Lymphoma Medicine is Precision Medicine: A Conversation with Dr. John Leonard

Last week, Dr. Leonard held a lecture to discuss how lymphoma medicine is precision medicine. Precision medicine treatment options are tailored to each patient’s specific genetic profile and medical history. With the availability of genomic sequencing tools, it is now feasible to profile a patient’s genome and locate the mutations that cause cancer.

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Dr. John Leonard

Each year more than 80,000 cases of lymphoma are reported, spanning over 100 different classifications. The majority of these are non-Hodgkin lymphomas. The most common forms of which are follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic lymphoma, and mantle cell lymphoma. Although these are all subtypes of the same disease, the variances in their biology require different treatment approaches.

To illustrate the effectiveness of precision medicine approaches in lymphoma, Dr. Leonard cited the treatment of DLBCL. For patients with DLBCL, the standard initial treatments are the chemotherapy combination R-CHOP and dose adjusted R-EPOCH. Around 70% of cases are cured with either of these two treatments, proving that chemotherapy is effective.

The other 30% of patients who do not respond to treatment proceed to 2nd and 3rd lines of therapy. For patients whose DLBCL returns, there is only a 20% survival rate. This low survival rate for patients with recurrent lymphoma and patients who do not respond to chemotherapy necessitates different approaches to treatment. This is not an abandonment of effective chemotherapy, but a way to tailor treatment more specifically to the patient’s individual tumor biology.

Precision medicine in lymphoma treatment involves targeting the “cancer cell-of-origin” in patients, or in other words, the genetic source of the cancer. Through gene expression profiling, we are able to determine distinct molecular subtypes. This could allow us to detect malignancies earlier on and offer better preventative treatment for individuals at risk of developing blood cancer. Continued advances in our understanding of the genome fuels the growth of precision medicine which already plays an important role in treating certain lymphomas.

Although precision medicine is a huge advancement for the treatment of lymphoma, there are still challenges. This includes weighing the effectiveness of drugs used in targeted therapy, developing tools to categorize the different lymphoma subtypes, cost, and patient participation. Because it is a still a growing field, many precision medicine goals are still in the early stages of development.

Stay tuned for the American Society of Hematology (ASH) annual meeting in November where Dr. Leonard will be presenting new research regarding lymphoma and precision medicine. If you would like to learn more about precision medicine at Weill Cornell Medicine visit the Englander Center for Precision Medicine website. If you are interested in learning about the new innovative treatment options at Weill Cornell Medicine visit our JCTO website listing our open clinical trials.

Clinical Trial Participation May Improve Outcomes for Patients with Lymphoma

Picture1By Peter Martin, M.D.

Recently researchers from the Mayo Clinic presented data at the 2016 ASCO annual meeting suggesting that clinical trial participation might be associated with a survival benefit. The researchers used the Mayo Clinic Lymphoma Database to identify patients with relapsed Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), or relapsed mantle cell lymphoma (MCL), and compared the characteristics and outcomes of those enrolled in clinical trials versus those who were eligible, but not enrolled in clinical trials. Between January 2001 and December 2014, 340 patients with DLBCL, 159 with MCL, and 115 patients with HL were identified. Over this same period 47 unique Phase 1-3 trials led to the FDA approval of 17 treatments.

94 of 340 (27%) DLBCL, 63 of 159 (41%) MCL and 66 of 115 (57%) HL patients were enrolled on a clinical trial at some point during therapy, with 38% of patients enrolled in more than 1 study. Researchers found that the median survival of patients treated in a clinical trial was roughly twice as long as patients not treated on a clinical trial in all 3 lymphoma subtypes. There are several possible sources of bias or confounding that might explain the difference, despite the researchers’ efforts to control for these variables. Clearly, more research in this areas is indicated. Nonetheless, the magnitude of benefit was striking and should be reassuring to patients considering clinical trial participation.

REDLAMP 14: Does Routine Imaging After DLBCL Remission Improve Post-Treatment Survival?

Most patients with diffuse large B-cell lymphoma (DLBCL) patients achieve a long-term remission after first line treatment with combined immunotherapy and chemotherapy. Relapse can, however, sometimes occur after a period of DLBCL remission. Once a patient is in remission, the appropriateness of routine imaging (with CT or PET scans) for DLBCL patients is controversial and is believed by some to have limited value in detecting relapse. In a population based study published in the Journal of Clinical Oncology researchers from Denmark and Sweden compared the survival of different patients undergoing different types of routine imaging. In this video Dr. John Leonard explains the findings of this study in order to provide guidance in follow up monitoring strategies.

Previous #REDLAMP entries can be viewed on our Youtube channel.

We encourage you to follow the Lymphoma Program on Twitter, Youtube, and Facebook where we will highlight new videos are about research publications as they are released. We also welcome your feedback, suggestions and questions about this project. If you have other questions about our lymphoma program or clinical trials or would like to see one of our lymphoma specialists, please contact us at 212-746-2919.

REDLAMP 13: How Are Outcomes Improving for Patients with Transformed Follicular Lymphoma?

The diagnosis for follicular lymphoma that has transformed into diffuse large B-cell lymphoma (DLBCL) has in the past been associated with a poor prognosis for patients. However, in a National LymphoCare Study recently published in Blood, researchers assessed the incidence, prognostic features, and outcomes associated with the transformation of follicular lymphoma in enrolled patients. In this video Dr. John Leonard discusses the findings of the study. Specifically reviewed are new data on outcomes, based on novel approaches and therapies for patients whose follicular lymphoma has transformed.

Previous #REDLAMP entries can be viewed on our Youtube channel.

We encourage you to follow the Lymphoma Program on Twitter, Youtube, and Facebook where we will highlight new videos are about research publications as they are released. We also welcome your feedback, suggestions and questions about this project. If you have other questions about our lymphoma program or clinical trials or would like to see one of our lymphoma specialists, please contact us at 212-746-2919.

Targeting New Pathways for the Treatment of an Aggressive Form of B-Cell Lymphoma

lecBy Leandro Cerchietti, MD

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and fast-growing lymphoma that is the most common form of non-Hodgkin lymphoma in the United States. Nearly 1/3 of DLBCL patients experience relapse. The outcome can be worse for patients with DLBCL that harbor activation of multiple oncogenes. An oncogene is a gene that can “hit” a cell to transform it into a cancer cell. Some cells are “hit” with more than one oncogene. When hit by two or three oncogenes they transform into a very aggressive lymphoma called double-hit and triple-hit lymphomas (DH/TH). These DH/TH are largely insensitive to combinatorial chemotherapy and are more frequently found in the elderly. To grapple with the complexities of treatment of DH/TH lymphomas, alternate pathways for the development of future treatments must be found by researchers.

The three oncogenes that could drive these lymphomas are MYC, BCL2 and BCL6, but it is not know whether all three work simultaneously. In a paper recently published in OncoTarget, researchers from my lab at Weill Cornell Medicine found that DLBCL cells that survive BCL6 targeted therapy induce a phenomenon of “oncogene-addiction switching” and super activate one of the other oncogenes, preferentially BCL2. The activation of BCL2 by the anti BCL6 therapy allows lymphoma cell to survive this targeted treatment. My team found that to be effective in killing lymphoma cells a therapy should inhibit both the BCL6 and BCL2 oncogenes.

This phenomenon occurs because these three oncogenes share the regulation of common pathways responsible for the survival of DLBCL. If one oncogene is targeted, the others can take the leading role. In the case of BCL6, specific targeting of BCL6 releases BCL2 inducing on-target feedback resistance to this therapeutic strategy. However, this “oncogene-addiction switching” mechanism can be harnessed to develop rational combinatorial therapies for DLBCL.

An alternative strategy to target DH/TH DLBCLs could be to simultaneously dismantle all three oncogenic networks. In a separate paper recently published in Blood, researchers from my lab and the University of Montreal found another potential therapeutic pathway for the treatment of these aggressive DLBCLs. They found that the protein Hsp90 binds to and maintains activity in eIF4E a protein that controls MYC, BCL6, and BCL2 networks. Inhibition of eIF4E using the antiviral drug Ribavirin decreases simultaneously MYC, BCL6, and BCL2 avoiding “oncogene-addiction switching” and inducing regression of DH/TH DLBCLs. The researchers used a novel pre-clinical model of lymphoma called “patient-derived tumorgrafts”, that are mouse models faithfully resembling the complexity of human lymphomas.

They also found that DH/TH could be targeted with Hsp90 inhibitors. Still targeting Hsp90 activity has met with limited success in the past due to the counter regulatory elevation of Hsp70, which induces resistance to Hsp90 inhibitors. However, researchers were able to identify Hsp70 as a target for eIF4E. Accordingly the combination of eIF4E and Hsp90 inhibitors should result in a potential new pathway for the development of new treatments for DLBCL, an approach WCM clinicians will test in future clinical trials.

Dr. John Leonard Discusses New Data from PYRAMID Study on Non-Germinal Center B-Cell-Like Subtype Diffuse Large Cell Lymphoma

In this video from the ASCO Post, Lymphoma Program Director, Dr. John Leonard discusses results presented at the 2015 meeting of the American Society of Hematology from the recently completed Pyramid trial.  This multi-center phase II study sought to determine whether R-CHOP was more effective with or without bortezomib in patients with untreated non-germinal center B-cell-like subtype diffuse large cell lymphoma. (non-GCB DLBCL)

The study’s full abstract can be read here.

Dr. Sarah Rutherford Describes Recently Opened Trial for Selinexor and RICE Chemotherapy in relapsed/refractory DLBCL

In this video Dr. Sarah Rutherford discusses a trial for men and women with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), who were not cured by initial treatment with R-CHOP or a similar chemotherapy.

The purpose of this study is to determine the maximum tolerated dose of selinexor when given in combination with rituximab, ifosfamide, carboplatin, and etoposide (RICE) in patients with relapsed or refractory aggressive B-cell lymphomas. This is an open-label, phase 1 trial with a standard dose escalation schema.

Tumor biopsies and peripheral blood will be taken pre- and post-treatment with selinexor to examine the study’s biologic objectives.

Key Eligibility

  • Men and woman greater than or equal to 18 years of age
  • Confirmed diffuse large B-cell lymphoma, double/triple hit lymphoma, indolent lymphomas transformed to DLBCL or other aggressive B-cell lymphoma, and follicular lymphoma grade 3B
  • Treatment with at least two cycles of one prior anthracycline-based regimen administered with curative intent
  • Detailed eligiblity reviewed when you contact the study team

If you’re interested in participating in this trial please call 212-746-2919 for more information. A full listing of DLBCL trials at Weill Cornell Medicine can be found on our clinical trials listing.


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