New Pre-clinical Research Shows Transcription-Targeting Drug Useful in T-cell Lymphoma

Peripheral T-cell Lymphomas (PTCL) are uncommon, but aggressive forms of non-Hodgkin lymphoma that develop from mature T cells, a type of white blood cell. The most prevalent subtypes include PTCL-NOS (not otherwise specified), AITL (angioimmunoblastic T-cell lymphoma), and ALCL (anaplastic large cell lymphoma). Patients with PTCL are usually treated with a combination of chemotherapy agents, mostly commonly CHOP (cyclophosphamide, adriamycin, vincristine and prednisone). With the exception of a rare variant called ALK-positive ALCL, only about a third of all patients could enjoy long-term disease-free survival, with most patients either having diseases resistant to treatment or recurrent after chemotherapy. As PTCL evolves, it becomes even more molecularly complex due to factors in the tumor microenvironment that make it hard to treat. Ongoing research has been performed in order to try and improve treatment options and increase overall survival for patients with this challenging disease.

To ultimately cripple tumors in patients with PTCL and eradicate the disease from the body, it’s necessary to target the molecular feature of PTCL that helps it grow. Leandro Cerchietti, M.D. Jia Ruan, M.D., Ph.D., and other collaborators from the Lymphoma Program at Weill Cornell Medicine and NewYork-Presbyterian are trying to do just that. New research conducted by the team has shown positive results for this hard-to-treat cancer.

Dr. Cerchietti and his research group have discovered that PTCL are sensitive to THZ1, a drug that targets transcription, the first step during gene expression when DNA is copied into RNA. THZ1 was developed by Dr. Nathanael S. Gray and collaborators from the Dana-Farber Cancer Institute. THZ1 works by stopping an enzyme called CDK7 (cyclin-dependent kinase 7) that controls the transcription of lymphoma genes. This interference changes the cells and primes the tumor to better respond to biologic agents, such as BCL2 inhibitors.

For this work, Dr. Cerchietti’s Lab established a collaboration with Drs. Nathanael S. Gray from Dana-Farber and Graciela Cremaschi from the Institute for Biomedical Research and the National Research Council of Argentina. After testing more than 120 FDA-approved compounds and new biologic agents from the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health and the Meyer Cancer Center Pre-Clinical Oncology Pharmacy, the investigators found that PTCL are susceptible to inhibitors of the proteasome, epigenetic drugs and compounds that target transcription, like THZ1.

tcell-lymphoma-graphic_cerchietti_thz1According to Cerchietti, they decided to focus on THZ1 since it demonstrated pre-clinical activity against PTCLs harboring the hard-to-target mutation STAT3. STAT can drive T-cell lymphomas and other tumors when activated by extracellular signaling that involves the phosphorylation of intermediate proteins like JAK. Although inhibitors of JAK proteins have been developed, they are thought to be inactive in tumors harboring the STAT3 mutation that does not require the activity of JAK. STAT proteins drive tumors by inducing the transcription of oncogenes like MYC and BCL2. Since this process requires CDK7, THZ1 can decrease the activity of STAT and the production of BCL2 and other proteins.

“Growing scientific evidence supports CDK7 inhibition as a treatment approach for cancers that are dependent on a high and constant level of transcription,” said Dr. Cerchietti. “Targeting CDK7 with THZ1 offers a way to circumvent the aggressive pathway responsible for tumor growth in many cancers, but particularly T-cell lymphomas which respond more positively to BCL2 inhibitors.”

BCL2 inhibitors are a class of drugs that are being tested to treat a variety of blood cancers. Venetoclax is an FDA-approved BCL2 inhibitor that is used to treat chronic lymphocytic leukemia (CLL) with a specific mutation.

“We are excited about these research results and the potential to bring a new treatment to patients with this aggressive lymphoma who otherwise have very few options if their cancer does not respond to chemotherapy,” said Dr. Ruan who leads the T-cell lymphoma clinical program at Weill Cornell Medicine and NewYork-Presbyterian.

“We aim to create transformative medicines that control the expression of disease-driving genes and believe this treatment can provide a profound and durable benefit for patients with a range of aggressive and difficult-to-treat solid tumors and blood cancers,” said Nancy Simonian, M.D., CEO of Syros, the biopharmaceutical company that is developing a next-generation version of the THZ1 compound for clinical trials. “Building on this research, we’ve used THZ1 as the starting point to create a selective CDK7 inhibitor that has better drug-like properties for use in humans.”

According to Syros, a phase I clinical trial built on this research is slated to open later this year to test the dosing and safety in people with solid tumors. The company plans to expand into hematological malignancies once the appropriate dose has been established in the initial phase I trial.

The bulk of this work was supported by the Leukemia and Lymphoma Society through a Translational Research Program awarded to Dr. Cerchietti.

Additional Weill Cornell Medicine contributors to this research include: Florencia Cayrol, Pannee Praditsuktavorn, Tharu Fernando, Rossella Marullo, Nieves Calvo-Vidal, Jude Phillip, Benet Pera, ShaoNing Yang, Kaipol Takpradit, Lidia Roman, Marcello Gaudiano, Ramona Crescenzo and Giorgio Inghirami.


FDA Approves First-Ever Targeted Marginal Zone Lymphoma Treatment

On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).

MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.

Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.

The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.

The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.

Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.

At Weill Cornell, we are currently studying ibrutinib in combination with the immunotherapy drug durvalumab in people with previously treated indolent non-Hodgkin lymphoma, including MZL.


Dr. Peter Martin’s Manuscript Selected as Top 10 Manuscript for 2016

Earlier today the editors of Blood, the journal of the American Society of Hematology selected the top 10 most outstanding manuscripts of 2016. Dr. Peter Martin was the first author in one of the selected abstracts titled ‘Post Ibrutinib outcomes in patients with mantle cell lymphoma‘. (MCL)

Dr. Peter Martin

Dr. Peter Martin

Dr. Martin led a team of researchers at Weill Cornell Medicine and centers from around the world in a retrospective study of patients with MCL who experienced disease progression while receiving ibrutinib. These researchers found that MCL patients who progressed during treatment with ibrutinib have a poor outcome. As there are no therapies that appear to be uniquely successful in the post-ibrutinib setting this represents an unmet need.

You can read about the full results from their study in the abstract.

Congratulations Dr. Martin!


Dr. Peter Martin on Promise of Ibrutinib + Palbociclib for Previously Treated Mantle Cell Lymphoma

pm-pic

In an interview with MDLinx during the 2016 American Society of Hematology Annual Meeting, Dr. Peter Martin discusses results from a phase I clinical trial designed to evaluate the safety and activity of ibrutinib plus palbociclib in people with previously treated MCL.


Living with Lymphoma: Updates in Treatment

Join us for a special event as the Lymphoma Program faculty host a discussion on the latest updates in the treatment of lymphoma with our partners at the Leukemia & Lymphoma Society. Details are below. To attend the event you must register here with the LLS.

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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 


Dr. Kristy Richards and Comparative Research for Lymphoma

Splitting her time between the main Cornell campus in Ithaca and the Weill Cornell Medical campus in New York City, Dr. Kristy Richards has developed a unique plan to research new lymphoma treatments. Lymphoma is a common form of cancer in humans and also the most common form of cancer found in dogs. So as human oncologist, Dr. Richards thought that treatments for canine patients could lead to advances in the treatment of human lymphoma patients,

“Dog and human lymphoma patients share many biological similarities, as well as the unfortunate fact that rates of the disease are rising for both species. “We don’t know why this is,” Richards says. “It could be something in the environment, which both dogs and humans share. So in a way, dogs could be a canary in the coal mine.”

“Richards plans to test cutting-edge approaches such as immunotherapy, which harnesses the body’s natural defenses to fight off cancer cells, in dogs suffering from lymphoma. This September, she was awarded a supplement grant from the National Cancer Institute, in partnership with the Roswell Park Cancer Institute in Buffalo, to further explore canine immunotherapy with veterinary patients that come to the Cornell University Hospital for Animals.”

The full article can be read here. More information about Dr. Richards work and the practical benefits so far accrued for both two and four legged lymphoma patients can be found in the below video.