Latest Data Further Support Ibrutinib’s Efficacy in CLL

Anna Azvolinsky, PhD
Published Online: Tuesday, December 10, 2013
Dr. Philip L. McCarthy

Philip L. McCarthy, MD

Several trials of ibrutinib, an oral kinase inhibitor, either alone or in combination with currently used therapies for patients with chronic lymphocytic leukemia (CLL) were presented at the 55th Annual Meeting of the American Society of Hematology.

Ibrutinib (Imbruvica), which is marketed by California-based Pharmacyclics, was recently approved as a monotherapy for patients with mantle cell lymphoma who have received at least one prior therapy. The oral drug received a Breakthrough Therapy Designation from the FDA in April 2013 for particularly poor prognosis and high-risk CLL or small lymphocytic lymphoma (SLL) patients who carry a deletion in chromosome 17 (17p deletion). CLL patients who harbor the 17p deletion generally have poor outcomes when treated with standard chemotherapy and immunotherapy regimens.

Ibrutinib specifically inhibits the Bruton’s tyrosine kinase (BTK), a crucial component of both normal and malignant B-cell receptor signaling that has been shown to modulate the tumor microenvironment and promote survival and growth of CLL. Thus far, the drug has demonstrated less toxicity for patients compared with standard treatment regimens.

In the phase Ib/II PCYC-1102 monotherapy study in relapsed, refractory CLL (N = 85), patients who received 420 mg of ibrutinib daily had an overall response rate (ORR) of 71% (N Engl J Med. 2013;369[1]:32-42). The estimated progression-free survival (PFS) rate at 26 months was 75%.

“This is one of several compounds that are targeting specific pathways in the CLL cell that will likely lead to long-term control and possibly cure of this disease,” said Philip L. McCarthy, MD, of the Blood and Marrow Transplant Program at the Roswell Park Cancer Institute in Buffalo, New York.

Activity in Combination with Bendamustine and Rituximab

Combining ibrutinib with the chemoimmunotherapy regimen of bendamustine (Treanda) plus rituximab (Rituxan) demonstrated a high level of activity and was tolerable for patients with relapsed or refractory CLL.1 Presenting the final results of the 30-patient study, Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston, Massachusetts, said those patients with a molecular marker of high-risk disease and those with bulky disease were as likely to respond as all patients on the trial.

Dr. Jennifer R. Brown

Jennifer R. Brown, MD, PhD

The ORR was 93.4% (28/30) including five complete responses and three nodal partial responses, with no differences in responses based on risk features such as a 17p deletion. An additional patient had a partial response with lymphocytosis (PRL). The estimated PFS at 12 months was 90% but the median PFS has not yet been reached.
 
“Although it is difficult to compare studies, these results suggest that these responses are higher than those seen in previous phase II studies of bendamustine plus rituximab alone,” said Brown.

Twenty-one of the patients are continuing on an ibrutinib extension study and 18 are still on treatment about 12 months later with no evidence of progression, Brown said during her presentation. Nine patients have discontinued, with five going on to a stem cell transplant and four with disease progression.

“This is a very nice study with good outcomes in these [previously treated patients]. It will be important to see how long these responses are maintained,” said McCarthy, who was not involved in the study.

The median age of patients on the trial was 62. Patients had a median of two prior therapies and 13% had three or more prior therapies. The median treatment follow-up was 16 months. Twenty-three percent of patients had a 17p deletion and 43% had an 11q deletion.

Patients tolerated the three-drug regimen relatively well: the median number of completed cycles was the full six. No patients have discontinued the drug due to adverse events (AEs) and no deaths were reported on the study.

The most frequent treatment-related AEs were diarrhea (70%), nausea (66.7%), fatigue (46.7%), neutropenia (40%), and upper respiratory tract infection (36.7%). Grade ≥3 AEs included neutropenia (40%), maculopapular rash (10%), and fatigue (10%), as well as cellulitis, thrombocytopenia, and febrile neutropenia (6.7% each).

A randomized phase III trial is testing the combination in 580 patients with relapsed or refractory CLL (NCT01611090).

Ibrutinib Plus Rituximab Generates 95% Response Rate in CLL

A 14-month update of a phase II trial of ibrutinib plus rituximab (N = 40) has shown higher response rates for the combination compared to historical response rates with rituximab alone.2 The combination resulted in a response in 37 of the 39 CLL patients on the trial who could be evaluated. Thirty-four patients achieved a partial remission (87%) and three patients had a complete remission (8%).

Jan A. Burger, MD, PhD

Jan A. Burger, MD, PhD

The combination resulted in profound activity in high-risk CLL patients and was well tolerated, said Jan Burger, MD, PhD, and associate professor of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, who presented the results. “The addition of rituximab clearly accelerates responses in CLL,” said Burger. “But the question is whether this response will translate into substantial benefit for patients in the long run. That is what we are currently testing.”

The combination also improved the quality of life of patients. In self-reported quality-of-life questionnaires, the proportion of patients reporting high quality of life increased from 46% prior to treatment to 89% after 6 months of ibrutinib therapy.

At a median follow-up of 14 months, 31 of the 40 patients are still on treatment (including 16 of 20 patients with a 17p deletion or TP53 mutation) with no disease progression. The estimated overall survival at 18 months is 84%.

The combination resulted in a more rapid redistribution of lymphocytosis, noted Burger during his presentation.

Several patients had infection complications including six patients with pneumonia and three upper respiratory infections. Low-grade adverse events included bruising, subdural hematoma, fatigue, bone pain, and arthralgia.

The combination is currently being tested in an ongoing phase III, randomized, 150-patient clinical trial (NCT01973387).

Ibrutinib Proves Effective, Regardless of 17p Deletion Status 

Further evidence of ibrutinib’s activity in CLL was presented by Mohammed Farooqui, DO, of the hematology branch of the National Institutes of Health in Bethesda, Maryland. Analysis by Farooqui et al of patients with 17p deletion–positive CLL showed that treatment with ibrutinib does not select for 17p deletion specific clones, suggesting that ibrutinib alone is equally effective in treating CLL patients, regardless of whether the patient’s disease harbors a 17p deletion.3

Farooqui et al’s phase II, single-center trial enrolled both previously treated and treatment-naïve patients into two cohorts: those with no 17p deletion (n = 24) and those with a detectable 17p deletion (n = 29).

At 20 months, none of the 17p deletion–negative patients have progressed and 85% of 17p deletion–positive patients remain on treatment.

Eighty-one percent of patients with no 17p deletion had a partial response and 53% of those with a 17p deletion responded. Another 9% of patients with no 17p deletion and 43% of patients with a 17p deletion had a PRL. Nodal response was 100% in both cohorts, including a >70% tumor reduction and >40% spleen volume reduction, as well as a >75% reduction in tumor infiltration in the bone marrow in both patient cohorts.

At 14 months, the estimated event-free survival is 93%. At 6 months, 66% (31 patients) had a partial response and 28% (13 patients) had a PRL.

References

  1. Brown JR, Barrientos JC, Barr PM, et al. Ibrutinib in combination with bendamustine and rituximab is active and tolerable in patients with relapsed/refractory CLL/SLL: final results of a phase 1b study. Presented at: the ASH 55th Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 525.
  2. Burger JA, Keating MJ, Wierda WG, et al. ibrutinib in combination with rituximab (iR) is well tolerated and induces a high rate of durable remissions in patients with high-risk chronic lymphocytic leukemia (CLL): new, updated results of a phase II trial in 40 patients. Presented at: the ASH 55th Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 675.
  3. Farooqui M, Aue G, Valdez J, et al. Single agent ibrutinib (PCI-32765) achieves equally good and durable responses in chronic lymphocytic leukemia (CLL) patients with and without deletion 17p. Presented at: the ASH 55th Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 673.

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