Rituximab Plus GM-CSF Active in CLL Patients, Including Elderly Untreated

February 1, 2006

A combination regimen of rituximab (Rituxan) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to induce objective responses in patients with chronic lymphocytic leukemia (CLL), particularly in elderly untreated patients, according to a study presented at the 47th Annual Meeting of the American Society of Hematology (abstract 721).

ATLANTA-A combination regimen of rituximab (Rituxan) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to induce objective responses in patients with chronic lymphocytic leukemia (CLL), particularly in elderly untreated patients, according to a study presented at the 47th Annual Meeting of the American Society of Hematology (abstract 721).

Supplementation of rituximab therapy with GM-CSF is thought to increase therapeutic efficacy by upregulating surface CD20 expression and also enhancing the antibody-dependent cell-mediated cytotoxicity induced by ritux-i-mab. In previous studies, rituximab plus GM-CSF has demonstrated significant responses in patients with follicular lymphoma. In the current phase II study, Alessandra Ferrajoli, MD, assistant professor, Department of Leukemia, M.D. Anderson Cancer Center, and her colleagues looked at the combination in patients with CLL.

Three Groups

Patients enrolled in the trial were divided into three groups according to their disease profile:

Group 1: Untreated patients older than 70 years of age with indications for treatment based on National Cancer Institute Working Group (NCI-WG) criteria (n = 14).

Group 2: Untreated patients with Rai stage 0-2 disease at high risk for progression, defined as a β2-microglobulin level greater than 3 mg/dL, B symptoms, or severe fatigue (n = 35).

Group 3: Patients with relapsed/refractory active disease (n = 36).

All patients received 250 µg subcutaneous GM-CSF three times per week for 8 weeks and 375 mg/m2 intravenous rituximab weekly for the first 4 weeks.

As expected, responses to treatment varied by group, ranging from an overall response rate of 47% in previously treated patients (group 3) to 86% in untreated older patients (group 1) (see Table). Dr. Ferrajoli noted that the addition of a second cycle of therapy may increase the response rate.

Analysis of prognostic factors revealed that genetic profile, determined by fluorescence in situ hybridization (FISH), and ZAP-70 status were significantly predictive of response to treatment. Patients with trisomy 12 were more likely to respond to treatment than were those with other genetic profiles analyzed by FISH, and patients with ZAP-70-negative disease were significantly more likely to respond to treatment than were those with ZAP-70-positive disease (P ≤ .05 for each). Analysis of CD20 expression showed a trend toward increased expression 24 hours after the second dose of GM-CSF was given.

The regimen appeared well tolerated, with hematologic toxicity limited to four incidents of grade 3-4 neutropenia and one case of grade 3-4 thrombocytopenia. Common nonhematologic toxicities included grade 1-2 GM-CSF site reaction (24%), bone pain (11%), and fatigue (11%). Plasma levels of several cytokines significantly increased following two doses of GM-CSF, including IL-2, IL-4, IL-12, interferon-α, and tumor necrosis factor-α (TNF-α).

Dr. Ferrajoli concluded that priming with GM-CSF was able to increase CD20 expression in vivo, and that rituximab plus GM-CSF appeared beneficial in elderly frontline patients. She added that the combination is being further explored within the CLL Research Consortium (CRC).

A phase II study suggests that adding GM-CSF to rituximab may boost response rates in patients with CLL, particularly in previously untreated elderly patients. The combination is being further explored.