Catherine M. Diefenbach, MD, associate professor, Department of Medicine, clinical director of lymphoma, NYU Langone Medical Center, discusses polatuzumab vedotin (Polivy) plus obinutuzumab (Gazyva) and lenalidomide (Revlimid) in patients with follicular lymphoma.

Fifty-six patients were enrolled in the phase Ib/II GO29834 trial, which treated heavily pretreated patients with follicular lymphoma. The patient population had a median of 3 prior lines of therapy; 50% were refractory to last line of prior regimen, and 25% had progression of diease within 2 years of their initial chemotherapy, which is an independent negative prognostic factor. At the end of the trial 39 patients were evaluated for efficacy ofpolatuzumab vedotin plus obinutuzumab and lenalidomide.

All patients had ≥1 adverse event (AE). The most common grade 3/4 AEs were myelosuppression; however, with growth factor support, most patients were able to continue on therapy. Eleven percent incidence of neutropenic fever, which Diefenbach theorizes is due to the patients being heavily pretreated.

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Catherine M. Diefenbach, MD, discusses polatuzumab vedotin (Polivy) plus obinutuzumab (Gazyva) and lenalidomide (Revlimid) in patients with follicular lymphoma.

Dr. Diefenbach on Polatuzumab Vedotin Plus  Obinutuzumab and Lenalidomide in FL

Catherine M. Diefenbach, MD, assistant professor, Department of Medicine, NYU Langone Medical Center, discusses a phase I study with an expansion cohort examining the combination of ipilimumab and brentuximab vedotin for the treatment of patients with relapsed/refractory Hodgkin lymphoma.

Brentuximab vedotin is an antibody drug conjugate currently approved for use as a single agent for patients with Hodgkin lymphoma who have relapsed after two therapies, are refractory to therapy, or have failed on autotransplant.

Prior to the E4412 trial, most chemotherapy regimens focused on targeting tumor cells and not using the tumor microenvironment to assist in tumor recognition and elimination. In this study, researchers want to directly target the tumor, reduce tumor bulk, release tumor antigen with brentuximab vedotin, and activate T cells in the tumor microenvironment with ipilimumab. Researchers predict this combination will demonstrate improved overall and complete response rates in patients.

Dr. Diefenbach on Ipilimumab/Brentuximab Vedotin in Patients With RR Hodgkin Lymphoma

	Assistant Professor, Division of Hematology and Medical Oncology

Lymphomas are a heterogeneous and complex group of malignancies, with more than 67 distinct subtypes. The American Cancer Society estimates that lymphoma will account for nearly 72,000 new cases of cancer this year and, even more alarming, 20,000 deaths in 2015 alone. Fortunately, recent developments in research activity have unveiled new findings on the biology of lymphomas, and the complex relationship between the lymphoma cell and the cells that surround it. These biologic insights point to distinct mechanisms that will aid in better stratifying patients for individualized therapies, and provide increased options for patients with advanced disease, where treatments remain limited.

Research and development are proliferating at such an accelerated pace that the promise of biomarker-driven targeted therapies is moving closer toward reality. It is bound to proceed at an even more accelerated pace with an infusion of dollars from the new Precision Medicine Initiative, announced by President Obama in his State of the Union address in January. It is aimed at delivering the right treatment at the right time to the right individual. This will definitely bolster our work in lymphoma, and enhance research and development into drug resistance, genomic heterogeneity of tumors, the monitoring of responses and tumor recurrence, and the use of drug combinations.

Our lymphoma research group at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center is actively involved in drug development and biomarker research, focusing primarily on patients with advanced disease who are no longer responding to standard treatments. We have a stellar group of researchers in the fields of clinical research, immunotherapy, radioimmunotherapy, radiation therapy, and small-molecule drug development.

My role includes serving as the national principal investigator of a phase I Eastern Cooperative Oncology Group study (NCT01896999), which is the first trial in Hodgkin lymphoma that combines immune stimulation with direct tumor targeting. Patients with relapsed or refractory Hodgkin lymphoma are eligible for enrollment. The trial combines direct tumor targeting with the anti-CD30 antibody—drug conjugate brentuximab vedotin, and the immune-activating agent ipilimumab, an anti-CTLA-4 agent. We hypothesize that in Hodgkin lymphoma, a tumor that is to a large extent dependent on its microenvironment, this combination strategy may result in increased tumor cell elimination by the immune system, and an increased clinical response. Recruitment for this trial at NYU Langone and its Perlmutter Cancer Center is now open.

I am also the lead principal investigator on a second phase I treatment study for patients with relapsed and refractory low-grade mantle cell and low-grade B-cell lymphoma (NCT01695941). This trial, sponsored by the National Cancer Institute’s Cancer Therapeutics Evaluation Program, is testing the combination of the novel aurora kinase inhibitor alisertib with the proteasome inhibitor bortezomib, and the anti-CD20 monoclonal antibody rituximab. It is founded on the hypothesis that these drugs may work better in combination than they work by themselves. We will investigate whether giving alisertib and bortezomib together with rituximab may be a better treatment for relapsed or refractory mantle cell lymphoma or B-cell low-grade non-Hodgkin lymphoma. Recruitment for the trial at NYU Langone is now open as well.

Another treatment trial under way is for patients with advanced mycosis fungoides. This trial, at NYU Langone and other sites, is designed to find out whether a novel treatment regimen, consisting of focal lesional radiation with or without a second immune stimulant, can induce a response to the therapy out of the radiation field in patients receiving histone deactylase inhibitor therapy (NCT02061449). The overall goal is to augment both immune activation and the response to that therapy.

What is abundantly clear in multiple relapsed lymphoma subtypes is that current management strategies need to improve, and we need to have more novel and biologically based therapies to offer our patients. In addition to the above-described studies, we also are participating in many clinical trials sponsored by industry that offer innovative and novel therapies for our patients with high risk or relapsed lymphoma.

Our group has also been actively pursuing research into developing better biomarkers to improve patient stratification, thus bolstering early recognition of relapses as well as pointing to more effective precision therapies. At NYU Langone and its Perlmutter Cancer Center, we are running a pilot study to evaluate biomarkers of treatment response in patients with Hodgkin lymphoma using systemic immune profiling. At the American Society of Hematology Annual Meeting in 2014, early results were presented, showing that systemic T cells from Hodgkin lymphoma patients displayed evidence of chronic activation and exhaustion (Blood. 2014;124(21):abstr 4400). This study is open at NYU Langone for all patients with Hodgkin lymphoma.

In yet another study, in collaboration with Martin J. Blaser, MD, the Muriel G. and George W. Singer Professor of Translational Medicine and director of the NYU Human Microbiome Program at the NYU Langone, we are investigating the intestinal micro- biome and systemic immune function in lymphoma patients. This study is due to begin soon, and is open to all patients with active lymphoma and patients whose lymphoma is in remission.

Prognostic Indices and Clinical Trial Planning

Part and parcel of working in oncology is deriving the best prognostic tools for our patients. Toward that end, I have been leading a group effort in reevaluating the International Prognostic Factors Project Score and in developing a new prognostic index for advanced Hodgkin lymphoma. In this study we reviewed clinical factors from 850 patients with advanced-stage Hodgkin lymphoma treated on the Intergroup trial E2496 comparing ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with the combined modality Stanford V regimen. We have learned that in this patient population, a streamlined three-factor risk score consisting of age, stage, and hemoglobin may provide a more accurate framework for risk prediction.

It wasn’t that long ago that there were limited options we could offer our patients with relapsed or advanced lymphoma. However, with new drug approvals and a plethora of ongoing research, we have plenty to be excited about at NYU Langone and in the field of lymphoma research.

Articles

Research and development in lymphomas are proliferating at such an accelerated pace that the promise of biomarker-driven targeted therapies is moving closer toward reality.

Molecular Biology and Immunology Discoveries Drive Novel Strategies for Lymphoma

Catherine M. Diefenbach, MD, assistant professor, medicine (hematology and medical oncology), Perlmutter Cancer Center at NYU Langone, explains antibody drug conjugates (ADCs).

Diefenbach says an ADC is a “smart bomb” that delivers chemotherapy to a tumor cell without targeting neighboring cells. ADCs work by choosing an antibody, which allows for differential targeting. However, many naked antibodies are not active, Diefenbach says.

The premise of the ADC is to use the antibody as a means for differential drug delivery. Diefenbach says an ADC conjugates the antibody to a cytotoxic molecule. The molecule that is conjugated to the ADC needs to be something that can be cleaved once the antibody is taken up inside the cell, Diefenbach says, or else the cytotoxic molecule will not be able to do its job.

Designing a good ADC is not easy, as there are many variables surrounding the delivery of the agent, Diefenbach says.

Catherine M. Diefenbach, MD, assistant professor, medicine (hematology and medical oncology), Perlmutter Cancer Center at NYU Langone, explains antibody drug conjugates (ADCs)

Catherine M. Diefenbach, MD

Articles

Dr. Diefenbach on Polatuzumab Vedotin Plus Obinutuzumab and Lenalidomide in FL

Dr. Diefenbach on Ipilimumab/Brentuximab Vedotin in Patients With RR Hodgkin Lymphoma

Molecular Biology and Immunology Discoveries Drive Novel Strategies for Lymphoma

Dr. Diefenbach Explains Antibody Drug Conjugates