Tag: research publications

Ibrutinib Promotes a High Frequency of Durable Response in Relapsed/Refractory and Older Treatment Naive CLL Patients

BTK is an essential mediator of B-cell receptor signaling in normal and malignant B-cells.  Ibrutinib (PCI-32765), an oral inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Chemoimmunotherapy (CIT) treatment approaches such as fludarabine, cyclophosphamide and rituximab have markedly improved outcomes of younger, fit patients as initial or second-line therapy. Unfortunately, fludarabine-based therapy is less well tolerated in the elderly and carries significant risk of cellular immune suppression, myelosupression, and subsequent myeloid neoplasia. Additionally, virtually all patients eventually relapse after fludarabine-based CIT, leading to the need for effective salvage regimens that induce durable remissions.

Recently, at the biennial international workshop on CLL (iwCLL), in Cologne, Germany, Dr. Richard Furman presented final results from a large (n=116 patients) multi-cohort Phase Ib/II trial of ibrutinib in treatment-naive (TN) or relapsed/refractory (RR) CLL/SLL.  Patients demonstrated a high frequency of durable responses extending beyond 24 months in both TN and RR CLL/SLL including those with high-risk genomic features.

Patients who were TN (all age ≥65 years) or RR (≥ 2 prior therapies including a purine analog and with  high-risk (HR) (relapsed within 2 years from combination CIT) were treated with  ibrutinib at fixed doses of 420mg or 840mg daily until disease progression (PD). The study’s primary objective was to determine the safety and response rates of both dosing regimens.  The overall response rates for the TN and RR patients were 84% and 88% respectively.  The progression free survival (PFS) estimated at 26 months for the 85 RR patients is 74% and for the 31 TN patients is 96%. Estimated 26 month overall survival (OS) for 85 RR patients is 78% and for the 31 TN patients is 97%.  Median duration of response, PFS, and OS have not been reached at the time of this analysis.

In conclusion, Ibrutinib monotherapy was found to be highly active, well tolerated, and induced durable responses in CLL patients with high-risk disease, R/R patients, and older TN patients. At present there are ongoing randomized trials comparing the safety profile of ibrutinib with other CLL therapeutic agents. Ongoing CLL trials at Weill Cornell Medical College can be found here.

Novel Weill Cornell Drug Displays Promise in Treating DLBCL

Following up on an earlier breakthrough confirming the feasibility of shutting down the Bcl6 protein — an important master regulatory transcription factor that is the key to survival for diffuse large-B cell lymphoma and other aggressive B-cell lymphomas– Weill Cornell’s Dr. Ari Melnick and other researchers recently completed a study where five doses of the experimental drug eradicated human lymphoma in mice.

Published online in the journal Cell the researchers described specifically how Bcl6 promotes the survival of DLBCL, before detailing how the Weill Cornell developed Bcl6 inhibitor effectively gums up the protein. Initially developed by Dr. Melnick nine years ago, the interim period has seen him working to improve the design for use by DLBCL and other lymphoma patients, collaborating with other world class researchers to understand how both Bcl6 and its inhibitor functions.

The researchers found that Bcl6 has two independent functions required for the survival of DLBCL. Dr. Melnick described how the first function, “builds a huge shopping mall-style complex”. This complex rests on top of a stretch of the genome. Through this binding Bcl6 deactivates the DNA, prohibiting genes from producing RNA and proteins. As Dr. Melnick noted, “Bcl6 acts like a barcode reader. When it sees that barcode — the DNA sequence — it attaches there”.

He went on, “Normally, the protein complex goes away after an immune reaction has been successfully mounted against the pathogen. But when it doesn’t, and remains stuck to the genes, DLBCL can result. That’s because Bcl6 is inhibiting genes that stop cells from dividing and that sense damage to the genome. We now know the genes that Bcl6 is repressing and how that helps lymphoma develop and survive.”

According to Dr. Melnick the second function, “acts like a switch on railroad track that routes a train in one direction or another. One track is needed when antibodies are required for an immune response, while the other keeps B cells in a constant state of division.”

Importantly the researchers were surprised to find that both the complex and the train switch attach to the Bcl6 protein at the same site. “They fit into the same keyholes on Bcl6,” Dr. Melnick said. “There are two identical binding sites on the protein surface.”

As Dr. Melnick exclaimed, “This is wonderfully serendipitous — our drug just happens to be able to overcome both of the biological mechanisms that are key to survival of aggressive lymphoma,” before adding that the inhibitor completely eradicated DLBCL in mice in a short time, with no detectable side effects.

The team is conducting additional research toward an investigational new drug application from the federal Food and Drug Admission.

Ibrutinib is Effective Therapy for Relapsed CLL Patients

Reporting results in the New England Journal of Medicine, Weill Cornell’s Dr. Richard Furman and others recently completed a large phase 1b/2 clinical trial on the effects of ibrutinib in patients with Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL). Recently granted a third breakthrough therapy designation as a monotherapy for CLL and SLL, ibrutinib acts as an oral, irreversible inhibitor of the enzyme, Bruton tyrosine kinase (BTK).  BTK is an essential component of the B-cell receptor signaling pathway and  facilitates interactions between the CLL cells and their micro-environment, promoting the survival of CLL/SLL cells.

In the clinical study, ibrutinib was administered orally to 85 previously treated patients with CLL once daily at doses of 420 mg and 840 mg. Both doses demonstrated an overall response rate of 71%, with an additional 20% and 15% in each group achieving a partial response with lymphocytosis. At a median follow up of 26 months, estimated progression-free and overall survival for the 85 patients overall were 75% and 83% respectively. Side effects were mild and included diarrhea, fatigue, and infections. The study concluded that ibrutinib produces, “a high frequency of durable remissions for relapsed or refractory CLL/SLL, including those patients with high-risk genetic lesions.”

Ibrutinib represents an important improvement in the treatment of patients with CLL/SLL.  Treatment previously consisted of regimens utilizing chemotherapies, including chlorambucil, cyclophosphamide, fludarabine, and bendamustine in various combinations that effectively generated responses in patients, but with significant toxicities.  Ultimately, patients relapsed and became unresponsive to or unable to tolerate chemotherapy.  Additionally, the subset of patients characterized by having del 17p13.1  who respond extremely poorly to chemoimmunotherapy, demonstrated response rates equivalent to the rest of the patient population.

Currently there are ongoing trials of ibrutinib in CLL and other lymphomas at the Weill Cornell CLL Research Center and Lymphoma Program. Additional clinical trials are available here.