ASH 2020: Dr. Mato Discusses a Once Daily, Oral Triple Therapy Clinical Trial for Richter’s Transformation and De Novo Large B-Cell Lymphoma

In this video, Dr. Anthony Mato, MD, MSCE, the Director of the CLL Program at Memorial Sloan Kettering Comprehensive Cancer Center, in New York City, is interviewed by CLL Society, founder and Chief Medical Officer, Dr. Brian Koffman, MD, a retired family physician and a CLL patient. This video was recorded at the 62nd^t Annual Meeting of the American Society of Hematology in December 2020 in a virtual format.  Dr. Mato also serves on the Medical Advisory Board of the CLL Society, Inc.

Despite the many advances in CLL treatment over the past decade, effective therapies for Richter’s Transformation remains an unmet need. Richter transformation (RT; Richter’s syndrome) was first described in 1928 by Maurice Richter as developing an aggressive large-cell lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL / SLL). Although diffuse large B cell lymphoma (DLBCL) is the most common form seen in patients with RT, Hodgkin’s lymphoma and T cell lymphomas are less common. Richter’s occurs in approximately 5% of CLL / SLL patients.

RT is a rapidly progressing condition with a median survival of fewer than 12 months. Treatment options include chemo-immunotherapy (CIT), often R-CHOP, a five-drug combination followed by an allogeneic hematopoietic stem cell transplant (alloHSCT) or bone marrow transplant if the patient responds to CIT. Clinical trials including CAR-T therapy and new drug combinations are often recommended.

In this interview, Dr. Mato discusses a trial that introduces the concept of “synthetic lethality,” where multiple targeted agents are used at low doses to block different pathways and to achieve the ability to kill cancer cells without the associated toxicities of putting three drugs together at usual doses. The concept of synthetic lethality is not new, in that it proposed in 1922. This concept’s application is relatively new and an outgrowth of expanding knowledge of cancer cells’ pathways that either promote proliferation or retard cell death. https://www.future-science.com/doi/full/10.4155/fmc-2018-0227

Take-Aways:

• This study was a Phase I, the first-in-human trial that explored DTRM-555, an optimized one-pill oral combination of a novel irreversible BTKi DTRMWXHS-12 (DTRM-12), everolimus (EV), and pomalidomide (POM)
• Researchers performed “preclinical” studies in mice attempting to find optimal “low” dosing schemes for blocking multiple parallel pathways and lower the toxicities associated with past treatment. They studied two-drug and three-drug combinations. For earlier background on this trial see from last year: ASH 2019: Dr. Mato Discusses a Novel Triple Therapy Clinical Trial for CLL / SLL, Richter’s Transformation and other Lymphomas. At ASH 2020, follow-up data was presented
• This preclinical work led to the selection of DTRM-12, Everolimus, and Pomalidomide to study in patients (clinical-trial).” In combination, targeting three specific pathways was determined to yield the most effective way to kill cancer cells in RT and lymphoma. Like other Phase I trials, this trial assessed optimizing effectiveness and safety by selecting the lowest doses possible.
  1. DTRMWXHS-12 (DTRM-12) is a new BTK inhibitor developed by Zhejiang DTRM Biopharma Company, Ltd of China. DTRM-12 is the “backbone” of therapy given at a “low dose” within this regimen.
  2. Pomalidomide (POM) is an oral thalidomide analog (similar to lenalidomide.) Used in combination with the steroid dexamethasone, POM has FDA approval for multiple myeloma patients. Pomalidomide is an immunomodulatory imide drug (IMID), which affects the “micro-environment” of the cancer cell, “making the neighborhood “unfriendly” to the cancer. This drug is used at an “extremely low” dose within the trial when compared to its other uses.
  3. Everolimus is a derivative of sirolimus used as an immunosuppressant to prevent organ transplant rejections and treat several advanced solid tumor cancers. This drug works by blocking the mTOR (mammalian target of rapamycin) pathway, a component of the phosphatidylinositol 3-kinase (PI3K) cell survival pathway. PI3K inhibitors such as idelalisib, umbralisib, and duvelisib currently used in relapsed/refractory or R/R CLL / SLL. Everolimus also is dosed at an “extremely low” level compared to other indications for this medication.
• Thirty-nine patients were enrolled and treated. The treatment group included twelve patients with RT and twelve with relapsed/refractory DLBCL. The safety analysis included all 39 patients, while the efficacy data focused on RT and R/R DLBCL. The median number of prior therapies for the RT + R/R DLBCL group was (range 1-10). Forty-nine (49) percent of treated patients had previously received a BTK inhibitor as monotherapy. Also, thirteen percent had received either a stem cell transplant or CAR-T.
• Adverse events were manageable and similar to the know side effects of BTK inhibitors, EV, or POM. The most common adverse effects were hematologic, including thrombocytopenia (low platelets), neutropenia (low neutrophils), and anemia (low hemoglobin or red blood cell count.)
• The effectiveness of this combination drug therapy was evaluated in eleven RT patients and ten DLBCL patients before the poster data cut-off date (8/6/2020). The overall response rate in the RT group was 60 percent, with two complete responses and four partial responses. The estimated duration of response (DoR) for these six patients was fifteen months. While not the high response numbers we are used to seeing in CLL trials, these are impressive results for patients with Richter’s.

Conclusions:

This very early Phase I trial is exciting and promising. In mouse studies, they found that this combination resulted in faster and deeper remissions. Phase I trials are by design small in number (N=39). The primary goal is to evaluate the safety of a drug or drug combination.  DTRM has an acceptable safety profile.

Encouraging clinical activity was observed in several high-risk, multi-refractory patients with RT.

A Phase II expansion study is underway in the U.S., targeting pts with RT, R/R DLBCL, R/R transformed follicular lymphoma, and BTKi/BCL2 inhibitor (venetoclax) exposed R/R CLL pts.

To learn more about clinical trials, in general, go to https://cllsociety.org/clinical-trials/.

Here is the  ASH Zoom interview by Dr. Koffman of Antony Mato:

Here is the link to the actial abstract: A Once Daily, Oral, Triple Combination of BTK Inhibitor, mTOR Inhibitor and IMiD for Treatment of Relapsed/Refractory Richter’s Transformation and De Novo Diffuse Large B-Cell Lymphoma

Stay strong; we are all in this together.

Thomas. E. Henry III, MBA, RPh, CPh

Thomas Henry is a Registered Pharmacist and CLL Patient. He is President and Senior Consultant for Burlington Consulting Associates, a company that provides consulting services to health systems nationwide. Tom is a CLL Society Medical Advisory Board member and strives to educate other CLL patients through his blog https//www.cllpharmacist.com. He has a forty-two-year career in pharmacy and has served as Chief Pharmacy Officer at two Top-15 Comprehensive Cancer Centers, Moffitt (Tampa, FL) and Roswell Park (Buffalo, NY).