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.


ASCO 2014: Routine Surveillance has Limited Impact in Detecting Remission of Peripheral T-cell Lymphoma

By Tiffany Tang, MD

The role of routine surveillance imaging (RSI) in first complete remission (CR1) for peripheral T-cell lymphoma (PTCL) patients is unclear. Theoretically, RSI should allow for the earlier detection of asymptomatic relapses, thus leading to the earlier initiation of second line therapy. In an abstract presented during a session of the 2014 ASCO conference, we investigated the proportion of PTCL relapses detected by RSI and those found through clinical finding, before comparing the outcomes in patients from those two groups.

341 patients were retrospectively identified through the T-cell lymphoma databases of the National Cancer Centre Singapore/Singapore General Hospital and Weill-Cornell Medical College. These patients were divided into groups based on their mode of relapse detection; through RSI or clinical findings. PTCL subtypes included PTCL-NOS, AITL, ALCL (ALK positive and negative), EATL, GDT, HSTL and ATLL, while patients with leukemias, indolent, composite and cutaneous lymphomas were excluded. Of the 341 patients, 145 patients achieved CR1 and 64 relapsed. Relapses were detected by clinical findings in 51 patients, RSI in 9 patients and only 3 patients did not have any clinical findings at the time of relapse.

This data from our findings suggests that RSI does not often impact the detection of CR1 in patients with PTCL.


New Treatment for Systemic and Cutaneous T-cell Lymphomas: Antibody-drug Conjugate Brentuximab Vedotin

jruanBy Jia Ruan, MD

The peripheral T-cell lymphomas (PTCL) are uncommon lymphoid diseases that account for 5-10% of all non-Hodgkin lymphomas in adults in North America.  Compared to B-cell non-Hodgkin lymphomas, the PTCLs are generally aggressive and less responsive to current treatment options. Relapsed and refractory diseases are common.  Novel and target therapies are in much need to improve quality and duration of response.  At the 2012 American Society of Hematology (ASH) meeting in Atlanta, several research groups reported encouraging study results with the antibody-drug conjugate Brentuximab vedotin for T-cell lymphomas. Brentuximab vedotin (BV) is an anti-CD30 chimeric antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E. BV received accelerated FDA approval in 2011 for relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), 2 diseases that express abundant CD30.  Several new studies have looked at the treatment outcome of BV in patients with systemic or cutaneous T-cell lymphomas that express variable amount of CD30.

Studies in Systemic T-cell Lymphomas

Dr. Jacobsen from Dana Farber Cancer Institute reported an interim analysis of a phase II multicenter study which evaluated the antitumor activity of BV in patients with relapsed or refractory CD30-positive NHL. BV was administered at 1.8 mg/kg every 3 weeks by IV infusion. The study also explored the correlation between antitumor activity and quantitative CD30 expression.  Fifty-three patients with various CD30-positive NHLs have been enrolled, including 18 patients with mature T-/NK-cell lymphomas. Of the T-cell lymphoma patients enrolled, 9 have angioimmunoblastic T-cell lymphoma (AITL), 8 have PTCL-NOS, and 1 has cutaneous T-cell lymphoma.  The ORR was 27% (3/11) for mature T-/NK-cell NHLs.  Thus far, response was particularly noteworthy in in AITL where 3 of 5 patients (60%) have responded (2 CR, 1 PR).   Treatment-emergent adverse events were generally mild and moderate (grade 1/2), and expected including peripheral neuropathy and cytopenias, which was consistent with the safety profile of BV.  CD30 expression levels for patients with a CR or PR were widely variable and ranged from <1% to 90%.  Preliminary data seems to suggest that BV may be beneficial for patients with T-cell lymphomas that have low CD30 expression. Dr. Fanale from MD Anderson Cancer Center reported a phase I study with BV administered concurrently with multi-agent chemotherapy as frontline treatment of systemic ALCL and other CD30 positive T-cell lymphomas.  The study was Read the rest of this entry »


New Clinical Trial: Alisertib (MLN8237) or Investigator’s Choice for Relapsed/Refractory Peripheral T-Cell Lymphoma

A Phase 3, Randomized, Two-Arm, Open-Label, Multicenter, International Trial of Alisertib (MLN8237) or Investigator’s Choice (Selected Single Agent) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Update: this study is closed to enrollment. 

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for people with relapsed or refractory Peripheral T-Cell Lymphoma (PTCL). The sponsor is Millennium Pharmaceuticals, and the principal investigator at Weill Cornell is Dr. Jia Ruan. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Study Details

The purpose of the study is to assess how well people with PTCL respond to treatment with the experimental drug Alisertib (also known as MLN8237) as compared to other PTCL treatments.

Study participants will be randomly assigned to receive Alisertib or one of the following drugs used to treat PTCL: pralatrexate, romidepsin or gemcitabine.

Alisertib has been developed to interfere with cell division, which is required for normal and cancer cell growth. By blocking an enzyme that cells need to reproduce, alistertib may slow the growth of cancer cells.

Key Eligibility

  • PTCL relapsed or refractory to at least 1 prior systemic, cytoxic therapy for PTCL
  • Must have received convential therapy (not experimental) as prior therapy

Treatment Plan

Study participants will be randomly assigned to one of two study arms:

  • Arm A: Alisertib tablet twice daily by mouth for 7 consecutive days (Cycle Days 1-7) in a 21-day cycle for up to 32 cycles of treatment (2 years)
  • Arm B: Single-arm comparator. Participants will be assigned by the investigator to receive 1 of the following for up to 2 years:
    • Pralatrexate via infusion once weekly for 6 weeks in 7-week cycles. Cycles repeated every 7 weeks
    • Romidepsin via infusion on Days 1, 8 and 15 of a 28-day cycle. Cycles repeated every 28 days
    • Gemcitabine via infusion on Days 1, 8 and 15 of a 28-day cycle. Cycles repeated every 28 days

ASH 2011: New Treatment for T-Cell Lymphoma

By Jia Ruan, MD

Update: The below mentioned trials are closed to enrollment. 

The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphoid diseases that constitute less than 15 percent of all non-Hodgkin lymphomas in adults in North America. The most common subtypes are 1) Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS); 2) Anaplastic large cell lymphoma, primary systemic type (ALCL); and 3) Angioimmunoblastic T-cell lymphoma (AITL).  The PTCLs are generally aggressive, and tend to run a more relapsing and less favorable clinical course compared to B-cell NHLs.  Relapsed and refractory diseases are common. Novel and target therapies are in much need.

At the recent Annual Society of Hematology (ASH) meeting, Dr. Friedberg of the University of Rochester reported the result of a phase 2 trial of Alisertib (MLN8237), a potent inhibitor of aurora A kinase, in patients with relapsed aggressive non-Hodgkin’s lymphoma (NHL). Aurora kinases regulate mitosis during cell division. Inhibition of aurora A kinase can lead to mitotic errors and premature cell death. Alisertib is taken orally twice daily for 7 days on 21-day cycles. This phase 2 study enrolled a total of 48 patients, including 8 patients with peripheral T-cell lymphoma. The overall response rate was 32%.  Response in T-cell NHL was the most impressive at 57%: four out of eight patients responded, and the some of the responses were durable. The response rates in DLBCL and MCL were modest around 20%. Treatment-related side effects were generally tolerable and included low blood counts, fever, fatigue and inflammation in mouth. Based on these results, additional clinical trials (phase II sponsored by SWOG / NCI and phase III sponsored by Millennium) with this orally available compound are moving forward in T-cell lymphoma. Both of these studies will be available soon at Weill Cornell Medical College  (click here to read about the SWOG/NCI trial and click here to read about the Millennium trial on clinicaltrials.gov).

Dr. Advani of Stanford University discussed the updated results of an international phase 2 study of Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma Read the rest of this entry »