ASH 2013 Preview: CAR Modified T Cells, Novel Assays, and Ibrutinib

Marcel R.M. van den Brink, MD, PhD

The 2013 American Society of Hematology (ASH) Annual Meeting and Exposition will provide insight into all areas of hematology, not just oncology. As a result, sifting through the thousands of abstracts could represent a daunting task.

To gain insight into the studies being presented at the meeting, we interviewed Marcel R.M. van den Brink, MD, PhD, on abstracts being presented by faculty at Memorial Sloan-Kettering Cancer Center (MSKCC), where he serves as the head of the division of hematologic oncology. Overall, 110 abstracts by faculty at MSKCC were selected for presentation at the meeting, including several focused on chimeric antigen receptor (CAR)-modified T cells, next-generation sequencing, and novel agents.

The first abstract highlighted by van den Brink detailed collaboration between MSKCC and Foundation Medicine, Inc., for the investigation of a novel CLIA-certified next-generation sequencing-based assay (abstract 230).

“This [assay] will give us, for the first time, a genomic profile for hematological cancers,” van den Brink noted in the interview. “This will be a first step toward what you could call true personalized medicine.”

The novel assay was designed to provide information on somatic alterations in hematologic malignancies using archived formalin-fixed paraffin-embedded specimens, blood samples, and bone marrow aspirates. In the study, which will be presented by Ross L. Levine, MD, from MSKCC, DNA and RNA were successfully extracted from specimens collected from 319 patients. Overall, the specimens represented multiple myeloma and several types of leukemia and lymphoma.

According to the abstract published prior to the meeting, a total of 885 alterations were identified, with the most prominent including mutations in TP53 (9%), ASXL1, KRAS, NRAS, IDH2, TET2, SF3B1, JAK2, MLL2, DNMT3A, RUNX1, and SRSF2 (2-5% each), internal tandem duplications in FLT3 (2%), and MLL protein transduction domains (1%).

The assay was also able to reliably identify gene fusions and rearrangements. Additionally, the test demonstrated a high-level of accuracy at detecting gene substitutions, copy number alterations, insertions, and deletions. When tested on known samples, the assay was able to demonstrate a sensitivity of 97%.

“This test could be used for [determining] diagnosis, prognosis, therapy, for choosing if a patient needs a transplant–and, if so, when–and it can also be used if a patient relapses, to find out if there is a mutated gene that can be targeted with an experimental drug,” van den Brink explained.

Another study highlighted by van den Brink examined ibrutinib, a promising novel agent that blocks Bruton's tyrosine kinase activity. In this phase I study being presented by Anas Younes, MD, from MSKCC, the combination of first-line ibrutinib and rituximab (R)-CHOP was explored in treatment-naive patients with CD20-positive B-cell non-Hodgkin’s lymphoma (abstract 852).

According to the abstract, the objective response rate (ORR) for the 15 evaluable patients was 100%, with a 73% complete response (CR) rate. Interim data specifically for the 22 patients with diffuse large B cell lymphoma (DLBCL) also demonstrated a 100% ORR, with a CR rate of 64%.

In the study, the combination of ibrutinib and R-CHOP had an acceptable safety profile. Many of the side effects associated with the treatment were similar to R-CHOP alone, the currently accepted standard of care for patients in this setting.

“This is a very promising study because the response rates were actually higher than what we would normally see with these first-lines of therapies,” van den Brink explained. As a result of this high-level of response, the addition of ibrutinib “has been chosen as the starting point for a large phase III study to now demonstrate that this should be the new standard of care.”

Addressing the topic of CAR-modified T cells, van den Brink highlighted a study being presented by Marco L. Davila, MD, PhD, from MSKCC (abstract 69). In this study, a novel CD19-targeted therapy was engineered using a CAR construct termed 19-28z on the T cells of adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Following the engineering process, the modified T cells are reintroduced into patients along with salvage chemotherapy.

In the study, 13 patients with B-ALL received treatment with the CAR modified T cells. Twelve of the patients had detectable disease prior to the infusion. In these patients, 10 demonstrated an MRD-negative response. Additionally, 5 patients who previously were MRD-positive became MRD-negative after receiving treatment. In general, responses to the T cell infusion were rapid, with results occurring in as early as 7 days following the infusion.

“The data that we have now for ALL is that this can now be used for those patients who have failed every other therapy,” van den Brink explained. “In about two-thirds of these patients, we were able to get them again into a remission.”

Many of the side effects associated with the treatment were reversible and included high-grade fevers, hypotension, hypoxia, mental status changes, and seizures. Following treatment with the T cell therapy, 4 patients were able to undergo allogeneic stem cell transplantation and 5 patients were being prepped for transplantation.

“We are using this as a bridge toward transplant, so that these patients will be eligible to receive a life-saving bone marrow transplant,” commented van den Brink. “We think that this therapy holds great promise for ALL”

These studies, plus more, will be discussed December 7-10, 2013, at the Ernest N. Morial Convention Center in New Orleans, Louisiana.