Bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL.
The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.
Treosulfan-based conditioning was feasible at all three doses. The 3 x 14 g/m(2) dose was selected for additional studies, because it combines desired characteristics of low toxicity and a low relapse rate.
To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P ؍ .22), 5-year EFS (7% versus 8%; P ؍ .53), disease-free survival (DFS; 13% versus 17%; P ؍ .06) nor overall survival (OS; 10% in both arms; P ؍ .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.
IntroductionThe overall outcome of treatment of patients of older age with acute myeloid leukemia (AML) has remained highly unsatisfactory. In patients older than 60 years, complete response (CR) rates are 45% to 60% only, while median disease-free survival (DFS) values have been estimated at less than 12 months and the 4-to 5-year overall survival (OS) rates are approximately 10%. [1][2][3][4][5] A potentially important biologic factor that may account for chemotherapy resistance of AML in patients of higher age is the high incidence of the intrinsic multidrug resistance (MDR) phenotype of leukemic blast cells. 6 The MDR phenotype results from expression of the MDR1 gene 7,8 and its 170-kDa protein product, P-glycoprotein (P-gp), 9 also designated as adenosine triphosphate (ATP)-binding cassette (ABC) transporter B1 (ABCB1). 10 P-gp is a transmembrane protein that acts as an energy-dependent drug efflux pump for chemotherapeutic drugs such as the anthracyclines and epipodophyllotoxins, commonly used in AML therapy.Increased P-gp expression and enhanced drug efflux have been reported with increasing age: from 17% in patients under the age of 35, 27% at 35 to 50 years, and 39% in patients over 50 years 11 to 71% in a group with median age 68 years (range, 56 to 88 years). 6 In retrospective studies MDR1/P-gp expression was associated with lower CR rates and decreased OS and DFS in AML. [12][13][14][15][16] Also For personal use only. on May 11, 2018. by guest www.bloodjournal.org From P-gp positivity of AML is associated with other adverse prognostic factors such as CD34 expression, secondary leukemia, and unfavorable cytogenetics. 6,13,14,17 Based on these studies a rationale was developed for MDR1 modulation as a therapeutic approach. 18 A variety of noncytotoxic agents, such as verapamil,...
Acute graft-versus-host disease (aGVHD) occurs in up to 80% of patients who undergo allogeneic stem cell transplantation (SCT) and contributes significantly to transplant-related mortality (TRM). We conducted a prospective phase II trial to assess the efficacy and feasibility of treating steroid-refractory aGVHD with basiliximab, a chimaeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor. Basiliximab was administered intravenously at a dose of 20 mg on days 1 and 4. Twenty-three patients were enrolled between October 1999 and July 2004. We found a primary overall response rate of 82AE5% with four patients (17AE5%) showing a complete response and 15 patients (65%) a partial response. Six patients were again treated successfully with an IL-2 receptor antagonist because of recurrence of aGVHD. The rates of infections, chronic GVHD, malignancy recurrence and 1-year TRM following immunosuppression with basiliximab were comparable with those found with other treatment modalities for aGVHD. We conclude that basiliximab is efficient and feasible for steroid-refractory aGVHD and merits further evaluation.
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