Dr. John Leonard Discusses CHOP Versus DA-EPOCH-R for the Use of Untreated Diffuse Large B-Cell Lymphoma

jl-healio

In an interview during the 2016 American Society of Hematology Annual Meeting, Dr. John Leonard discusses results from a phase III trial where researchers compared the treatments R-CHOP to DA-EPOCH-R in DLBCL patients specifically from either the GCB or ABC subtypes.

A full link to the video of Dr. Leonard discussing the trial can be found by clicking above or be seen on Healio.com.

Weill Cornell Medicine – 2016 ASH Abstracts

2016 has been another productive year for research in the Lymphoma Program at Weill Cornell Medicine. Listed below are the abstracts we were involved in whole or in part to be presented at this year’s 58th Annual Meeting of the American Society of Hematology (ASH).

Look to this space for more information about developments during the ASH meetings this December 3-6.

CLL/SLL

60 – Acalabrutinib Monotherapy in Patients with Richter Transformation from the Phase 1/2 ACE-CL-001 Clinical Study

188 – The Landscape of Dynamic Genetic Changes in Ibrutinib-Treated CLL

192 – Outcome of Patients with Complex Karyotype in a Phase 3 Randomized Study of Idelalisib Plus Rituximab for Relapsed Chronic Lymphocytic Leukemia

233 – Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

304 – Targeting Cellular Metabolism and Survival in Chronic Lymphocytic Leukemia and Richter Syndrome Cells By a Novel NF-Kb Inhibitor

621 – Phase 1 Study of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody, in Patients with CD20+ B-Cell Malignancies Previously Treated with CD20-Directed Antibody Therapy

638 – Acalabrutinib Monotherapy in Patients with Ibrutinib Intolerance: Results from the Phase 1/2 ACE-CL-001 Clinical Study

642 – Venetoclax (VEN) Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapsed after or Were Refractory to Ibrutinib or Idelalisib

969 – Mutations in NOTCH1 PEST Domain Orchestrate CCL19-Driven Homing of Chronic Lymphocytic Leukemia (CLL) Cells By Modulating the Tumor Suppressor Gene DUSP22

1047 – Single Cell Bisulfite Sequencing Defines Epigenetic Diversification in Chronic Lymphocytic Leukemia

3705 – A Retrospective Analysis of Pneumocystis Jirovecii Pneumonia Infection in Patients Receiving Idelalisib in Clinical Trials

4349 – FAT1 Mutations Influence Time to First Treatment in Untreated CLL

Diffuse Large B-Cell Lymphoma

469 – Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303

473 – A Multicenter Open-Label, Phase 1b/2 Study of Ibrutinib in Combination With Lenalidomide and Rituximab in Patients With Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

734 – EZH2 Enables the Proliferation of Germinal Center B Cells and DLBCL through a Rb-E2F1 Positive Feedback Loop Involving Repression of CDKN1A

837 – RNA Interference Screen Implicates TNFAIP3 and FOXO1 in MALT1 Inhibition Resistance

1045 – AICDA Introduces Epigenetic Plasticity in Germinal Center-Derived Lymphomas and Accelerates Lymphomagenesis

1087 – Integrative Genetic and Clinical Analysis through Whole Exome Sequencing in 1001 Diffuse Large B Cell Lymphoma (DLBCL) Patients Reveals Novel Disease Drivers and Risk Groups

3045 – Ribavirin, an eIF4E Inhibitor, As a Potential Anti-Lymphoma Therapeutic – Preclinical and Early Clinical Data

Follicular Lymphoma

616 – Continued Excellent Outcomes in Previously Untreated Follicular Lymphoma Patients after Treatment with CHOP Plus Rituximab or CHOP Plus (131) Iodine-Tositumomab – Long Term Follow-up of Phase III Randomized Study SWOG S0016

1217 – Ibrutinib As Treatment for Chemoimmunotherapy-Resistant Patients with Follicular Lymphoma: First Results from the Open‑Label, Multicenter, Phase 2 DAWN Study

1804 – Ibrutinib Combined with Rituximab in Treatment-Naive Patients with Follicular Lymphoma: Arm 1 + Arm 2 Results from a Multicenter, Open-Label Phase 2 Study

2953 – Early Relapse of Follicular Lymphoma after Rituximab-Based Biologic Doublet Upfront Therapy Is Associated with Increased Risk of Death: A Combined Analysis from CALGB Studies 50402, 50701 and 50803 (Alliance)

Hodgkin Lymphoma

924 – Subsequent Malignant Neoplasms Among Children and Adolescents with Hodgkin Lymphoma Treated with Response-Adapted Therapy: A Report from the Children’s Oncology Group Study AHOD0031

2949 – Hodgkin Lymphoma Patients Demonstrate Evidence of Systemic Perturbation of the Monocyte-Dendritic Cell Axis

3502 – Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) after Treatment with Nivolumab for Relapsed/Refractory Hodgkin Lymphoma

4088 – CD25 Enables Oncogenic BCR Signaling and Represents a Therapeutic Target in Refractory B Cell Malignancies

Mantle Cell Lymphoma

150 – A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

610 – PIK3IP1 Inhibition of PI3K in G1 Arrest Induced By CDK4 Inhibition Reprograms MCL for Ibrutinib Therapy

1096 – Lymphoid-like Environment, Which Promotes Proliferation and Induces Resistance to BH3-Mimetics, Is Counteracted By Obinutuzumab in MCL:  Biological Rationale for the Oasis Clinical Trial

1786 – Effectiveness of Lenalidomide in Patients with Mantle Cell Lymphoma Who Relapsed/Progressed after or Were Refractory/Intolerant to Ibrutinib: The MCL-004 Study

2937 – PRMT5 Targets Tumor Suppressor Micro RNAs to Regulate Cyclin D1 and c-MYC in Mantle Cell Lymphoma

Non-Hodgkin Lymphoma

536 – Toxicities and Related Outcomes of Elderly Patients (pts) (≥65 Years) with Hematologic Malignancies in the Contemporary Era (Alliance A151611)

756 – Molecular Basis of Ibrutinib Resistance in Waldenstrom’s Macroglobulinemia

1213 – Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study

4651 – Autologous Transplantation As Consolidation for High Risk Aggressive T-Cell Non-Hodgkin’s Lymphoma: A SWOG S9704 Intergroup Trial Subgroup Analysis

T-Cell Lymphoma

461 – Novel Long Non Coding RNA Blackmamba Is Associated to ALK- anaplastic Large Cell Lymphoma

621 – Phase 1 Study of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody, in Patients with CD20+ B-Cell Malignancies Previously Treated with CD20-Directed Antibody Therapy

2741 – VAV1 Activating Mutations and Translocations in Peripheral T-Cell Lymphomas

4096 – Molecular Subgroups of Peripheral T-Cell Lymphoma Evolve By Distinct Genetic Pathways 

The Cooperation that Causes Cancer

This article was originally published on the Meyer Cancer Center website.

The enemy approaches. Scouts pick up the scent and send signals to the relay team. The troops are rallied and an attack is prepared, strategically aligned to the specific weaknesses of the foe.

So it is with the body’s immune system. The scouts are T-cells, which pick up the antigen ‘scent’ of foreign invaders and notify their B-cell brethren to shift forms into plasma cells and produce weapons – antibodies – to attack.

Most of the B-cells respond by rapidly producing plasma cells, but this first line of defense is often weak. Luckily, a select few form into a special forces unit: the germinal center. Germinal centers are balls of furiously dividing B-cells that are mutating in order to tailor their antibody genes to attack offending antigens. The result is a much more powerful immunological army, with high affinity antibodies that can fully get rid of the antigen.

Once the job is done, the special forces unit is disbanded, the rapid proliferation and mutations end, and the germinal center cells are reprogrammed into normal plasma cells.

Ari Melnick, M.D.

Exactly how this shape shifting process happens has been a mystery – until now. A team of researchers at Weill Cornell Medicine, led by Gebroe Family Professor of Hematology and Oncology Ari Melnick, M.D., has uncovered the mechanisms by which B-cells transform, and found that it requires a special cooperation between regulatory protein EZH2 and transcription protein BCL6.

“The transition from a resting mature B-cell to a germinal center B-cell is nothing short of astonishing, as these cells are radically different from each other and this dramatic change requires extensive epigenetic reprogramming, or loading completely different software into the B-cell hardware,” Melnick said.

The discovery is key to understanding how certain blood cancers, such as the fast-growing diffuse large B-cell lymphoma, form and evolve. And it may have an impact on a potential new therapy.

“The basic properties of germinal center B-cells is to proliferate and mutate. Hence, they are prone to becoming lymphomas if something stops them from unloading the germinal center software,” Melnick said.

Scientists have long debated which regulatory system was responsible for B-cell programming.

EZH2 is an enzyme that chemically modifies the regulatory backbone proteins that control our genomes. It drives germinal center formation by suppressing cell-cycle checkpoint genes, repressing genes involved in plasma cell differentiation, and possibly impairing DNA damage responses.

BCL6 is a master regulator protein that attaches to the genome at sites that are crucial for the development of germinal centers.

Both EZH2 and BCL6 are known to repress transcription, the first step of gene expression, in which a particular segment of DNA is copied into RNA (mRNA).

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Wendy Beguelin, Ph.D.

In a study published August 8 in Cancer Cell, Melnick and first author Wendy Beguelin, Ph.D., show that neither alone is responsible – rather, the two form separate but nearby attachment points to the genome to capture a molecular machine called “BCOR complex” which then carries out the actual work of shutting down regions of the genome.

Just as the Air Force requires two officers to simultaneously punch in personal codes and insert and turn individual keys in order to launch dangerous missiles, the immune system seems to require two biochemical keys to shapeshift a friendly B-cell into a freakazoid germinal center B-cell capable of causing lymphomas.

“We show that the ‘missile’ that causes the final effect of controlling B-cell genes is the BCOR complex, which requires the EZH2 and BCL6 key to launch,” Melnick said. Lymphomas occur when these keys get “stuck” due to mutations or other influences.

“Although it may seem a subtle point it is actually quite profound,” Melnick added. “This is the first time it has been shown that such combinatorial repressive mechanisms exist between these kinds of regulatory proteins.”

The Melnick team also discovered the key missing link between EZH2 and BCL6: the CBX8 protein. It acts as a biochemical bridge by attaching to the histone mark placed by EZH2 and the BCOR protein that interacts with BCL6.

“It is the glue that makes the whole thing work,” Melnick said.

To stop out-of-control, lymphoma-generating germinal centers, the Melnick team suggests that disarming the biochemical “keys” could be key.

“If you hit both keys, then the missile silo goes dark and the germinal center B-cells fall apart,” Melnick said. “Either one alone is only partially effective; you have to disable both arms of the PRC1-BCOR tethering mechanism.”

This is possible by combining BCL6 and EZH2 inhibitors. EZH2 inhibitors are in clinical trials for patients with lymphomas at Weill Cornell and elsewhere, and BCL6 drugs have been developed by Dr. Melnick and colleagues and are not yet in human trials. The Melnick team showed that the EZH2-BCL6 drug combination synergistically suppressed human diffuse large B-cell lymphomas in pre-clinical studies.

“Although both EZH2 and BCL6 inhibitors inhibited tumor growth alone, the combination more potently and significantly suppressed lymphoma growth,” Melnick said. “In addition, the combination was not toxic to normal cells.”

The work was supported in part by grants from the National Institutes of Health, the National Cancer Institute, the American Society of Hematology, and the Leukemia and Lymphoma Society.

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