sdz-psc-833 and Myelodysplastic-Syndromes

New combination therapies against hematological malignancies have recently been reported. Anti-CD20 chimeric antibody adds a therapeutic benefit to standard-dose CHOP therapy without causing significant additional toxicity in the treatment of indolent B cell lymphoma. Multidrug resistant modifiers such as PSC833 and MS209 in combination with chemotherapy are useful for treating poor risk AML patients, whose leukemia/lymphoma cells express P-glycoprotein. Fludarabine containing FL and FLAG therapy were effective in patients with AML in relapse. The early addition of chemotherapy to ATRA, and maintenance therapy with chemotherapy and intermittent ATRA, can reduce the incidence of relapse in cases of acute promyelocytic leukemia.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cyclosporins; Cytarabine; Doxorubicin; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, B-Cell; Myelodysplastic Syndromes; Prednisone; Quinolines; Rituximab; Tretinoin; Vidarabine; Vincristine

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclosporins; Cytarabine; Cytogenetic Analysis; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Multivariate Analysis; Myelodysplastic Syndromes; Prognosis; Remission Induction; Survival Rate

To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).. A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n=66) versus MEC (n=63) to treat patients with relapsed or refractory AML and high-risk MDS.. For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P=not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased--35% versus 15% for the remaining patients (P=.018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients' overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR- patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P=.09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents.. CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclosporins; Cytarabine; Disease-Free Survival; Etoposide; Female; Genes, MDR; Humans; Logistic Models; Male; Middle Aged; Mitoxantrone; Multivariate Analysis; Myelodysplastic Syndromes; Survival Analysis; United States