Ibrutinib Continues to Demonstrate Viability in Treatment of CLL

Based on the results of the first in-human clinical trial of ibrutinib in chronic lymphocytic leukemia (CLL) – conducted in 2010 at Weill Cornell Medicine/NewYork-Presbyterian Hospital and other centers – researchers led in part by Dr. Richard Furman moved forward with the first phase II trial of the drug. According to a five-year follow-up study recently published in the American Society of Hematology’s Blood journal, ibrutinib continues to demonstrate excellent efficacy and tolerability as a single agent therapy for people with previously untreated and relapsed or refractory CLL.

CLL is characterized by uncontrolled growth of mature B-cells that accumulate in the blood, bone marrow, lymph nodes and spleen. As CLL cells fill these various organs, they interfere with normal cell functions. Ibrutinib is an oral treatment that inhibits Bruton’s tyrosine kinase (BTK), an enzyme involved in B-cell development that plays a critical role in CLL cell survival.

Prior to the Food and Drug Administration (FDA) approval of ibrutinib for CLL in 2014, chemoimmunotherapy (CIT), typically with fludarabine, cyclophosphamide and rituximab (FCR), was one of the only treatment options available for people with CLL. Chemoimmunotherapy often generates deep responses that last a median of five to six years, but it is associated with significant toxicities. When patients relapse after CIT, their disease becomes more resistant to subsequent treatments, and due to the accumulation of toxicities, many patients are unable to receive further CIT. Given the associated toxicities, the use of CIT is limited in older patients with comorbidities – the cohort that comprises the majority of CLL patients.

The phase II study in which Dr. Furman was involved tested ibrutinib as a single agent in over 100 patients – some of whom received no prior therapy, and others who relapsed following initial treatment. Patients received daily oral doses of ibrutinib until their disease progressed or until the presence of side-effects warranted discontinuation of therapy.

Almost 90 percent of all patient participants demonstrated a response to treatment at the five-year mark, and complete remission rates increased over time with ongoing treatment. Ninety-two percent of treatment-naive patients and 44 percent of relapsed/refractory patients remained free of disease progression five years out from the start of treatment.

Side-effects, including infections, diarrhea, bleeding and low-blood counts, were mild. They did not prevent patients from remaining on treatment long-term and often improved with continued dosing.

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Dr. Richard Furman, M.D.

“These data demonstrate the excellent long-term outcomes for CLL patients treated with ibrutinib, especially those who receive ibrutinib as their first therapy,” says Dr. Furman.

CT Scans for Monitoring Chronic Lymphocytic Leukemia: Dr Richard Furman Comments in Panel Discussion

In this video from OncLive, CLL Program Director, Dr. Richard Furman joins a panel of chronic lymphocytic leukemia (CLL) experts to discuss the practice of using CT scans to monitor CLL.

In agreement with the other members of the panel, Dr. Furman commented,

“One of the additional factors that I think really has to be taken into account, and I couldn’t agree with the both of you more, is that now that our CLL patients have options beyond chemotherapy, their longevity is going to dramatically increase. Radiation tends to have a late effect, and now our patients have a future to be thinking about. And so, I really think doing away with CT scans as much as possible is certainly important. And there’s tremendous overuse of PET scanning, which is really not necessarily more radiation, but it’s the idea that, unless you suspect someone has Richter’s transformation, a PET scan doesn’t really add a lot to the care of the patient. And it really is just unnecessary radiation.”

ACP-196 Displays A Favorable Safety Profile for Patients with Relapsed/Refractory CLL

Dr. Richard Furman
Dr. Richard Furman

This Phase 1/2 trial was designed to evaluate the safety profile and efficacy of orally administered ACP-196 in patients with relapsed or refractory CLL/SLL. ACP-196 is a second generation BTK inhibitor that is more selective than the first generation BTK inhibitor ibrutinib. Bruton’s tyrosine kinase (BTK) is an enzyme involved in B cell receptor pathway signaling that has been shown to be critical for CLL cell survival. Trials with ibrutinib established BTK as an effective therapeutic target for the treatment of CLL.

As part of the trial, patients were treated continuously with escalating doses of ACP-196, once or twice daily. No dose limiting toxicities were identified and 100 mg twice daily was established as the most efficacious dose. The median age of the patients and number of prior therapies were 62 years and 3 prior therapies respectively. The median time on the study was 10.3 months. As of June 2015 there were 60 patients who were evaluable for response.

The overall response rate was 93% for all patients and 100% in the deletion 17p patient. ACP-196 was well tolerated, with 93% of patients remaining on treatment. The most common adverse events were headache and diarrhea. No disease progression has occurred to date.

Results from this study show that ACP-196 is a highly potent and selective oral BTK inhibitor with a favorable safety profile. Currently there is a Phase 3 trial comparing ACP-196 to Ibrutinib in Patients with High Risk CLL open to eligible patients at Weill Cornell Medicine.