Targeted Therapies Usher in a New Era in CLL: Wierda Discusses Key Facets of Emerging Agents

Anita T. Shaffer
Published Online: Friday, April 4, 2014
William G. Wierda, MD, PhD

William G. Wierda, MD, PhD

The approval of the first small-molecule, targeted therapy for patients with chronic lymphocytic leukemia (CLL) launches a new era that promises to transform management of the disease, yet significant challenges in translating research advances into improvements in long-term outcomes remain, according to William G. Wierda, MD, PhD, a leading researcher in the field.

Wierda discussed emerging therapies for the most prevalent form of adult leukemia in an interview during the 18th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma. Physicians’ Education Resource® , LLC, hosted the conference on February 14-15 in New York City.

The conference occurred within days of the FDA’s accelerated approval of ibrutinib (Imbruvica) for patients with CLL who have received at least one prior therapy. Ibrutinib, the first Bruton tyrosine kinase (BTK) inhibitor on the market, was approved in November for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

In CLL, ibrutinib demonstrated an overall response rate of 58.3% (95% CI, 43.2%-72.4%) among 48 heavily pretreated patients with a median age of 67 years (range, 37-82 y).1 All responses were partial. The duration of response (DOR) ranged from 5.6 months to greater than 24.2 months, with the median DOR not yet reached. The indicated dosage is 420 mg daily orally.

It remains to be seen what impact ibrutinib and other targeted therapies will have over the long term in CLL. In chronic myeloid leukemia (CML), imatinib (Gleevec), a tyrosine kinase inhibitor (TKI), has helped transform the natural history of the disease.

Already, ibrutinib is among a growing list of targeted inhibitors under development for CLL (Table). The four major groups of inhibitors target BTK, phosphatidylinositol 3-kinase (PI3K), the spleen tyrosine kinase (Syk), and BCL2 proteins. “It is the whole class of agents that is transformative,” said Wierda, a professor and center medical director in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas, who also served on the program committee for the PER conference. “We’re entering a phase of a more targeted treatment approach and hopefully a less chemoimmunotherapy/ chemotherapy- based era.

“We will see a clear improvement in outcomes for patients with CLL, and when I think in terms of during my career, this is clearly a transformative period with significant incremental advances in therapy, particularly for the elderly who have difficulty tolerating myelosuppressive chemoimmunotherapy, and for patients with 17p CLL, for whom we have no effective treatment,” noted Wierda, who has been conducting research in CLL for more than a decade.

However, Wierda said the introduction of TKIs to the armamentarium for CLL would likely present issues of resistance like what was experienced in CML and other tumor types.

“Our work is not done,” he said. “We still have a lot of issues to address, and I think there still is clearly room for advances in treatments for patients with CLL.”

Ibrutinib is the second new therapy that the FDA approved for patients with CLL in less than four months. In November, the agency approved the monoclonal antibody obinutuzumab (Gazyva) in combination with chlorambucil for patients with previously untreated CLL.

Table. Targeted CLL Therapies in Development1,2


Agent by Class Clinical Trial Overview Sponsors/Collaboratorsa
BTK inhibitors
Ibrutinibb
  • 17 active studies
  • Various combination regimens, including ibrutinib with either rituximab, bendamustine, or lenalidomide
  • Settings include untreated and relapsed/refractory CLL
Janssen Research & Development Pharmacyclics, Inc National Cancer Institute
CC-292
  • 2 phase I trials
  • Combinations consist of CC-292 with either rituximab or lenalidomide
  • Relapsed/refractory settings
Celgene Corporation
ONO-4059
  • 1 phase I study of ONO-4059 as mono therapy
  • Relapsed/refractory CLL
Ono Pharmaceutical Co Ltd
ACP-196
  • 1 phase I safety study
  • Relapsed/refractory CLL
Acerta Pharma BV
PI3K gamma/delta inhibitors
Idelalisib
  • 9 active studies
  • Various combination regimens, including idelalisib with either ofatumumab, rituximab, or rituximab plus bendamustine
  • Settings include previously treated or untreated CLL
Gilead Sciences
GS-9820
  • 1 phase IB study
  • Dose escalation study evaluating GS-9820 mono therapy
  • Previously treated recurrent CLL
Gilead Sciences
IPI-145
  • 3 active studies
  • Phase III study regimens include IPI-145 vs ofatumumab
  • Settings include relapse/refractory or progressive CLL
Infinity Pharmaceuticals
AMG 319
  • First-in-human study
  • Relapsed/refractory lymphoid malignancies, including CLL
Amgen
TGR-1202
  • 2 phase I studies
  • Regimens include TGR-1202 as monotherapy or in combination with ublituximab
  • Relapsed/refractory advanced hematologic malignancies, including CLL
TG Therapeutics, Inc
SCRI Development Innovations, LLC
SAR245408
  • 1 active phase I trial
  • Safety study in metastatic or unresectable relapsed/refractory lymphoma, including CLL
Sanofi
Syk inhibitors
GS-9973
  • 1 phase II study
  • Monotherapy in relapsed/refractory hematologic malignancies, including CLL
Gilead Sciences
Cerdulatinib (PRT2070)
  • 1 phase I study
  • Dose escalation study in relapsed/refractory CLL
Portola Pharmaceuticals
BCL2 inhibitors
ABT-199
  • 6 active studies in CLL
  • Various regimens, including ABT-199 as monotherapy and in combination with rituximab, obinutuzumab, or with rituximab plus bendamustine
  • Relapsed or refractory CLL, including 1 study for patients with del 17p
AbbVie
Genentech
Roche
AT-101
  • Phase I/II trial
  • Combination study of AT-101 with lenalidomide
  • Relapsed/refractory B-cell CLL
Mayo Clinic

aSponsors and collaborators may not be participating in every clinical trial for a given agent.
bIbrutinib is FDA-approved for patients with CLL who have received at least 1 prior therapy.
CLL indicates chronic lymphocytic leukemia; del, deletion on short arm of chromosome.
1. Wierda WG. 17p del CLL patients—first-line vs relapsed/refractory. Presented at: 18th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma. February 14-15, 2014; New York, NY. 2. NIH Clinical Trials Registry. www.ClinicalTrials.gov.

Wierda, who serves on the National Comprehensive Cancer Network (NCCN) committee that develops guidelines for treatment of CLL, said the panel has incorporated data concerning both ibrutinib and obinutuzumab into the latest update, and will further review the new therapies at its meeting in late June. In an interview with OncologyLive, Wierda discussed the emerging targeted therapies, including issues in translating new regimens into clinical practice.

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