The best response was PR and it was reported in 30% of patients, with a median duration of 6.7 months. multi-center phase II trial of the CLL Research Consortium between 10/2004 Hederagenin and 1/2007. Baseline characteristics are shown in Table 1. To be eligible for this study, patients were required to be at least 18 years or older, have adequate performance status, and renal and hepatic function. The study included 3 groups: 1) patients age 70 years or older with indication for treatment according to 1996 National Cancer Institute-Working Group (NCI-WG) guidelines, who refused or were deemed unsuitable for chemoimmunotherapy; 2) patients with previously untreated B-cell CLL with Hederagenin Rai stage 0-II disease, deemed at moderate/high risk for progression based on high beta-2 microglobulin ( 3mg/dL) or moderate constitutional symptoms without standard indications for therapy initiation 3) patients with relapsed CLL. Among these, 52% had received a fludarabine-containing regimen and 14% were fludarabine-refractory. Table 1 Patient pretreatment characteristics mutation ( 98%) 16/38 (42%)20/34 (59%)16/41 (39%) FISH 17p deletion 5/34 (15%)0/37 (0%)8/38 (21%) ? ? 11q deletion 2/34 (5%)2/37 (5%)2/38 (5%) ? ? Trisomy 12 7/34 (21%)9/37 (24%)7/38 (18%) ? ? negative 7/34 (21%)12/37 (32%)11/38 (29%) ? ? 13q deletion 13/34 (38%)14/37 (39%)10/38 (27%) Open in a separate window B2M, beta-2-microglobulin; em IgHV /em , immunoglobulin heavy chain variable gene; FISH, fluorescence in situ hybridization. The treatment consisted of recombinant human GM-CSF (sargramostim, Genzyme Corp., Cambridge, MA) given at the fixed dose Hederagenin of 250 mcg subcutaneously on day 1, 3 and 5 of each week for eight consecutive weeks. This dose was chosen based on the ongoing experience at that time in vaccine and immunotherapy trials. Rituximab was given at a standard dose of 375 mg/m2 intravenously on day 4 and continued weekly for 4 consecutive weeks. Two doses of GM-CSF were administered prior to the first dose of rituximab and GM-CSF was continued for four weeks after completion of rituximab to better allow increased surface expression of CD20 and ADCC potentiation. Hederagenin All patients received one course of therapy and the patients that achieved a response according to NCI-WG guidelines could be offered a second course of treatment. The primary objectives of this study were toxicity and efficacy. The efficacy of the combination was measured as overall response rate (ORR) and the sample size was established to be significant for each separate group. Toxicity was assessed using the NCI Hederagenin Common Terminology Criteria for Adverse Events (CTCAE) v3.0. FcRIIA, RIIIA and RIIB expression prior to treatment were measured as previously described7 and correlated with response.5 One hundred-twenty seven patients were included in the final efficacy analysis, 39 in group 1, 38 in group 2 and 50 in group 3. Responses consisted of complete response (CR) in 10 patients (8%), nodular partial response (nPR) in 11 patients (9%) and partial response (PR) in 56 (44%), for an overall response rate (ORR) of 61%. Rabbit Polyclonal to EDNRA The ORR was significantly higher in untreated patients with no indications for therapy (group 2, 82%) compared to elderly untreated patients with indications for therapy (group 1, 59%)(p=0.05) and to patients with relapsed disease (group 3, 46%)(p=0.01). After a median follow up of 79 (1-97) months, median Progression Free survival (PFS) was 15 (range, 2-83) months for patients in group 1 and 9 months (range, 1-86) for patients in group 3 (Figure 1A). Median PFS was longer for patients in group 2 (25 months, range 3-97) compared to group 1 (p=0.006) or group 3 (p=0.003). Time to next treatment was calculated for patients in group 2 and was 34 months (range, 1-110). Median Overall Survival (OS) has not been reached for patients in group 1 and 2 and is 86 months for patients in group 3. The estimated proportion of patients alive at 7 years is 87% in group 2, higher compared to group 1 (67%, p=0.01) and group 3 (54%, p 0.001)(Figure 1B). Three patients discontinued treatment within the first week: two due to severe (grade 3) bone pain following GM-CSF administration. One patient had a severe infusion reaction within minutes of the start of rituximab and refused further administration. The most common toxicity was.
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