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.
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 Discusses Ibrutinib Plus Palbociclib for Patients with Previously Treated Mantle Cell LymphomaPosted: December 6, 2016
In an interview 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. A full link to the video of Dr. Martin discussing the trial can be found by clicking above or be seen on Healio.com.
Data from three pooled clinical trials suggest that, by itself, ibrutinib works to keep mantle cell lymphoma (MCL) at bay for about one year. For reasons that we have previously discussed on this blog, these results are both impressive and discouraging. For people with MCL, ibrutinib is singular in its ability to produce durable remissions with minimal toxicity. Unfortunately, roughly one third of patients do not respond, while all responding patients eventually experience relapse or progression.
Data from the Chen-Kiang laboratory at Weill Cornell Medicine suggested that palbociclib, an oral inhibitor of CDK4/6, could prevent MCL cells from growing and dividing. Moreover, these arrested MCL cells become even more sensitive to the effects of ibrutinib, essentially overcoming some of the more common mechanisms of ibrutinib resistance and laying the groundwork for a clinical trial.
With the support of the National Cancer Institute, doctors at Weill Cornell Medicine, Ohio State University, Washington University, and the University of North Carolina initiated a phase I clinical trial designed to evaluate the safety and activity of ibrutinib plus palbociclib in people with previously treated MCL. I presented the results of the trial at the 2016 Annual Meeting of the American Society of Hematology. The early results of the trial appear promising, with 70% of patients responding including 45% of study patients experiencing a complete response. More interesting is the observation that only one responding patient has experienced lymphoma progression, corroborating the Chen-Kiang laboratory data that the combination might overcome some mechanisms of ibrutinib resistance. So far, the all-oral regimen appears well tolerated, with low blood counts being the primary side effect.
Although these data appear promising, the number of patients treated so far is relatively small and the follow up time is relatively short. A large, multicenter phase II trial is being planned and will likely open in early 2017. Details regarding that study will be available on this blog and clinicaltrials.gov as soon as they become available.
Most clinicians and researcher agree since mantle cell lymphoma (MCL) was first described 25 years ago patient outcomes have improved considerably. What remains unknown, however, is why outcomes are improving.
In an international, phase III clinical trial from the European MCL Network that was recently published in The Lancet, investigators demonstrated that progression-free survival could be doubled by the addition of rituximab, dexamethasone, cytarabine, cisplatin (R-DHAP) to standard chemotherapy and autologous stem cell transplantation. Whereas in the early 1990s, data suggested that patients might expect to live for 2-4 years, new findings demonstrated that patients can achieve decade long remissions. The strange thing about this remarkably positive study is that the overall survival was similar in both arms despite significant differences in virtually all other outcome measures. In fact, in the vast majority of MCL related phase III trials, despite great improvements in depth and duration of response, the overall survival of the experimental and control arms is the same.
While we celebrate the successes that each of these studies represents, important questions remain. Why are the patients in the control arms doing so well? Why are patients treated with the older, less effective therapies living as long as patients randomized to receive new therapies, and why are they living longer than patients receiving those therapies a couple decades ago?
Some of these questions can be answered by perception biases and advances in supportive care. For example, if patients in 2016 are being diagnosed with MCL earlier than they might have been diagnosed in the 1990s, they would appear to live longer, a phenomenon known as lead-time bias. Improvements in pathology may also lead to what is known as selection bias. Previously, patients with less aggressive variants of MCL were misdiagnosed as having other kinds of lymphoma, while a more representative sample is included in today’s studies. Similarly, perhaps people enrolled in recent clinical trials are healthier than they were in the past, another form of selection bias. Perhaps supportive care has improved, allowing people to live longer with lymphoma, or tolerate therapies that might have been considered overly aggressive in the past. If any or all of these hypotheses are true, hematologists around the world cannot claim credit for the perceived improvements.
It is clear that people with MCL are living longer with a higher quality of life. They have more options for treatment and these gains are due to clinical trials. In the past decade, the use of rituximab has expanded while bortezomib, temsirolimus, ibrutinib, and lenalidomide, all better tolerated than many historical options, have been approved. If this is true, it suggests that the path to continued improvements relies on the development of new, well-tolerated approaches, and it suggest that front-line therapies without curative potential must evolve to become less toxic so that subsequent lines of therapy remain feasible.
Venetoclax for the Treatment of CLL Patients who have Relapsed after or are Refractory to Ibrutinib/IdelalisibPosted: June 8, 2016
CLL patients who relapse after or are refractory to ibrutinib or idelalisib often have few treatment options and poor outcomes. In an ongoing phase II study, presented at the 2016 annual ASCO meeting, researchers investigated the activity of venetoclax in patients with CLL who have relapsed or become refractory to ibrutinib or idelalisib. Venetoclax (Venclexta, ABT-199), is the first FDA-approves treatment that inhibits the BCL-2 (B-cell lymphoma 2) protein. The BCL-2 protein plays an important role in enabling CLL cells to survive. CLL cells and other lymphomas over express and are more dependent upon BCL-2 protein than normal cells. Therefore, when venetoclax inhibits the protein, the CLL cells die, while the normal cells continue unharmed.
54 patients were enrolled into the two arms of the trial based upon whether they were relapsed or refractory to ibrutinib (Arm A, 38 patients) or idelalisib (Arm B, 10 patients). 48 patients were evaluable for responses. The overall response rate for ibrutinib treated patients was 61% (CR=8%; PR=53%) and for idelalisib was 50% (CR=0%; PR=50%). Side effects were found in less than 20% of patients with the most common including neutropenia, diarrhea, nausea, anemia, fatigue, and hypophosphatemia. These results show that venetoclax displays promising activity for CLL patients who have relapsed or are refractory to both ibrutinib and idelalisib and can be safely administered.
Further research is required to demonstrate the depth and duration of response, but these initial results are positive.
Acalabrutinib is a second generation Bruton’s tyrosine kinase (BTK) inhibitor that targets the B-cell receptor signaling and is considered a prime target for the treatment of CLL. Acalabrutinib inhibits BTK activity preventing the activation of the B-cell antigen receptor pathway, and leads to CLL cell death. Recently at the 2016 ASCO annual meeting researchers presented preliminary results from an ongoing phase 1-2 study using acalabrutinib to treat patients with previously untreated CLL. Of the 74 patients enrolled in the trial 72 were evaluable for response. Acalabrutinib was well tolerated, with 72 of 74 patients remaining on treatment at time of analysis and evaluable for response. Neither of the two patients discontinued treatment for drug related adverse events.
The most common side effects were headaches, diarrhea, arthralgia, contusion, nausea, and weight increase, all characterized as mild. Treatment related lymphocytosis occurred in 53% of patients and was resolved in 97% of the affected patients at a median of 7 weeks. Patients who took acalabrutinib experienced a 96% overall response rate (PR=86%, PR-L=10%) with the median time to response being 2-8 months. For patients with untreated CLL the initial safety profile and high response rates are promising. Based on these results a phase 3 trial of acalabrutinib versus ibrutinib has commenced to further study the use of acalabrutinib in the treatment of patients with CLL.