Top 10 Takeaways from ASH 2019
Our hematology/oncology experts select the abstracts from the American Society of Hematology’s 2019 annual meeting that could impact clinical practice in 2020 and beyond.
The American Society of Hematology’s (ASH) annual meeting is a great opportunity to discover and discuss the latest developments in the treatment of blood disorders and malignancies. The staff of Cleveland Clinic Cancer Center’s Department of Hematology and Medical Oncology has chosen these abstracts presented at ASH 2019 as the most compelling, clinically relevant and potentially practice-changing.
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The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission
In this study, older patients with acute myeloid leukemia who achieved remission following intensive chemotherapy were randomized to receive either a maintenance, oral-chemotherapy version of azacitidine or placebo. The researchers found that those receiving the oral chemotherapy lived longer than those who did not. This may change the paradigm of treatment in older adults with AML, for the first time introducing maintenance therapy as a standard.
Carfilzomib, Dexamethasone and Daratumumab versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688)
In an effort to improve the treatment of relapsed refractory multiple myeloma, researchers compared the combination of carfilzomib, dexamethasone and daratumumab with carfilzomib plus dexamethasone. The investigators found improvement in disease-free state with use of the three-drug combination. Patients in the three-drug cohort showed improvement within one month of starting treatment, achieved better disease control with deeper responses, and their disease remained under control for a longer duration, with a nearly 10-times higher minimal residual disease negative-complete response rate compared to patients treated with carfilzomib plus dexamethasone. The results add to our understanding about the efficacy and safety of the carfilzomib/dexamethasone/daratumumab regimen and represent continued improvement in the treatment options for multiple myeloma patients.
Post-Transplantation Cyclophosphamide after Allogeneic Hematopoietic Stem Cell Transplantation: Results of the Prospective Randomized HOVON-96 Trial in Recipients of Matched Related and Unrelated Donors
This trial showed evidence for use of post-transplant cyclophosphamide as an effective graft versus host disease prophylaxis regimen.
Rare Germline Mutations in Complement Regulatory Genes Make the Antiphospholipid Syndrome Catastrophic
Antiphospholipid syndrome (APS) is defined by arterial or venous thrombotic events, or recurrent pregnancy loss, accompanied by persistently positive tests for antiphospholipid antibodies. Catastrophic antiphospholipid syndrome (CAPS) is associated with acute thrombosis in three or more organs during a one-week period and is associated with a mortality of 30%-50%. The mechanisms by which antiphospholipid antibodies cause thrombosis are incompletely defined, and 10%-30% of patients with these antibodies have recurrent thrombosis despite anticoagulation. In this study, the authors evaluated complement activation in patients with thrombotic APS (N=53), CAPS (N=8, sera available for 6), and systemic lupus erythematosus (SLE; N=74), using the modified Ham (mHam) test, a functional assay for complement activation. The mHam assay is based on the principle that a paroxysmal nocturnal hemoglobinuria cell line (PIGA-null TF-1 cells) lacking the cell surface complement regulators CD55 and CD59 undergoes lysis in serum containing activated complement. A positive mHam assay was detected in 32.1% of patients with thrombotic APS and in 100% of CAPS patients compared with 6.8% in patients with SLE, (p <0.001). A history of thrombosis was present in 79.3% of patients with a positive mHam and in 38.4% of those with a negative mHam test. Additionally, purified anti-beta2 glycoprotein 1 antibodies activated complement in the mHams test. Finally, rare germline mutations in complement-related genes were present in 62.5% of patients with CAPS, 22.6% of patients with thrombotic APS, and 23.8% of patients with SLE, compared with 50% of patients with atypical hemolytic uremia syndrome and 19.4% of healthy individuals. A role for complement in thrombotic APS has long been suspected, but this has now been better defined through use of the mHam test. Future prospective studies will determine whether a positive test may be used to better define thrombotic risk in patients with antiphospholipid antibodies.
Understanding How Fc-Modification Transforms a Pathogenic Heparin-Induced Thrombocytopenia (HIT)-like Monoclonal Antibody into a Novel Treatment for Sepsis
Heparin-induced thrombocytopenia (HIT) is caused by antibodies against heparin platelet factor 4 (PF4) complexes, and is associated with arterial and venous thrombosis. Binding of these pathologic antibodies leads to immune complexes that activate numerous cell types, including platelets, endothelial cells and monocytes; cellular activation results in expression of tissue factor and other procoagulant activity that causes thrombosis. Recent studies also have demonstrated that neutrophils are activated in HIT and release neutrophil extracellular traps (NETs) — webs of negatively charged cell-free DNA complexed with positively charged histones that capture pathogens but also damage host tissue. NETs may be lysed by DNase, releasing NET degradation products (NDPs) that circulate and are highly toxic to the vasculature. In addition to HIT, NETs play a particularly important role in sepsis: Elevated levels of NDPs are associated with poor outcomes in septic patients. In this study, the authors demonstrated that PF4 binds to NETs and stabilizes them, protecting them from DNase degradation. When HIT antibodies were added to the system, they recognized NET-bound PF4 but led to worse outcomes in sepsis models due to their ability to fix complement. However, when the HIT antibodies were first deglycoslyated by enzymatic treatment, they continued to interact with NET-bound PF4, stabilized NETs by preventing DNase-induced degradation, and significantly improved survival in sepsis models. These results suggest that a new strategy for reducing morbidity and mortality in sepsis may involve targeting PF4 bound to NETs.
ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone vs. O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL)
The ELEVATE trial demonstrated the safety and efficacy of the oral twice-daily Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib for treatment-naïve CLL patients. The large phase III trial established a very high response rate of 85% with this agent, and 94% when combined with 6 months of treatment with the anti-CD20 monoclonal antibody obinutuzumab. Estimated progression free survival rates at 30 months were 82% and 90% for acalabrutinib and acalabrutinib + O, respectively, compared to the control arm’s rate of 34%. The primary toxicities for acalabrutinib + O or acalabrutinib alone were headache (generally reversible) and modest rates of atrial fibrillation and bleeding compared to the control arm. The results confirm that continuous-treatment acalabrutinib is highly effective in treatment-naïve CLL, although limited-duration therapies are also an option for frontline treatment of CLL.
Phase I/II, Open-Label Adaptive Study of Oral Bruton’s Tyrosine Kinase Inhibitor PRN1008 in Patients with Relapsed/Refractory Primary or Secondary Immune Thrombocytopenia
Immune thrombocytopenic purpura (ITP) is characterized by antibodies that bind and enhance clearance of circulating platelets as well as impair thrombopoiesis. T-cells also play a critical role in ITP. An abundance of new therapies has emerged for the treatment of ITP in recent years. In this study, the authors report the results of a phase I/II open-label study of PRN1008 in patients with relapsed/refractory primary or secondary ITP. PRN1008 is a novel oral inhibitor of Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase that plays a key role in B-cell development, functioning of normal B cells and oncogenic signaling in B cell malignancies. (Ibrutinib, an approved BTK inhibitor, is effective in CLL and mantle cell lymphoma.) BTK also is involved in Immunoglobulin G-mediated Fc receptor activation, which is important in uptake of antibody-coated platelets in ITP. BTK also is present in platelets and its inhibition by ibrutinib inhibits platelet function. PRN1008 is a more specific BTK inhibitor and in this study was shown not to inhibit platelet aggregation to several agonists. Patients eligible for this study had to have two platelet counts < 30,000 /µL within 15 days before treatment. The study followed an intra-patient dose escalation regimen, beginning at 200 mg daily, with a maximum dose of 400 mg twice daily. The primary endpoint was two or more consecutive platelet counts ≥ 50,000 /µL without rescue therapy. For patients on study for ≥ 12 weeks, 47% achieved the primary endpoint (N = 17), and for those on higher doses this rate was 54% (N = 13). Overall, the drug was well-tolerated, with a 35% incidence of Grade I or II drug-related treatment-emergent adverse events. PRN1008 has considerable efficacy in a highly pretreated population of ITP patients and is a promising therapy for treatment of ITP.
Are Racial Disparities in Acute Myeloid Leukemia (AML) Clinical Trial Enrollment Associated with Comorbidities and/or Organ Dysfunction?
In this abstract, our Cleveland Clinic team explored whether African Americans with acute myeloid leukemia have organ dysfunction or laboratory abnormalities that would be more likely to exclude them from clinical trials than white patients would experience. We found that clinical trials that exclude patients because of kidney abnormalities were more likely to exclude African Americans than whites.
KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study
This study reported the outcomes of the largest series of patient with mantle cell lymphoma treated with CAR-T cell therapy. All patients were very high risk, as defined by being relapsed or refractory to both chemotherapy and a Bruton’s tyrosine kinase inhibitor. The overall response rate was > 90%, with the majority of responses being complete remission. Toxicities, including cytokine release syndrome and neurotoxicity, were manageable and largely reversible. These results set the stage for broader use of CAR T-cell therapy for patients with mantle cell lymphoma in the upcoming year.
Does Addition of Rituximab to BEAM Conditioning Improve Outcomes of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)?
This registry study shows no benefit of adding rituximab to autologous transplant chemo-immunotherapy for lymphoma.