Showing papers by "Stefan Faderl published in 2002"

Imatinib Mesylate for Philadelphia Chromosome-positive, Chronic-Phase Myeloid Leukemia after Failure of Interferon-α Follow-Up Results

Abstract: We treated 261 patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) in chronic phase after failure of IFN-alpha with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (400 mg/day given p.o.) and analyzed hematological and cytogenetic responses, long-term prognosis, factors associated with achievement of major cytogenetic response and survival, and comparative survival in similar patients treated with other regimens. Median patient age was 55 years; 34% were 60 years or older, and median chronic-phase duration was 33 months. Overall, 94% achieved a complete hematological response, and 71% had a cytogenetic response [major (Ph+ cells <35%) in 62% and complete in 45%]. At a median follow-up of 17 months, 241 patients (92%) were still taking imatinib mesylate; estimated 18-month freedom from progression and survival rates were 93 and 96%. Multivariate analysis of factors associated with major cytogenetic response identified long chronic phase, marrow basophilia, high percentage of Ph+ cells before therapy, and prior hematological resistance to IFN-alpha as being adverse factors. This model was used to generate good-, intermediate- and poor-risk subgroups who had estimated major cytogenetic response rates of 93, 53, and 34%, respectively. Univariate analysis in terms of survival identified leukocytosis, high percentages of peripheral and marrow blasts, marrow basophilia, and the presence of cytogenetic clonal evolution as being adverse factors. Achieving a cytogenetic response at 3 or 6 months of therapy was associated with prolonged survival. In a subset analysis, survival rates among 161 patients with Ph-positive CML after hematological or cytogenetic failure after IFN-alpha who had been treated with imatinib mesylate were better than those for similar patients treated previously with other regimens. In summary, imatinib mesylate is highly effective in chronic-phase CML after IFN-alpha failure. We identified pretreatment and treatment-associated factors that were associated with higher major cytogenetic response rates and with improved survival.

Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate.

Abstract: Purpose: Imatinib mesylate, a specific Bcr-Abl tyrosine kinase inhibitor, has shown encouraging activity in chronic myelogenous leukemia (CML). Experimental Design: We treated 237 patients (median age, 50 years; age range, 18–82 years) with Philadelphia chromosome (Ph)-positive accelerated-phase CML with oral imatinib mesylate at daily doses of 400 mg (26 patients) or 600 mg (211 patients) and evaluated response and survival characteristics in univariate and multivariate analyses. Results: Among the 200 patients with accelerated-phase CML for whom follow-up was 3 months or more, rates of complete and partial hematological response were 80% and 10%. Cytogenetic responses were evident in 90 patients [45%; complete response in 47 patients (24%) and partial response (Ph 1–34%) in 21 patients (11%)]. The estimated 18-month survival rate was 73%. The estimated complete hematological response rate at 18 months was 68%; that for cytogenetic response was 82%. In multivariate analyses, a diagnosis-to-treatment interval of 3 years or more, splenomegaly, and peripheral blasts predicted poor major cytogenetic response; age >60 years, marrow basophilia, and clonal evolution predicted poor survival. The 600-mg drug dose was associated with better cytogenetic response and survival in univariate analysis (P Conclusions: Imatinib mesylate was active against Ph-positive, accelerated-phase CML, and the prognostic factors identified in this study could aid in tailoring treatment strategies to specific risk groups.

Simultaneous homoharringtonine and interferon-α in the treatment of patients with chronic-phase chronic myelogenous leukemia

Abstract: BACKGROUND Homoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon-α (IFN-α), and cytarabine (ara-C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN-α therapy in patients with chronic-phase CML who were not exposed previously to either agent. METHODS Forty-seven patients were treated: 37 patients with early chronic-phase CML (2 patients with clonal evolution) and 10 patients with late chronic-phase CML. Their median age was 62 years (range, 23–73 years). HHT was given at a dose of 2.5 mg/m2 by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN-α was given daily at a target dose of 5 × 106 units/m2 subcutaneously. Response, survival, and treatment toxicity were analyzed. RESULTS Overall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with major cytogenetic responses (Ph positive in 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 36% of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6–24 courses, the median daily IFN-α dose was 1 MU/m2, and the median number of days on HHT per month was 2 days. With a median follow-up of 26 months, the estimated 2-year survival rate was 90% (95% confidence interval, 79–100%). CONCLUSIONS The simultaneous combination of HHT and IFN-α is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal-transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN-α chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored. Cancer 2002;94:2024–32. © 2002 American Cancer Society. DOI 10.1002/cncr.10436

Phase II Study of Fludarabine, Cytarabine (Ara-C), Cyclophosphamide, Cisplatin and GM-CSF (FACPGM) in Patients With Richter's Syndrome or Refractory Lymphoproliferative Disorders

Abstract: A phase II study was conducted to evaluate the safety and efficacy of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) treatment in patients with Richter's syndrome (RS), refractory prolymphocytic leukemia (PLL) or refractory non-Hodgkin's lymphoma (NHL). Twenty-two patients with RS, refractory PLL, or refractory NHL were entered into this trial between March 1997 and February 2001. Median age was 62 years (42-74); 77% were over 60 years of age. Histologic diagnosis was large cell NHL transformation in 15 patients with CLL, immunoblastic transformation of CLL in one, refractory PLL in three, and refractory NHL in three patients. Treatment consisted of fludarabine 30mg/m2 (days 1-3), ara-C 0.5g/m2 (days 3-4), cyclophosphamide 250 mg/m2 (days 2-4), cisplatin 15 mg/m2 IV CI (days 1-4) with GM-CSF 250 microg/m2 from day 5 to recovery of neutrophils and antibiotic prophylaxis. Patients with response were to receive a maximum of six cycles of therapy. Eighteen patients were evaluable for response; one patient achieved a complete remission (5%), 12 stable disease/no response (67%) and five patients had progressive disease (28%). The median survival was 2.2 months (range, 1-19); the median failure-free survival was 1.5 months (range, 0.5-18.6). Grade III/IV toxicities were as follows: anemia in 62% of cycles; leucopoenia in 66%; granulocytopenia in 90%; thrombocytopenia in 83%; hyperbilirubinemia in 14%; hyperuricemia in 17%; hyponatremia in 17%; hypokalemia in 14%; hypophosphatemia in 10%; hypoalbulinemia in 14%; hypocalcemia in 7%; and hypercalcemia in 3%. One (3%) patient developed cardiac failure. Forty-one percent of the cycles were complicated with fever, 34% with non-neutropenic fever, and 55% cycles with infections (fungal 31%; bacterial 57%; HSV 6%; VZV 6%). FACPGM had very limited activity and significant toxicity in a cohort of patients with heavily pretreated refractory lymphoproliferative disorders.

Philadelphia chromosome-positive acute lymphoblastic leukemia- current concepts and future perspectives.

Abstract: Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) is diagnosed rarely in children, but constitutes the most frequent cytogenetic abnormality in adults with ALL. In contrast to chronic myeloid leukemia (CML), patients with Ph-positive ALL usually demonstrate expression of a truncated version of the BCR-ABL protein called p190bcr-abl. Irrespective of age and breakpoint location, Ph-positive ALL carries a poor prognosis. Although remission rates are identical to those of Ph-negative ALL, relapse is almost universal and long-term survival remains rare. Given the poor outcome with current chemotherapy consolidation programs, stem cell transplantation is usually recommended for these patients in first remission or as soon as feasible. Even with transplantation the impact on outcome is limited and new therapeutic concepts are urgently needed. One of the most promising developments in recent years has been the introduction of the tyrosine kinase inhibitors such as STI571. An overview of current treatment modalities in Ph-positive ALL will be provided and the rationale for new therapies will be discussed.

A phase I study of idarubicin dose escalation with amifostine and high-dose cytarabine in patients with relapsed acute myelogenous leukemia and myelodysplastic syndromes

Abstract: BACKGROUND AND OBJECTIVES: Early studies have suggested that increasing doses of anthracycline improve outcome in younger patients with acute myelogenous leukemia (AML), but dose escalation has been precluded by the acute and chronic toxicities of these agents. Amifostine is a cytoprotective compound that has been shown to protect against the acute cytotoxicities of anthracyclines in animal models. We report the results of a phase I study of dose escalation of idarubicin with amifostine and high-dose ara-C in patients with relapsed or refractory AML or myelodysplastic syndrome (MDS). DESIGN AND METHODS: The continuous reassessment method was used to predict the probability of toxicity. RESULTS: Five patients were treated at an idarubicin dose of 18 mg/m2/day x 3, three of whom developed grade 3 diarrhea or mucositis. Subsequently, three additional patients were treated at a dose of 15 mg/m2 x 3 days, all of whom experienced grade 3 diarrhea or mucositis. One patient achieved complete remission (CR rate 12.5%, 95% CI 0-0.52%). INTERPRETATION AND CONCLUSIONS: The addition of amifostine does not allow dose escalation of idarubicin when combined with high-dose ara-C.

Time to platelet recovery predicts outcome of patients with de novo acute lymphoblastic leukaemia who have achieved a complete remission.

Abstract: Survival in acute leukaemia depends on the achievement of complete remission (CR). However, CR is not a clear-cut phenomenon and certain variables of its definition could more accurately characterize the quality of the remission. Because platelet recovery > 100 x 10(9)/l is an essential component of CR in acute leukaemia, we hypothesized that time to platelet recovery (TPR) might be predictive of overall survival (OS) or disease-free survival (DFS) in acute lymphoblastic leukaemia (ALL). We analysed TPR in 249 patients with ALL who entered CR after one course of induction chemotherapy and correlated TPR with DFS and OS. TPR was significantly associated with both DFS and OS if it occurred within a maximum of about 60 d from start of therapy. Furthermore, during that time period, the relative risk of death increased with increasing TPR. Although presence of the Philadelphia chromosome was the single most important adverse feature at diagnosis, the effect of TPR on survival continued to be significant within this patient subgroup. This effect was so pronounced that Philadelphia chromosome-positive patients with a TPR of 12 d had a better outcome than Philadelphia chromosome-negative patients with a TPR of 48 d. Thus, a short TPR seems to be able to override adverse characteristics in the outcome of ALL patients treated with chemotherapy. We conclude that a quicker TPR predicts longer DFS and OS in patients with ALL. As platelet counts are obtained almost daily in patients undergoing chemotherapy, TPR can readily be utilized to assess the prognosis of these patients.

B-Cell Precursor Cell Lines

Abstract: Many BCP cell lines have been described, but most are used only for a specific purpose, and few have been adequately characterized. Cell lines provide a useful laboratory tool, but scientists should be aware of their limitations and care should be taken in extrapolating data to in vivo situations.