ASH Conference: Radioimmunotherapy as Part of First Line Therapy for Low Grade Lymphoma

By Rebecca Elstrom, MD

Update: this study is closed to enrollment. 

Radioimmunotherapy (RIT), or radiation targeted to lymphoma cells through conjugation to a monoclonal antibody, has long been known to be effective therapy in patients with relapsed indolent non-Hodgkin’s lymphomas.  Its use as first line therapy has been limited, however. This weekend at the American Society of Hematology (ASH) meeting, several studies exploring the use of RIT in initial therapy of low grade lymphomas, either alone or following chemotherapy, were reported.

Two studies explored the use of 90Y-ibritumomab tiuxetan (Zevalin) alone;  one presented by Dr. Pica of Genova on behalf of an Italian cooperative group exploring a single dose, and one presented by Dr. Illidge from the University of Manchester with fractionated dosing (multiple doses of the RIT, in this case 2). Both studies showed high response rates with this brief and simple strategy, and durations of remission comparable to front line chemotherapy with no excessive toxicity.

Two other studies explored the use of RIT as consolidation following initial chemotherapy. The first, presented by Dr. Press of the University of Washington, was a large multicenter study comparing Rituximab plus CHOP chemotherapy (R-CHOP) to CHOP followed by 131I-tositumomab (Bexxar). There was no difference between the two groups in response rate or duration of response. A caveat to this study is the fact that, at the time it was designed, there was concern that giving the anti-CD20 antibody rituximab prior to RIT would inhibit radiation dose delivery, as 131I-tositumomab also requires binding to CD20 in order to deliver the radiation dose to lymphoma cells. This concern does have support in laboratory studies, but it has become clear in the years since this study was designed that anti-CD20 antibody therapy with rituximab is a critical contributor to response and survival in follicular lymphoma. The second study of chemotherapy followed by RIT was presented by Dr. Fowler of MD Anderson Cancer Center. This group evaluated an induction chemotherapy regimen containing rituximab, fludarabine, mitoxantrone and dexamethasone (R-FND) followed by 90Y-ibritumomab tiuxetan. This study showed high response rates and long time to progression, but toxicity of the regimen was of some concern, possibly due to the fact that fludarabine has significant bone marrow suppressive effects, which is also the main side effect of RIT.

Overall, these presentations confirmed the impressive activity of RIT in low grade lymphoma, and extended the experience using RIT as part of first line therapy, demonstrating feasibility, safety and efficacy of this simple and very well tolerated therapeutic approach.

At Weill Cornell Medical College we are exploring radioimmunotherapy as first treatment of follicular lymphoma using a combined strategy of non-radiation tagged antibody to CD20 in combination with radio-labeled antibody against an alternative protein, CD22. This study is designed to maximize the benefit of anti-CD20 directed therapy in addition to radiation dose delivery by targeting the radio-labeled antibody to an alternative target. Click here to read more about this study.

Weill Cornell Researcher: A Personalized Approach for Targeting Cancer Tumors

Through a collaboration between researchers at Weill Cornell Medical College, Memorial Sloan-Kettering, and the National Cancer Institute, researchers have reported that a tumor-targeting compound called PU-H71 can reveal with great accuracy the set of altered pathways that contribute to malignancy, thus allowing physicians to “fish-out” entire networks of abnormal proteins in tumor cells.

One major obstacle in the fight against cancer is that anticancer drugs often affect normal cells in addition to tumor cells, resulting in significant side effects. Yet research into development of less harmful treatments geared toward the targeting of specific cancer-causing mechanisms is hampered by lack of knowledge of the molecular pathways that drive cancers in individual patients.

“A major goal of cancer research is to replace chemotherapy with drugs that correct specific molecular pathways disrupted by cancer,” said Weill Cornell’s  Dr. Ari Melnick, one of the study’s lead investigator. The research was published in Nature Chemical Biology.

The researchers have uncovered that PU-H71 can reveal, with great accuracy, the set of altered pathways contributing to malignancy, thus allowing physicians to “fish-out” entire networks of abnormal proteins in tumor cells. PU-H71 binds to these abnormal protein complexes which are part of protein networks supporting cancer cell growth, division and survival. This knowledge could lead to more targeted, effective and individualized therapies for the personalized treatment of cancer – a disease in which no two tumors are alike – while producing fewer side effects and ultimately sparing patients from undergoing chemotherapy.

Based on these findings Dr. Melnick and colleagues have received a multi-investigator collaborative grant from the National Cancer Institute in support of clinical trials for the treatment of cancer. Currently, patients are being recruited for the first clinical trial to test the safety of PU-H71 as a drug used for the treatment of a variety of tumors. Subsequent trials will include patients with cancers such as breast, lymphomas, and chemotherapy-resistant leukemia.

PYRAMID: A Personalized Medicine Study in Lymphoma

Update: this study is closed to enrollment. 

Pyramid Trial Background

With increasing knowledge of cancer biology and availability of new drugs, it is expected that therapy will be increasingly tailored to individual patients’ tumor subtypes. Examples of this in breast cancer, colon cancer and CML have emerged over the past ten years. Often referred to as “personalized medicine” or “precision medicine”, this targeted approach to cancer therapy relies on translational research that defines a drug’s clinical activity in the context of the tumor’s cellular and genomic pathology.

Translational research has characterized the molecular basis of the clinical heterogeneity in various lymphomas, and many new agents are in development for lymphoma. Although the targeted development of these drugs in specific lymphoma patient subgroups could potentially speed their availability to the right patients, there are two major challenges to targeted trials in lymphoma. First, the empiric clinical research has led to highly active drug combinations that improve outcomes for many patients with lymphoma and in some specific types current therapy does in fact successfully treat a portion of the patients; leaving fewer patients with an unmet medical need to enter clinical trials. Second, it is a practical challenge to test and quickly identify specific lymphoma patient subgroups that can be enrolled in clinical trials of targeted drugs. Therefore a personalized study should ideally use a practical, rapid test to identify a lymphoma group that is not responsive to known treatment and test a therapy that targets an important pathway in those tumors.

Pyramid Trial Summary

The PYRAMID trial addresses both of these issues in order to test an investigational combination of R-CHOP with or without VELCADE, a known NFKB inhibitor, specifically in non-GCB lymphoma. Continue reading “PYRAMID: A Personalized Medicine Study in Lymphoma”