: Source of Factor VIII Replacement (Plasmatic or Recombinant) and Incidence of Inhibitory Alloantibodies in Previously Untreated Patients with Severe Hemophilia A: The Multicenter Randomized Sippet Study
2) Abstract No. 0758: Domain Distribution of Type 1 VWD Sequence Variants and Impact on Clinical and Laboratory Phenotype in the Zimmerman Program
3) Abstract No. 0759: Safety and Effectiveness of Desmopressin for the Management of Delivery and Major Surgery in Patients with Mild-Moderate von Willebrand Disease: Final Analysis of the Prodeswil Study
4) Abstract No. 650: Post-Pulmonary Embolism Syndrome After a First Episode of PE: Results of the ELOPE Study
5) Abstract No. 771: Liberal Vs. Restrictive Transfusion Thresholds in Leukemia Patients: A Feasibility Pilot Study
6) Abstract No. 103: Modified Ham Test Distinguishes aHUS from TTP and Predicts Response to Eculizumab
7) Abstract No. 3457: Bortezomib Yields High Response Rates in Antibody-Mediated Autoimmune Hematological Diseases Refractory to Conventional Immunosuppression
8) Abstract No. 1054: Tapering Eltrombopag in Patients with Chronic ITP: How Successful Is This and in Whom Does It Work?
9) Abstract No. 3: TCD with Transfusions Changing to Hydroxyurea (TWiTCH): Hydroxyurea Therapy as an Alternative to Transfusions for Primary Stroke Prevention in Children with Sickle Cell Anemia
10) Abstract No. 73: Genes Influencing the Development and Severity of Chronic ITP Identified through Whole Exome Sequencin