During a pre-meeting webinar devoted to ASH 2019, experts highlighted important advances and practice-changing studies to be presented in Orlando, FL, December 7-10, 2019.
CAR T-cell Therapy Advances
Experts singled out 4 abstracts related to CAR T-cell therapy of particular import. “Most of you are aware that CAR-T therapies have captured the imagination of researchers, oncologists, and patients, because they are highly effective in B-cell leukemias and lymphomas. However, there are drawbacks, such as the time it takes to manufacture this personalized form of cell therapy. Only two thirds of candidates get CAR-T therapy because of the time involved in manufacturing it,” said Robert A. Brodsky, MD, ASH Secretary, who is affiliated with Johns Hopkins School of Medicine, Baltimore, MD.
All four abstracts focus on advances with potential to overcome obstacles associated with CAR T-cell therapy,
Abstract 301 is a proof-of-concept study supporting an off-the-shelf CAR-natural killer (NK) cell therapy for B-cell malignancies. This form of therapy relies on inducing pluripotent stem cells and differentiating them from NK cells that attack cancer. CAR-NK is engineered to target the CD19 antigen on B cells and have been found effective in preliminary studies of cell lines.
“CAR-NK is a big advance that offers the potential for a readily available source of CAR-NK cells,” Dr. Brodsky explained. The availability of an off-the-shelf product would overcome the manufacturing constraints of CAR T-cell therapy.
Abstract 577 describes promising early results of the phase 1b/2 CARTITUDE study of JNJ-4528, a CAR T-cell therapy directed against B-cell maturation antigen (BCMA) on malignant plasma cells in patients with relapsed/refractory multiple myeloma. The study included 25 patients first treated with chemotherapy followed by CAR T-cell therapy. At a median follow-up of 3 months, response rate was 91%, including 2 complete responses in patients who were relapsed/refractory to CAR T-cell therapy. Many other patients had deep responses, Dr. Brodsky noted.
Abstract 930 focuses on data from a phase 1 dose-escalation trial of BM38CAR-T in patients with relapsed/refractory multiple myeloma. BM38CAR-T is a bispecific CAR T-cell therapy that targets both BCMA and CD38 on malignant plasma cells.
“This product is designed to try to prevent resistance to CAR-T and preliminary results were interesting,” Dr. Brodsky said.
Patients (n=16) who received at least 2 prior treatment regimens were treated with lymphodepleting therapy with cytotoxin and fludarabine daily prior to BM38CAR-T infusion. At a median follow-up of 36 weeks after BM38CAR-T infusion, response rate was 87.5%, and 9-month progression-free survival was 75%. Although the data are early, Dr. Brodsky considered them “promising.”
“Abstract 6 is the most exciting [of the CAR-T abstracts discussed],” Dr. Brodsky said.
In an open-label, multicenter, phase 1/1b study, the bispecific antibody mosunetuzumab
showed favorable tolerability and durable efficacy in 218 patients with heavily pre-treated, relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including complete responses in patients with disease progression after CAR T-cell therapy. Twenty-three patients had previously received CAR-T. Response rate was 64% and complete response rate was 42%. Median duration of response in aggressive NHL is now 9 months.
“Mosunetuzumab is not a CAR-T therapy. It is an off-the-shelf bispecific antibody that targets CD3 and CD20 that engages patients’ own T-cells to do what a CAR-T would do,” Dr. Brodsky said.
“This product is simpler and faster to produce [than CAR-T], is likely to be cheaper and much less toxic,” he said.
Roy L Silverstein, MD, ASH President, discussed Abstract 164, which highlights results of the phase 3 Einstein Jr. study, showing that a dosing algorithm of the direct acting oral anticoagulant (DOAC) rivaroxaban based on body weight was as safe and effective as the standard of care to prevent VTE, low molecular weight heparin (LMWH), in more than 350 children hospitalized for cancer or congenital heart disease. LMWH requires daily and twice daily subcutaneous injections, while a new liquid formulation of rivaroxaban is much easier to administer.
“This will be the new standard of care for children when approved,” Dr. Silverstein predicted.
Dr. Silverstein turned his attention to five abstracts related to “inclusive medicine,” that is, the impact of socioeconomic status and demographic factors on access to clinical trials and treatments for hematologic cancers.
The first two studies he discussed relied on large datasets to draw conclusions.
Abstract 782 basically “breaks the glass ceiling of age for autologous hematopoietic cell transplant [AHCT] in patients with multiple myeloma,” Dr. Silverstein said. Although multiple myeloma is mainly a disease in older people, AHCT is typically reserved for patients under the age of 70 years. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database to identify 15,999 patients aged 20 or older who received AHCT within 1 year of multiple myeloma diagnosis, the researchers found that no difference in outcomes in patients over the age of 70 compared with those aged 60 to 70. They also found that 60% of patients received lower than standard dose of melphalan for conditioning, and this group had a worse outcome compared with those who got standard-dose melphalan along with AHCT.
“This study suggests that we are probably under-referring patients with multiple myeloma for AHCT based on age alone and under-treating them. Age should not be used as an exclusion/inclusion criterion for clinical trials of AHCT,” Dr. Silverstein said.
Abstract 793 was based on a Center for Medicare and Medicaid Services (CMS) claims database showing real-world descriptive data on 167 patients who were treated with CAR-T therapy for NHL.
“This is the first real-world look at healthcare utilization and costs associated with CAR-T therapy,” Dr. Silverstein said.
Mean age was 70 years old; 75% of patients were alive at 6 months. There was a 40% decrease in utilization of health care resources for these patients following CAR-T therapy.
“It is encouraging that real-world data show elderly patients with multiple comorbidities are doing well. Response rates are high and following CAR-T therapy, patients use fewer resources, such as emergency room visits, hospitalizations, and additional chemotherapy. If you consider the total costs of care, CAR-T may not be as expensive as presumed,” Dr. Silverstein said.
Data from a single-institution study of 196 patients with de novo diffuse large B-cell lymphoma (DLBCL) treated at the Levine Cancer Institute in Charlotte, NC, suggest that African-Americans with mild-to-moderate abnormalities in kidney function testing do not have worse survival outcomes than Caucasians (Abstract 425).
“African-Americans tend to have more abnormalities in kidney function testing than Caucasians. These data suggest that we should not be excluding African-Americans from clinical trials because of kidney function tests,” Dr. Silverstein emphasized.
“The fact that minorities have not been referred to experienced specialists probably underlies worse outcomes seen in other studies,” he added.
Abstract 703 is based on two different studies of children with newly diagnosed acute myeloid leukemia (AML) conducted by the Children’s Oncology Group (COG). Among 1467 children included in the final analysis, the risk of mortality was 25% lower for children from middle and high income areas compared with low income areas. Lower education was also associated with inferior event-free and overall survival in this retrospective study of mortality in pediatric AML.
“These findings suggest we need to pay attention to services we provide to children with AML who come from less advantaged neighborhoods,” Dr. Silverstein stated.
Dr. Brodsky gave a tantalizing preview of the 6 late-breaking abstracts to be presented Tuesday morning December 10. “Keep an eye on the late-breakers. Many are truly practice-changing,” he said.
By John McCleery, Content Director, OBR
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