Live From ASH 2015: Galvanizing Blood Cancer Research!

Andre Goy, MD

Editor-in-Chief of Oncology & Biotech News

Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates John Theurer Cancer Center at Hackensack University Medical Center

Gene Therapy

It is obviously impossible to summarize all of the significant data from the 2015 ASH Annual Meeting in this column, but I would like to highlight several key emerging trends that continue to illustrate the palpable ongoing revolution happening in cancer care and beyond!Though the outcome of patients with constitutive hemoglobinopathy or immunodeficiencies has improved over the years through supportive care, these patients have no long-term options and depend on life-long blood transfusions or IVIG supplementation or a stem cell transplant. Past efforts of gene therapy—based approaches were associated with toxicities and susceptibility to treatment-associated leukemia.

Immunotherapy

Thankfully, new methods (lentivirus-based technology to deliver DNA material to cells via a noncommunicable virus), show improved safety and long-term efficacy. One study showed follow-up data on beta thalassemia patients who can forgo blood transfusion, while two studies showed improvement of immune system function in Wiskott- Aldrich Syndrome and severe combined immunodeficiency (SCID-X1), also known as “bubble boy disease.”CAR T cells have made a dramatic entry in ALL with durable molecular complete response (CR) over the last 2 to 3 years. This year at ASH, the impressive number of CAR T-cell presentations reflects the momentum in the field.

Anti-CD19 CAR T cells showed durable CR (no relapses after 6 months in a series of 6 patients with refractory, heavily pretreated large cell lymphoma) as well as confirmed activity in CLL and follicular lymphoma.

Multiple initiatives are trying to build on the CAR T-cell story, including preemptive use after HDT-ASCT in DLBCL and also in multiple myeloma (trials ongoing). In multiple myeloma, interesting research presented as a late-breaking abstract showed very impressive activity in some multiple myeloma patients using BCMA (B-cell maturation antigen) as a target.

Though allogenic stem cell transplantation is actually a form of cell therapy, it usually takes months to develop an antitumor effect and relapse post transplantation is still a major challenge. Donor lymphocytes infusion (DLI) in that setting can induce some remissions but are limited by the risk of induced/worsening graft versus host disease (GVH). An elegant way around used CAR-DLI, as shown in a presentation from the NCI Immunology branch and our center. Molecular CRs were seen in relapsed ALL, but also durable responses in DLBCL and CLL. The advantage is that they do not require preemptive chemotherapy, showed no CRS (cytokine release syndrome) and contrary to standard DLI, did not induce worsening of GVH. Given preemptively, they might allow a bridge before full immune reconstitution happens post allogeneic bone marrow transplant.

Small Molecules/Targeted Biologicals

An “off-the-shelf” CAR T-cell strategy (using gene editing technology) is likely the most innovative approach in the field, expanding dramatically the potential of CAR T cells. Checkpoint inhibitors (which break the tumor cells’ induced immune tolerance) were again also highlighted during ASH, with very durable responses in relapsed/ refractory Hodgkin lymphoma seen with both nivolumab and prembrolizumab. Early data combining checkpoint inhibitors with chemotherapy were introduced in Hodgkin lymphoma or with lenalidomide in multiple myeloma with promising results; most studies are still ongoing, including checkpoint inhibitors with CAR T cells, which is a very logical step.Though some new compounds were presented at ASH— such as the second-generation BTK inhibitor ACP-196, which showed very impressive results in CLL—most data this year were in the combination setting. This approach might offer non-chemotherapy options (eg, R2/ibrutinib in lymphoma) or improve standard regimens through biologicals with chemotherapy.

For example in CLL, the bendamustine/rituximab backbone was tested in phase III with ibrutinib vs placebo with dramatic improvement as seen in an update at ASH, or with idelalisib, also in phase III, which was stopped early based on the superiority of the experimental arm. The addition in AML of the FLT3 inhibitor midostaurin to standard induction showed both improved duration of response and an overall survival advantage in a phase III trial, establishing a new standard.

In aggressive lymphoma, the current strategy is to go beyond R-CHOP, essentially by combining with rationale use of a biological agent. DLBCL is characterized at the molecular level by two main subtypes, GC and non-GC subtype by gene expression profiles and immunohistochemistry. The non-GC subtype outcome is much worse with R-CHOP.

Thankfully, several biological agents such as bortezomib, lenalidomide, and ibrutinib, seem to have a preferential activity in that subtype. Based on initial encouraging phase II data in combination with R-CHOP plus either of those biological agents, the field embarked on a number of large randomized studies of R-CHOP+X with a particular focus on ABC or non-GC DLBCL.

However two studies presented at ASH showed no clinical benefit of bortezomib added to R-CHOP in that setting. This is likely partially due to patient selection (time required to get on study, ABC subtype often sicker at presentation etc)—ie picking the “best of the high-risk patients” might neutralize the potential benefit of adding the biological agent. Besides questions related to the technology used to stratify patients in those trials, these data suggest that the landscape of DLBCL is much more complex than GC/non-GC. Hopefully using liquid biopsies, as suggested in several presentations, might help facilitate routine molecular characterization of DLBCL in the future and lead to better ways to rationalize our recommendations.

As innovation continues to blossom in oncology, I am happy to announce the 25th anniversary of our program at the John Theurer Cancer Center and I am proud to say that our center is very much part of this exciting journey!