Role of Chemotherapy Continues to Change in CLL

William G. Wierda, MD, PhD

Although advances are being made in novel therapies for patients with chronic lymphocytic leukemia (CLL), standard chemotherapy remains part of the treatment paradigm, but its role is undergoing a major shift, according to William G. Wierda, MD, PhD.

About 5 or 6 years ago, a majority of patients diagnosed with symptomatic CLL were started on a chemotherapy regimen. Now, as new small molecules are developed, the choice of therapy is influenced by a variety of factors, including line of therapy and cytogenetic analysis, Wierda indicated during a presentation at the19th AnnualInternational Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas and Myeloma, held February 20-21 in Miami.

“We’re transitioning to an era in which chemotherapy is being delayed for as long as possible in preference to using small-molecule inhibitors, which can control the disease for an extended period of time,” said. Wierda, who is chief of the CLL Section and medical director of the Leukemia Center at The University of Texas MD Anderson Cancer Center in Houston.

The strategy, if possible, is to avoid subjecting the patient to the toxic side effects associated with chemotherapy. These include myelosuppression and risk for infection, immune cell depletion, and risk for secondary hematologic malignancies, such as myelodysplastic syndrome and acute myeloid leukemia.

Pending further clinical trial results, chemotherapy remains the standard of care in first-line settings for most patients, with the choice of regimen dependent upon the age and fitness level of the individual, and molecular aberrations, said Wierda.

For the young or fit, the options include fludarabine/ cyclophosphamide/ rituximab (FCR), bendamustine/rituximab (BR), and fludarabine/rituximab (FR). “For patients who can tolerate chemotherapy, FCR is favored over other chemotherapy combinations, although there are some data suggesting that the FCR regimen has a higher cause of myelosuppression, as compared with BR,” Wierda said.

He emphasized that there is a group of patients who do exceptionally well with chemotherapy. These are patients with the mutated immunoglobulin heavy chain variable (IGHV) gene. In two-thirds of these patients, FCR can extend progressive free survival (PFS) beyond 10 years. In this subgroup, “chemotherapy may be the ideal option and further strategies may not be directed at eliminating it. The objective may be to reduce the number of cycles or the exposure to chemotherapy,” he said.

The treatment strategy changes, however, for older patients who are frail or who have comorbidities. In those patients, chlorambucil plus obinituzumab is the standard frontline therapy, with chlorambucil plus ofatumumab as another option, Wierda said. Obinutuzumab and ofatumumab are monoclonal antibodies (mAbs) that target the CD20 antigen expressed on the surface of B cells.

Meanwhile, small-molecule inhibitors are considered frontline treatment for untreated patients who have chromosomal deletion 17p. “Ibrutinib is the first-line choice of treatment in these patients. And that’s the only group in which the small-molecule therapy is indicated as frontline [therapy],” said Wierda.

In the relapsed setting, however, chemotherapy does not have a role now, “because we have these two small-molecule inhibitors, ibrutinib and idelalisib,” said Wierda. “These agents would be considered standard therapy for relapsed CLL.” Ibrutinib is employed as monotherapy while idelalisib is paired with rituximab, he said.

Wierda expects that when results from the RESONATE-2 trial become available that “ibrutinib will replace chemotherapy as the standard in the elderly population.” RESONATE-2 is a randomized, multicenter, open-label trial of ibrutinib as a monotherapy versus chlorambucil in patients with treatment-naïve CLL or small lymphocytic leukemia who are 65 years or older.¹

There are numerous nonchemotherapy treatments for CLL that have been approved or are in various stages of clinical development, said Wierda. These include the CD20 mAb agents (obinutuzumab and ofatumumab), the BCL-2 inhibitors (venetoclax), BTK inhibitors (ibrutinib, ACP-196, CC-292, and ONO-4059), the PI3K-delta inhibitors (idelalisib, GS-9820, IPI-145, AMG/ACP-319, TGR-1202, and SAR245408), and Syk inhibitors (GS-9973, fostamatinib, and PRT-2070).

With all these potential options, it’s an exciting time in CLL, he said.

“We’re realizing now that it’s possible to manage patients without chemotherapy. These newer agents are effective at controlling the disease, but our work isn’t done,” said Wierda. “Most of the patients have a partial remission with the newer agents, but there is still a significant level of disease, even at a best response.”

The goal is to get patients off treatment, or to experience a treatment-free period.

“I think there has to be a way to correct and reestablish the immune system. In an era of small-molecule inhibitors, we need to minimize complications like Infections, pneumonia, hypogammaglobulinemia, reactivation of herpes virus, and reduction of second malignancies,” Wierda said. “Our work is not done.”

Reference

1. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01722487.