Age, Health, Risk Define Treatment Groups and Options in CLL

Thomas J. Kipps, MD, PhD

Fitness, age, and disease risk status form the basis for decision-making about first-line therapy for chronic lymphocytic leukemia (CLL), according to a review of recent data presented at the 2015 Society of Hematologic Oncology (SOHO) annual meeting.

Evaluation of standard clinical and disease-related factors can separate most patients with previously untreated CLL into “go-go,” “slow-go,” and “no-go” categories, Thomas J. Kipps, MD, PhD, a professor of Medicine at the University of California, San Diego, said at SOHO.

“Go-go” patients are completely independent and have no comorbidities and a normal life expectance. Aggressive chemoimmunotherapy is recommended for patients in this category.

“Slow-go” patients have one or more comorbid conditions, impaired organ function, and/or reduced performance status. In most cases, these patients can tolerate and benefit from less aggressive chemoimmunotherapy.

Patients in the “no-go” category are severely handicapped, have a heavy comorbidity burden, and have a reduced life expectancy. Palliative care is the frontline option for these patients.

In addition to organ function and comorbidities, determination of a patient’s fitness for therapy should include assessment of bone marrow, functional status, and performance status. Commonly used instruments include the Comprehensive Geriatric Assessment (functional status), Eastern Cooperative Oncology Group performance status, and the Cumulative Illness Rating Scale (CIRS, comorbidity).

Using the CIRS as an example of the decision-making process, Kipps said a CIRS score ≤6 and a creatinine clearance (CrCL) rate ≥70 mL/min suggests a patient is a suitable candidate for standard therapy. A CIRS score >6 and CrCL <70 mL/min suggests a patient is suitable for less aggressive chemoimmunotherapy. Any patient with severe comorbidities and a short life expectancy should receive supportive care only.

Recent clinical developments have expanded the number of options for first-line systemic therapy in CLL, Kipps noted. Chemoimmunotherapy with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) remain appropriate choices in frontline treatment.

“FCR currently is the standard regimen for younger CLL patients,” said Kipps. “The regimen is not well tolerated in older patients, as cytopenias and infections occur more often and older patients are more likely to prematurely discontinue treatment.”

Intolerance of FCR is associated with older age, advanced disease stage, anemia, increased creatinine levels, and elevated levels of beta-2 microglobulin, he added.

The FCR and BR regimens were compared in a randomized trial involving patients who met “go-go” criteria, reported at the 2014 American Society of Hematology annual meeting (Blood. 2014;124[21]:19). The results showed greater activity with FCR, including a higher rate of complete remission (39.7% vs 30.8%; P = .03) and significantly better median progression-free survival (PFS, 55.2 vs 41.7 months; P = .001). However, overall survival did not differ between treatment groups, median PFS did not differ among patients older than 65, and FCR was associated with significantly more neutropenia (84% vs 59%; P <.001) and infections (39% vs 27%; P <.001).

Next-generation anti-CD20 monoclonal antibodies may be used in combination with chlorambucil (eg, obinutuzumab [Gazyva] or ofatumumab [Arzerra]) or bendamustine (eg, obinutuzumab). For patients with del(17p) CLL, monotherapy with the BTK inhibitor ibrutinib (Imbruvica) is an appropriate option.

The obinutuzumab/chlorambucil regimen was compared with chlorambucil alone and with rituximab (Rituxan)/chlorambucil as initial therapy for patients who met “slow-go” criteria (N Engl J Med. 2014;370:1101-1110). The obinutuzumab group had a median PFS double that of patients who received only chlorambucil (26.7 vs 11.1 months; P <.001) and also outperformed the rituximab regimen (15.2 months; P <.001).

Updated results from the trial (Leukemia. 2015;29:1602-1604) showed that patients treated with obinutuzumab and chlorambucil maintained the PFS advantage over chlorambucil alone (29.9 vs 11.1 months, P <.001) and versus the rituximab/chlorambucil group (15.4 months; P <.001). Obinutuzumab/chlorambucil was associated with a 53% reduction in the survival hazard versus chlorambucil alone (HR = 0.47; P = .0014) and by 30% versus rituximab/chlorambucil (HR = 0.70; P = .06).

Obinutuzumab and bendamustine were compared against fludarabine/cyclophosphamide/obinutuzumab in 41 patients with CLL (Blood. 2015;1235:2779-2785). The results showed that 18 of 20 patients treated with obinutuzumab and bendamustine had objective responses, including four complete responses (CR) and five CRs with incomplete marrow recovery (CRi). That compared with responses in 13 of 21 patients who received the three-drug regimen, including two CRs and CRi in three patients.

The combination of ofatumumab and chlorambucil was compared against chlorambucil alone as first-line therapy in 447 patients with CLL not suitable for treatment with fludarabine (Lancet. 2015;385:1873-1883). The combination led to a median PFS of 22.4 months versus 13.1 months for chlorambucil alone (P <.001) and an overall response rate of 82% (vs 69%; P = .001). The addition of ofatumumab to chlorambucil did not increase the incidence of grade ≥3 adverse events as compared with chlorambucil alone.

“For younger, fitter patients with untreated CLL, chemoimmunotherapy—with rituximab or obinutuzumab—is standard of care,” Kipps concluded. “For older patients and those with significant comorbidities, a combination of chlorambucil plus a next-generation anti-CD20 antibody is appropriate. Bendamustine, combined with rituximab or obinutuzumab, or fludarabine with rituximab, also might be acceptable but is associated with slightly greater toxicity.

“Avoid fludarabine-based regimens in elderly and/or frail patients or in the presence of autoimmune hemolysis.”

Ibrutinib has approval as initial therapy for patients with del(17p) CLL. A recent review of 3-year follow-up of patients with CLL and del(17p) included 31 patients who received ibrutinib in the first-line setting (Blood. 2015;125:2497-2506). The data showed a 30-month PFS of 96% and a 30-month overall survival of 97%. The patients had an overall response rate of 84%, including complete responses in 23%. In contrast, 34 patients with relapsed/refractory del(17p) CLL had a 30-month PFS of 48% and overall survival of 65%.