This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4–14.4) vs 10.0 months (95% CI 7.7–12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760–1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.
In this prospective randomized trial, we compared the efficacy and toxicity of cladribine (2-CdA) alone to 2-CdA combined with cyclophosphamide (CC) or cyclophosphamide and mitoxantrone (CMC) in untreated progressive chronic lymphocytic leukemia (CLL). Study end points were complete response (CR), overall response, minimal residual disease (MRD), progression-free survival, overall survival, and toxicity. From January 1, 1998 to December 31, 2003, 508 patients from 15 hematology departments were randomized. Compared with 2-CdA, CMC induced higher CR rate (36% vs 21%, P ؍ .004), and a trend for higher CR rate with CC was observed (29% vs 21%, P ؍ .08). Furthermore, the percentage of patients who were in CR and were MRD negative was higher in CMC compared with 2-CdA (23% vs 14%, P ؍ .042). There were no differences in overall response, progressionfree survival, and overall survival among treatment groups. Grade 3/4 neutropenia occurred more frequently in CC (32%) and CMC (38%) than in 2-CdA (20%) (P ؍ .01 and P ؍ .004, respectively). Infections were more frequent in CMC compared with 2-CdA (40% vs 27%, P ؍ .02).In conclusion, CMC used in first-line treatment of CLL results in a higher CR rate and suppresses MRD more efficiently than 2-CdA monotherapy, although associates with increased toxicity. No important differences in efficacy and toxicity were found between CC and 2-CdA regimens.
SummaryHypereosinophilic syndrome (HES) is defined as chronic, unexplained hypereosinophilia with organ involvement. A subset of HES patients presents an interstitial deletion in chromosome 4q12, which leads to the expression of an imatinib‐responsive fusion gene, FIP1L1‐PDGFRA. These patients are diagnosed as chronic eosinophilic leukaemia (CEL). We treated seven CEL and HES patients, six of which expressed FIP1L1‐PDGFRA, with imatinib using initial daily doses ranging from 100 to 400 mg. In a remission maintenance phase, the patients were treated with imatinib once weekly. All imatinib‐treated patients achieved a complete haematological remission (CHR), and five of the six patients with FIP1L1‐PDGFRA expression exhibited molecular remission. The decreased imatinib doses were as follows: 200 mg/week in three patients, 100 mg/week in two patients and 100 mg/d in the remaining two patients. For remission maintenance, imatinib doses were set at 100 mg/week in five patients and 200 mg/week in two patients. At a median follow‐up of 30 months all patients remained in CHR and FIP1L1‐PDGFRA expression was undetectable in five of the six FIP1L1‐PDGFRA‐expressing patients. These data suggest that a single weekly dose of imatinib is sufficient to maintain remission in FIP1L1‐PDGFRA‐ positive CEL patients.
PURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. PATIENTS AND METHODS Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m(2) combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. RESULTS Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. CONCLUSION Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.
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