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.
According 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.
Paola Ghione, MD
Dr. Ghione is a visiting hematology fellow from Torino, Italy who is working with the Weill Cornell Lymphoma Program for six months.
Minimal residual disease (MRD) detection refers to a group of techniques used to find a very small amount of disease, normally undetectable with imaging or clinical exam. Usually, this detection is performed after treatment and, in many cases, is predictive of outcomes such as whether patients will relapse, and how quickly this might happen. Often, the reappearance of MRD can anticipate recurrence of lymphoma before it becomes clinically evident. In other hematologic disorders, such as acute leukemia and chronic myeloid leukemia, MRD is used in standard clinical practice to monitor disease status or to evaluate response to treatment. In the setting of lymphoma, measurement of MRD is still considered experimental, but a lot of research is taking place around the world to find the best way to perform it.
Our laboratory in Torino, Italy, run by Dr. Marco Ladetto and Dr. Simone Ferrero, leads many MRD projects for lymphoma and is part of the EuroMRD Network, an institution born in Europe to standardize MRD techniques. Currently, we look for tumor-specific DNA alterations in the blood before and after treatment using a technique called Allele-Specific Oligonucleotide (ASO)-PCR. Depending on how much tumor DNA is present in the blood, we can figure out the relative amount of tumor left in the body. Unfortunately, ASO-PCR requires an expert laboratory team, and the method is expensive and time-consuming, which makes it hard to use outside of specialized settings. In addition, it seems more reliable if performed directly on bone marrow aspirate (blood from the interior of the bone) than peripheral blood (coming from a normal vein), making it less attractive to clinicians and people with lymphoma.
New techniques that can speed the procedure and reduce the cost are being evaluated. For example, the droplet digital (dd)-PCR is interesting because it is faster and uses less material (i.e., requires less blood for the test). Another interesting method is Next Generation Sequencing (NGS), which allows the detection of several different DNA mutations at once. NGS analysis of cell-free circulating DNA(cfDNA) (the DNA present in circulating blood outside the cells) could give a lot information. Studying cfDNA from the blood could give us a more accurate picture of the lymphoma that in theory could be even better than studying DNA derived from an open biopsy at one site of disease. This is also sometimes referred to as a liquid biopsy. The reason it might be better is that the circulating cfDNA could show us mutations coming from all the sites where the tumor is actively growing, not only the one site from which the open biopsy is taken.
In Italy, although MRD is not yet available in routine clinical practice for treating lymphoma, it is being tested in some innovative clinical trials to guide treatment decisions. In some studies MRD negativity at the end of treatment is the primary goal, while in others reappearance of MRD prompts a preemptive approach. As an example, if MRD reappears when the person is off therapy, we can give a short re-treatment in order to avoid clinical relapse. In one of our clinical trials, evaluation of MRD has been used to rule out the presence of lymphoma in the cells collected prior to autologous stem cell transplantation.
Measurement of MRD has a lot of potential uses, and experience from other diseases proves that it can be practice changing. The challenges provided by more than 50 different lymphoma subtypes as well as the rapid evolution of new laboratory techniques have delayed the adoption of a universal test for MRD. In the near future, however, we expect to see MRD analysis in standard clinical practice everywhere.
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.