Highlights from ASH 2019: Major clinical findings and implications for your practice

 

At the 61^st annual meeting of the American Society of Hematology in December 2019, nearly 5,000 abstracts were presented. Among this massive volume of research were several studies that had significant implications for community oncology practices. Additionally, researchers from Cardinal Health Specialty Solutions presented research showcasing both real-world experiences on CAR-T therapies among underrepresented patient populations and barriers to adoption of these therapies among community oncologists.

Vice President and Senior Medical Director Ajeet Gajra, MD, FACP, and Marjorie Zettler, PhD, MPH, Director of Research Strategy for Cardinal Health Specialty Solutions, compiled some of the most notable findings here.

CHOOSE A TOPIC:

• Chronic Lymphocytic Leukemia (CLL)
• Myeloma
• Acute Myeloid Leukemia (AML)
• Chimeric Antigen Receptor T-Cell Therapy (CAR-T)
• CAR-T therapies: Analyzing real-world results and barriers to adoption– research from Cardinal Health Specialty Solutions

CAPTIVATE: Ibrutinib + Venetoclax Achieves Undetectable Minimal Residual Disease in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Abstract 35: Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Results from the MRD Cohort of the Phase 2 CAPTIVATE Study

Findings from the CAPTIVATE (PCYC-1142) study , a multi-center phase 2 study evaluating the potential for the combination of ibrutinib (an oral Bruton tyrosine kinase inhibitor) and venetoclax (an oral BCL2 inhibitor) to achieve remission with undetectable minimal residual disease (uMRD) in first-line treatment of CLL/SLL, show the combination may have synergistic anti-tumor activity. A total of 164 patients received single-agent ibrutinib lead-in for 3 cycles followed by the combination for 12 cycles. Seventy-five percent of patients achieved uMRD at any time after baseline in in peripheral blood (72 percent in bone marrow). Adverse events leading to dose reductions occurred in 20 percent of patients, while adverse events leading to discontinuation occurred in 7 percent of patients.

While results from this phase 2 study cannot be considered practice-changing, it addresses several critical issues in CLL management:

• It utilizes uMRD as a valid end-point in CLL
• Given the concerns of long-term adverse effects and financial burden from lifelong therapy with ibrutinib, it investigates the role of time-limited therapy in first line therapy of CLL by evaluating the proportion of patients treated with 15 cycles achieving uMRD status
• It evaluates whether discontinuation of therapy after achievement of unMRD status is safe. To address this issue, the study randomized patients with uMRD to receive ibrutinib or placebo, but those results are awaited. The study also found high levels of uMRD across subgroups, including these high-risk patients: deletion 17p, 75 percent; deletion 17p or TP53 mutation, 70 percent: deletion 11q, 84 percent; complex karyotype, 83 percent, and unmutated IGHV, 81 percent.

CANDOR: Triple Therapy with Daratumumab Improves Progression Free Survival in Relapsed or Refractory Multiple Myeloma

Abstract LBA-6: 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)

Findings from CANDOR, a multicenter, phase 3, randomized study comparing carfilzomib, dexamethasone, and daratumumab (KdD) vs carfilzomib and dexamethasone (Kd) in relapsed or refractory multiple myeloma (RRMM) patients, show the combination is effective and safe for patients with this disease. KdD resulted in a significant progression-free survival (PFS) benefit over Kd, with 37 percent reduction in the risk of progression or death. Patients treated with the triple combination also had a nearly 10-times higher minimal residual disease negative-complete response rate vs. Kd-treated patients. The incidence of grade ≥3 adverse events and the rate of treatment discontinuation due to adverse events was similar in both arms.

Daratumumab, a CD38-directed cytolytic antibody has demonstrated activity with various combinations of immunomodulatory agents (IMids) and proteasome inhibitors (PIs) leading to multiple approved indications in multiple myeloma.

In the phase 3 CANDOR trial, the addition of daratumumab to carfilzomib and dexamethasone (KdD) reduced the risk of disease progression or death compared with carfilzomib and dexamethasone alone (Kd). 90 percent of patents had prior bortezomib and 42 percent of patients had prior lenalidomide. One-third of patients were lenalidomide-refractory. The progression free survival (PFS) benefit of KdD was maintained in both lenalidomide-exposed and -refractory patients. Notably, prior treatment with anti-CD38 and carfilzomib individually was permitted. While there are a plethora of treatment options in RRMM, KdD offers an IMiD-free treatment option in this patient population.

QUAZAR: Oral Azacitidine Improves Survival for Older Adults with Relapsed Acute Myeloid Leukemia

Abstract LBA-3: 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

The benefit of post-remission maintenance treatment for patients with AML is unclear, as no therapy has shown to significantly improve overall survival. This abstract reports the primary results of QUAZAR AML-001, a phase 3 international, randomized, double-blind, placebo-controlled study evaluating CC-486 (an oral hypomethylating agent) as maintenance therapy in patients with AML in first remission following induction chemotherapy. A total of 472 patients were randomized to receive CC-486 (n=238) or placebo (n=234); the median age was 68 (range 55–86) and 91 percent of patients had de novo  AML. At a median follow-up of 41.2 months, overall survival (OS) was significantly improved with CC-486 vs . placebo: median overall survival was 24.7 months vs. 14.8 months from time of randomization, respectively (P =0.0009; HR 0.69 [95 percent CI 0.55, 0.86]). CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. 

This study offers an important therapeutic advance in patients aged 55 years and older with AML who are in first remission after induction chemotherapy and are not candidates for stem cell transplant. Maintenance treatment with CC-486, an oral formulation of azacitidine, extended median OS compared with placebo for older patients with AML in first remission.  Thus, at 1 year, 47 percent of patients were free of relapse in the CC-486 arm compared with 29 percent in the placebo group. Benefits in both relapse-free survival and OS were seen across key prognostic AML subgroups. The median treatment duration was 12 cycles with CC-486 compared with 6 in the placebo group with an excellent adverse effect profile. If approved and available for use, it will likely be utilized in patients with AML who achieve remission but are not candidates for transplant.

Broader Use of Chimeric Antigen Receptor T-Cell Therapy (CAR-T) Therapy in the Real World Shows Similar Outcomes

Abstract 764: Post-Marketing Use Outcomes of an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, Axicabtagene Ciloleucel (Axi-Cel), for the Treatment of Large B Cell Lymphoma (LBCL) in the United States (US)

This abstract reports the first-year results of a planned 15 year follow-up registry for patients treated with axicabtagene ciloleucel (axi-cel). Using the infrastructure of the Center for International Blood and Marrow Transplant Research database (CIBMTR), post-approval safety and efficacy assessments for 295 patients from 43 U.S. centers that had at least the first follow-up assessment submitted at 3 months were included. Compared to patients in the registrational ZUMA-1 trial, the registry included a larger proportion of older patients, patients with transformed or double-hit lymphoma, and patients with a worse performance status. Best responses and observed toxicities were comparable to those observed in the trials setting. Patients age ≥ 65 years had similar safety and efficacy outcomes to those <65 years, including comparable cytokine release syndrome.

This abstract provides evidence regarding the utilization and tolerability of axi-cel in patient population beyond that included in the registrational trial. The efficacy and toxicity based on age (65 year cut-off) is not statistically different. Longer follow up is needed to assess the duration of response in patients treated in the real-world.

CAR-T therapies: Analyzing real-world results and barriers to adoption– research from Cardinal Health Specialty Solutions

Abstract 1951 Real-World Analysis of Adverse Events Associated with CAR T-Cell Therapy Among Adults Age ≥65 Years

Abstract 1952: Neurological Adverse Events Following CAR-T Cell Therapy: A Real-World Analysis of Adult Patients Treated with Axicabtagene Ciloleucel or Tisagenlecleucel

Abstract 2198 - Perceptions of Community Hematologists/Oncologists on Barriers to Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Diffuse Large B-Cell Lymphoma

Two of the three abstracts presented by Cardinal Health Specialty Solutions focused on real-world post-marketing adverse events (AEs) associated with axicabtagene ciloleucel or tisagenlecleucel, as reported in the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The first of these examined AEs associated with CAR T-cell therapy among adults age ≥65 (a population under-represented in clinical trials). The authors found that 39 percent of the AE cases reported involved patients age 65 or older. These patients had a higher incidence of neurotoxicity and atrial fibrillation, while patients age <65 had increased incidence of some CRS components, especially pyrexia and tachycardia. Younger patients also had higher rates of hospitalization. A second abstract focused on neurological AEs associated with CAR T-cell therapy. Neurological AEs were common with CAR T-cell therapy in the real world, reported in 65 percent of AE cases. The types of neurological AEs reported largely resembled those reported in clinical trials, and were associated with the agent used, age ≥65 as well as the presence of CRS, cardiac and psychiatric AEs. 

A third abstract reported the perceptions of community hematologists and oncologists regarding their use of, referrals for and barriers to CAR-T therapy as well their perception of the value of the real-world CAR-T evidence, as collected during a live market research program conducted in 2019. There is significant interest in adopting and using CAR-T therapies in large B-cell lymphoma amongst community hematologists and oncologists. The top two reported barriers to prescribing/recommending CAR-T therapy were the cumbersome logistics of administering therapy and following patients (52 percent), and the cost of the therapy (46 percent). Perception of real-world CAR-T therapy evidence was favorable: 73 percent of participants indicated that this information is likely to cause them to recommend CAR-T therapy for more of their patients with diffuse large B-cell lymphoma.

In aggregate, these presentations demonstrate the approved CAR-T therapies are being utilized in the real-world setting in populations beyond those included in the registrational clinical trials. Further, they provide hypothesis-generating information regarding specific toxicities and associations with demographic factors as well as other toxicities. While there is significant interest in utilizing CAR-T therapy among community oncologists, cumbersome logistics and high cost are perceived as major impediments.