Tag: CLL

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.

Ofatumumab Granted Breakthrough Therapy Designation for Untreated CLL

Recently, on September 13 the FDA granted a Breakthrough Therapy Designation to ofatumumab (Arzerra) in combination with chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL) who are inappropriate for fludarabine-based therapy. This designation is awarded to drugs whose preliminary clinical evidence suggests an improvement over existing therapies on one or more clinically significant endpoints, speeding the bench to beside process. The designation was granted after preliminary results from a phase 3 clinical trial involving over 400 patients was announced in May.

Ofatumumab is a monoclonal antibody that targets an epitope on the CD20 molecule that encompasses parts of the small and large extra-cellular loops. The CD20 molecule is found on over 90% of B-cell lymphomas and assorted lymphoid tumors with a B-cell origin. Ofatumumab effectively kills cancer cells by directing the body’s immune system against normal and cancerous B-cells, and attaching to the CD20 molecule located on the surface of cancerous B-cells.

In addition to the aforementioned purposes, ofatumumab is being investigated for treatment in follicular lymphoma, diffuse large B-cell lymphoma, and Waldenstrom’s Macroglobulinemia.

Currently, there are ongoing ofatumumab trials at the Weill Cornell Lymphoma Program open to patients with CLL. Additional listings of clinical trials for CLL & SLL patients can be found here.

Please stay updated with our clinical trials listings for forthcoming trials involving ofatumumab and the Cornell Lymphoma Program website for further clinical research updates.

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.