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.


New Clinical Trial: Phase 1 Dose-escalation Study Evaluating the Safety, Pharmacodynamics, Pharmacokinetics, & Efficacy of GS-9901 in Subjects with Relapsed or Refractory Follicular Lymphoma, Marginal Zone Lymphoma, CLL/SLL

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with follicular lymphoma, marginal zone lymphoma, and CLL/SLL. The study sponsor is Gilead Sciences Inc., and the principal investigator at Weill Cornell is Richard Furman M.D.. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 and older.
  • Diagnosis of FL, MZL, or CLL/SLL.
  • Prior treatment with at least 1 chemotherapy or immunotherapy-based regimen.
  • Detailed eligibility reviewed when you contact the study team.

Study Details 

This clinical trial is for men and women with relapsed/refractory FL, MZL, or CLL/SLL.

GS-9901 is a second generation inhibitor of PI3K-delta which is critical for multiple signaling pathways that are hyperactive in B-cell malignancies and inflammation. The first generation PI3K-delta inhibitor idelalisib has been shown to induce durable disease control in patients with B-cell malignancies. Idelalisib as monotherapy or in combination with other agents (such as bendamustine, chlorambucil) and immunotherapy (rituximab, ofatumumab) has been shown to be tolerable and demonstrated clinical efficacy in clinical trials in patients with iNHL, CLL, and other hematological malignancies. This study will provide more information about whether GS-9901 can benefit subjects with B-cell malignancies in terms of efficacy and tolerability compared to first generation PI3K inhibitors.

Subjects will receive GS-9901 continuously throughout the study as long as they are responding to therapy and not experiencing unacceptable side effects. GS-9901 is administered orally once daily. After discontinuing treatment, follow-up information will be collected once every year for up to 5 years at clinic visits or through telephone calls.


New Clinical Trial: Phase 3 Study of Ibrutinib in Combination with Either Bendamustine and Rituximab or R-CHOP in Subjects with Previously Treated Indolent Non-Hodgkin Lymphoma

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with follicular and marginal zone lymphoma. The study sponsor is Janssen Research & Development LLC., and the principal investigator at Weill Cornell is Peter Martin, M.D.. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Key Eligibility

  • Open to men and women age 18 and older.
  • Follicular or Marginal Zone, non-Hodgkin lymphoma.
  • Relapsed or Refractory after receiving at least one prior chemotherapy regimen.
  • At least one site of measurable disease.
  • Detailed eligibility reviewed when you contact the study team.

Study Details 

This clinical trial is for men and women with follicular or marginal zone lymphoma who have been previously treated.

The purpose of this study is to compare whether adding ibrutinib to the standard chemotherapy options for this population bendamustine/rituximab (BR) or R-CHOP result in a longer progression-free survival than BR or R-CHOP alone.

The type of chemotherapy received will be dependent on refractory versus relapsed disease, type of indolent non-Hodgkin lymphoma, and number of prior lines of therapy.

All participants will be randomized in a one to one ratio to receive the study drug, ibrutinib, or placebo.

Randomization arms: This study is comparing BR or R-CHOP in combination with ibrutinib or placebo. This is a double blind study so neither the patient or the physician will know if you’re receiving the study medication, ibrutinib or placebo. Placebo is a blank pill that will look similar to ibrutinib but contains no medicine. The physicians will decide whether patients will receive BR or R-CHOP chemotherapy depending on prior treatments.

Patients will receive the standard 6 cycles of BR or R-CHOP and will continue taking ibrutinib or placebo as long as they are responding to therapy and not experiencing unacceptable side effects.


ASH 2014 – WCMC Related Abstracts

It has been another productive year for research in the Lymphoma Program at Weill Cornell Medical College. Listed below are the abstracts we were involved in whole or in part to be presented at this year’s 56th Annual Meeting of the American Society of Hematology (ASH).

Look to this space for future updates about developments at ASH 2014.

Anaplastic Large Cell Lymphoma
781 – Convergent Mutations and New Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma
1679 – Identification of a New Subclass of ALK Negative Anaplastic Large Cell Lymphoma Expressing Aberrant Levels of ERBB4 Transcripts

CLL/SLL
327 – Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial
330 – Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors
1990 – Pattern of Use of Anticoagulation and/or Antiplatelet Agents in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ibrutinib Therapy
3316 – Extracellular Nicotinamide Phosphoribosyltransferase (NAMPT) Shapes the CLL Microenvironment Promoting Macrophage M2 Polarization Via a Non-Enzymatic Mechanism
3331 – Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATETM Trial of Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
4615 – Cancer-Associated Mutations in SF3B1 Exhibit Neomorphic Splicing Activity and Block Erythroid Differentiation
3343 – Long-Term Follow-up of a Phase 1 Trial of Idelalisib (ZYDELIG®) in Combination with Bendamustine (B), Bendamustine/Rituximab (BR), Fludarabine (F), Chlorambucil (Chl), or Chlorambucil/Rituximab (ChlR) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

DLBCL
59 – Demethylase Activity of Aid during Germinal Center B Cell Maturation Could Contribute to Lymphomagenesis
143 – Akt Activation Confers an Inferior Survival in Patients with Activated B-Cell Subtype of Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program
567 – BCL6 Mediates a Stress Tolerance Phenotype through Its BTB Domain
864 – Strand-Specific Total RNA Sequencing Establishes the Complete Transcriptome and Alternative Splicing Repertoire in Diffuse Large B Cell Lymphoma
928 – A Virtual B Cell Lymphoma Model to Predict Effective Combination Therapy
1620 – NF-κB Subunit c-Rel Cooperates with Myc and Mutated p53 to Confer Significantly Worse Survival in Patients with Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program
1692 – Genetic Mechanisms of Immune Escape in Diffuse Large B Cell Lymphoma
1764 – Hsp90 at the Hub of Metabolic Homeostasis in Malignant B Cells
2032 – Whole-Genome Epigenomic Analysis in Multiple Myeloma Reveals DNA Hypermethylation of B-Cell Specific Enhancers
2963 – Mirna-181a expression Lead to Longer Animal Survival and Slower Tumor-Growth Rate in Diffuse Large B-Cell Lymphoma Xenograft Models
3021 – Characterization of DLBCL-Derived Exosomes and Investigation of Their Biological Properties
3091 – Unexpected and Serious Toxicity Observed with Combined Idelalisib, Lenalidomide and Rituximab in Relapsed/Refractory B Cell Lymphomas: Alliance A051201 and A051202
3547 – EBV Microrna Mir-BHRF1-2 Targets PRDM1/Blimp1: Potential Role in EBV Lymphomagenesis
4417 – A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Non-Leukemic Hematologic Malignancies

Hodgkin Lymphoma
501 – Results of a Phase II Trial of Brentuximab Vedotin As First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT
4400 – Circulating Memory T Cells Isolated from Hodgkin Lymphoma Patients Display Evidence of Exhaustion and Chronic Activation

Mantle Cell Lymphoma
625 – Sustained Remission with the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase II Study Report
2250 – Acquired in Vitro Resistance to Ibrutinib Is Associated with Transcriptional Re-Programming and Sustained Survival Signaling in Waldenströms Macroglobulinemia and Mantle Cell Lymphoma, Independent of BTK Cys481Mutation
3047 – Poor Overall Survival of Patients with Ibrutinib-Resistant Mantle Cell Lymphoma
4453 – Single-Agent Ibrutinib Demonstrates Safety and Durability of Response at 2 Years Follow-up in Patients with Relapsed or Refractory Mantle Cell Lymphoma: Updated Results of an International, Multicenter, Open-Label Phase 2 Study
4461 – Safety Results from the United States Cohort of the Ibrutinib Early Access Treatment Protocol (EAP: MCL4001) in Patients with Relapsed or Refractory Mantle Cell Lymphoma
4471 – Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Marginal Zone Lymphoma
705 – The Coding Genome of Nodal Marginal Zone Lymphoma Reveals Recurrent Molecular Alterations of PTPRD and Other Jak/Stat Signaling Genes

Non-Hodgkin Lymphoma
60 – Protein Arginine Methyltransferase 5 Directly Targets and Epigenetically Silences microRNAs miR33b and miR96 to Support Constitutive Cyclin D1 Activity in Non-Hodgkin’s Lymphoma
3063 – Durable Responses Following Treatment with the PI3K-Delta Inhibitor Idelalisib in Combination with Rituximab, Bendamustine, or Both, in Recurrent Indolent Non-Hodgkin Lymphoma: Phase I/II Results

T-cell Lymphoma
510 – Integrin αvβ3 Transduces Survival and Angiogenic Signals to T Cell Lymphomas and Is a Therapeutic Target
810 – Transcription Regulation Targeting in Peripheral T Cell Lymphomas Induces Apoptosis and Sensitization to BCL2 Inhibitors

Waldenstrom’s Macroglobulinemia
1689 – The Selective Bcl-2 Inhibitor ABT-199 Synergizes with BTK or Proteasome Inhibitors to Induce Potent Cell Death in Preclinical Models of Bortezomib or Ibrutinib-Resistant Waldenströms Macroglobulinemia
2250 – Acquired in Vitro Resistance to Ibrutinib Is Associated with Transcriptional Re-Programming and Sustained Survival Signaling in Waldenströms Macroglobulinemia and Mantle Cell Lymphoma, Independent of BTK Cys481Mutation
3115 – Therapeutic Sensitivity of CD20- Waldenströms Macroglobulinemia Cells Is Determined By Underlying Genomic and Epigenetic Events
3116 – Targeted Disruption of USP14 and UCHL5 with the Novel Deubiquitinase Enzyme (DUB) Inhibitor, VLX1570, Induces Immense Proteotoxicity and Cell Death in Malignant Plasma Cells
3551 – Methylation Patterns in Waldenströms Macroglobulinemia Cells That Are Inherently Resistant or Have Acquired Resistance to Bortezomib, Converge on the TP63 and Cepba Family of Transcription Factors