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Biomedical subjects

Stefan Faderl

Publications and source records attributed to Stefan Faderl.

At least 55 records · Page 3Linked to original sources
PubMed2005

Significance of myelofibrosis in early chronic-phase, chronic myelogenous leukemia on imatinib mesylate therapy.

BACKGROUND: Myelofibrosis is associated historically with a poor prognosis in patients with chronic myelogenous leukemia (CML). Its significance in the recent era of effective therapy with imatinib mesylate is unknown. METHODS: The current study evaluated the significance of the degree of pretreatment myelofibrosis on response and survival with imatinib therapy in patients with newly diagnosed CML. The study group comprised 198 patients with newly diagnosed Philadelphia chromosome-positive, chronic-phase CML treated with imatinib mesylate therapy. They were analyzed for the prognostic significance of bone marrow reticulin fibrosis. RESULTS: Severe reticulin (Grade 3-4) fibrosis was observed in 75 patients (38%): Grade 3 in 46 (23%) patients and Grade 4 in 29 (15%) patients. There was a trend towards a lower incidence of a complete cytogenetic response in patients with Grade 4 reticulin fibrosis (76% vs. 89%; P = 0.07), and a significantly worse survival (estimated 3-year survival rate of 87% vs. 97%; P = 0.04). CONCLUSIONS: Although the prognostic significance of severe reticulin fibrosis in patients with newly diagnosed CML receiving imatinib therapy was better, 15% of patients with Grade 4 reticulin fibrosis still had a worse outcome.

Adolescent↗
PubMed2005

The role of clofarabine in hematologic and solid malignancies--development of a next-generation nucleoside analog.

Clofarabine is a new-generation nucleoside analog that has been synthesized to combine the most favorable pharmacokinetic properties of its congeners fludarabine and cladribine. In addition to inhibition of DNA polymerases and DNA synthesis, clofarabine acts as a strong inhibitor of ribonucleotide reductase (RnR), an enzyme involved in regulating intracellular deoxynucleotide pools, and has a high affinity to the enzyme deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation.A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) data base and from abstracts based on the publication of meeting materials. Although it was synthesized early in the 1980s, the development of clofarabine was stalled until 1993, when, through efforts at The University of Texas M. D. Anderson Cancer Center, animal toxicology studies were conducted, and the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemias. By way of its unique metabolic properties, clofarabine also has lent itself to biochemical modulation strategies with other nucleoside analogs, such as cytarabine. Combinations of clofarabine with cytarabine have been studied in acute leukemia and currently are being evaluated in untreated elderly patients with acute myeloid leukemia. Novel schedules are being explored in lymphoproliferative disorders and solid tumors. Clofarabine is a new nucleoside analog with considerable activity and an acceptable safety profile in acute leukemias.

Adenine Nucleotides↗
PubMed2005

Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia--comparison with historic experience.

BACKGROUND: The effect of imatinib mesylate on survival in the accelerated phase of chronic myelogenous leukemia (CML) is unknown. The objectives of this study were to update the long-term experience with imatinib in patients who had accelerated-phase CML and to compare outcomes with historic experience. METHODS: The outcomes of 176 patients who received treatment with imatinib were reviewed and compared with the outcomes of 213 historic control patients with accelerated-phase CML who received treatment with interferon-alpha or with other modalities. RESULTS: With imatinib, the complete hematologic response rate was 82% versus a rate < or = 50% for others, and the complete cytogenetic response rate was 43% versus rates of 0-6% for others. The estimated 4-year survival rates were 53% with imatinib, 42% with interferon-alpha, and 0-21% for others. A multivariate analysis of the total population of 389 patients indicated that imatinib therapy (vs. other therapies) was an independent, favorable prognostic factor for survival (P < 0.0001; hazard rate, 0.62). A subset analysis that included only patients who were treated with imatinib and interferon-alpha (276 patients) also identified imatinib as an independent favorable prognostic factor (P < 0.0001; hazard rate, 0.65). The 3-month cytogenetic response to imatinib was associated with significantly different survival outcomes (P < 0.0001). A multivariate analysis that included pretreatment characteristics and 3-month cytogenetic response among 150 patients who received imatinib and were alive at 3 months identified only 2 adverse independent prognostic factors: lack of a cytogenetic response at 3 months (P < 0.001) and anemia (hemoglobin < 10 g/dL; P = 0.003). Patients who had neither factor (41%) had an estimated 4-year survival rate of 88%; in the other patients, the 4-year survival rate was < or = 60%. This may have implications in relation to subsequent therapy, because, according to the outcomes of patients who underwent allogeneic transplantation in accelerated phase at the authors' institution and from literature reports, the estimates of 5-year survival were 25-30%. CONCLUSIONS: The current results suggest that imatinib improved survival compared with other therapies in patients with accelerated-phase CML.

Adult↗
PubMed2005

Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate.

PURPOSE: To determine the clinical significance of molecular response and relapse among patients with chronic myelogenous leukemia (CML) treated with imatinib. EXPERIMENTAL DESIGN: We analyzed the results of quantitative PCR in 280 patients with CML in chronic phase who achieved complete cytogenetic remission with imatinib (117 after IFN-alpha failure and 163 previously untreated). Median follow-up was 31 months (range, 3-52 months). RESULTS: Median BCR-ABL/ABL ratio before the start of therapy was 39.44 (range, 0.252-170.53). A major molecular response (BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%), and transcripts became undetectable (complete molecular response) in 95 (34%). By multivariate analysis, only treatment with high-dose imatinib (P = 0.02) was associated with achievement of a major molecular response. Nine of 166 (5%) patients who achieved a major molecular response lost their cytogenetic remission, compared with 25 of 68 (37%) among those who did not achieve this response (P < 0.0001). Patients achieving a major molecular response 12 months after the start of therapy had significantly better complete cytogenetic remission duration than others. A >1-log reduction in transcript levels after 3 months of therapy predicted for an improved probability of achieving a major molecular response at 24 months. Increasing levels of BCR-ABL transcripts predicted for a loss of cytogenetic remission only among patients who did not achieve a major molecular response. CONCLUSIONS: Achieving a major molecular response, particularly within the first year of therapy, is predictive of a durable cytogenetic remission and may be the future goal of therapy in CML.

Adolescent↗
PubMed2005

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia.

PURPOSE: Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%. PATIENTS AND METHODS: We conducted a single-arm study of FCR as initial therapy in 224 patients with progressive or advanced CLL. Flow cytometry was used to measure residual disease. Results and safety were compared with a previous regimen using FC. RESULTS: The median age was 58 years; 75 patients (33%) had Rai stage III to IV disease. The CR rate was 70% (95% CI, 63% to 76%), the nodular partial remission rate was 10%, and the partial remission rate was 15%, for an overall response rate of 95% (95% CI, 92% to 98%). Two thirds of patients evaluated with flow cytometry had less than 1% CD5- and CD19-coexpressing cells in bone marrow after therapy. Grade 3 to 4 neutropenia occurred during 52% of courses; major and minor infections were seen in 2.6% and 10% of courses, respectively. One third of the 224 patients had >/= one episode of infection, and 10% had a fever of unknown origin. CONCLUSION: FCR produced a high CR rate in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).

Adult↗
PubMed2005

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia.

PURPOSE: The efficacy, toxicity, and tolerability of chemoimmunotherapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) were evaluated in previously treated patients with chronic lymphocytic leukemia (CLL). The purpose of this study was to improve the complete remission (CR) rate for previously treated patients and evaluate the quality of bone marrow response. PATIENTS AND METHODS: One hundred seventy-seven previously treated patients with CLL were evaluated. Treatment consisted of rituximab 375 mg/m(2) day 1 of course 1 and 500 mg/m(2) day 1 of courses 2 to 6; fludarabine 25 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6; and cyclophosphamide 250 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6. Courses were repeated every 4 weeks. RESULTS: CR was achieved in 25% of 177 patients, and nodular partial remission and partial remission were achieved in 16% and 32% of patients, respectively; the overall response rate was 73%. Twelve (32%) of 37 complete responders tested achieved molecular remission in bone marrow. Univariate and multivariate analyses were used to identify pretreatment patient characteristics associated with CR and overall remission, longer time to progression, and overall survival. CONCLUSION: The FCR regimen was an active and well-tolerated treatment for previously treated patients with CLL. Myelosuppression was the most common toxicity. FCR induced the highest CR rate reported in a clinical trial of previously treated patients with CLL. Furthermore, molecular remissions were achieved in a third of patients achieving CR.

Adult↗
PubMed2005

Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes.

PURPOSE: To investigate the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of BMS-214662, a farnesyl transferase (FTase) inhibitor, in patients with acute leukemias and high-risk myelodysplastic syndromes (MDS). PATIENTS AND METHODS: Patients with relapsed or refractory acute leukemias or MDS, or previously untreated but poor candidates for chemotherapy, were included in this phase I study with a 3 + 3 dose escalation design. BMS-214662 was administered as a 1-hour bolus once weekly at doses of 42 to 157 mg/m2. Once the MTD was identified, the schedule was changed to a 24-hour continuous infusion once weekly (starting dose, 300 mg/m2). RESULTS: Thirty patients were treated at a dose of 42 (n = 1), 56 (n = 3), 84 (n = 3), 118 (n = 13), 157 (n = 6) or 300 mg/m2 (n = 4). DLT occurred in 3 patients at 157 mg/m2, including nausea, vomiting, diarrhea, hypokalemia and cardiovascular problems. No DLT occurred with 24-hour continuous infusion. MTD with a 1-hour infusion was 118 mg/m2, with no MTD identified with the 24-hour infusion. Plasma concentrations of BMS-214662 correlated with the dose. Inhibition of FTase activity of approximately 60% occurred after the infusion with recovery to near baseline after 24 hours. Five patients had evidence of antileukemia activity, including two with complete remission with incomplete platelet recovery, one with hematologic improvement, and two with morphologic leukemia-free state. CONCLUSION: BMS-214662 is well tolerated at doses of up to 118 mg/m2 as a 1-hour infusion. The toxicity profile and efficacy may be improved with prolonged exposure. Further investigation of this agent in leukemia is warranted.

Acute Disease↗
PubMed2005

Drug insight: emerging new drugs in the treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders. Although the currently used classification schemes and prognostic algorithms, which are based predominantly on morphologic assessment of blood and marrow smears, have been shown to be valid for defining disease subgroups, they do not take into consideration the significant biological diversity of MDS. As the numerous pathophysiologic pathways that are involved in MDS are being unraveled, new molecular targets are being identified. Novel and targeted therapeutic agents, including inhibitors of farnesyltransferases and receptor tyrosine kinases, more potent thalidomide analogs and epigenetic therapies, have produced encouraging results and might offer durable benefits to patients with MDS. This review intends to provide a concise report on some of the most up-to-date therapies being investigated in MDS.

Antineoplastic Agents↗
PubMed2005

T-cell prolymphocytic leukemia: a single-institution experience.

BACKGROUND: T-cell prolymphocytic leukemia is an uncommon, aggressive, mature T-cell leukemia characterized by proliferation of T-cell lymphocytes. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of this disorder from its B-cell counterpart and other mature T-cell leukemias. PATIENTS AND METHODS: The clinical, pathologic, and cytogenetic features of 57 patients with T-PLL who were evaluated at the Department of Leukemia, M. D. Anderson Cancer Center (MDACC) from 1986 to 2004 were examined. RESULTS: The most common cytogenetic abnormality was inv(14)(q11;q32), which was present in 7 patients. In all 7 patients, this abnormality was associated with other chromosomal aberrations. Patients treated with alemtuzumab at MDACC had a significantly better response rate (P = 0.02) and survival rate (P = 0.002). There were no significant differences in survival based on Tcl-1 expression or different patterns of CD4 and CD8 expression. CONCLUSION: Treatment with alemtuzumab results in higher response rates and a better survival rate in patients with T-cell prolymphocytic leukemia.

Adult↗
PubMed2005

Adult acute lymphoblastic leukemia.

Much progress has been made in understanding the biology of and therapy for acute lymphoblastic leukemia (ALL). This progress has translated into the recognition of several subgroups of ALL and the institution of risk-adapted therapies. New therapies are emerging based on the definition of specific cytogenetic-molecular abnormalities. Changes in the pathologic classification of ALL have led to therapeutic consequences. Adaptation of successful treatment strategies in children with ALL has resulted in similar complete remission rates in adults. Prognosis has Improved especially in mature B-cell ALL and T-cell lineage ALL. However, regardless of ALL subgroup, long-term survival in adults is still inferior to that in children. Development of new drugs and agents tailored to subset-specific cytogenetic-molecular characteristics is vital to the therapeutic success in adult ALL.

Adult↗
PubMed2004

Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias.

Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).(1) Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m(2) per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m(2) per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.

Acute Disease↗
PubMed2004

Novel therapies for myelodysplastic syndromes.

BACKGROUND: The assessment of patients with myelodysplastic syndromes (MDS) and the choice of therapies remain challenging. New therapies are now emerging after the identification of molecular targets that result in improvement of hematologic parameters and may hold promise for the prevention of disease progression. METHODS: A review of the English literature was performed that included original articles and related reviews from MEDLINE (PubMed) and abstracts based on published meeting material. RESULTS: MDS is a heterogeneous group of disorders. Although current classification and prognostic schemes have proven valid to define subgroups, they are insufficient to take into consideration the significant biologic diversity of MDS. New molecular targets are identified as the mosaic of pathophysiologic pathways in MDS is being unraveled. Novel and targeted therapeutic agents, such as the inhibition of farnesyl transferases and receptor tyrosine kinases, more potent thalidomide analogs, and arsenic trioxide, have shown encouraging results and may offer durable benefit to patients with MDS. CONCLUSIONS: Although progress has been made in the understanding of clinical manifestations and some of the molecular pathways underlying ineffective hematopoiesis and leukemic transformation in MDS, intensive clinical and laboratory research continues to 1) identify further relevant pathophysiologic pathways, 2) better define MDS subgroups, and 3) develop new drugs based on a clearer understanding of disease biology.

Aged↗
PubMed2004

Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha.

We reviewed 261 patients with chronicphase chronic myelogenous leukemia (CML) after interferon-alpha (IFN-alpha) failure treated with imatinib mesylate 400 mg daily. With a median follow-up time of 45 months, the major cytogenetic response rate was 73% and the complete cytogenetic response rate 63%. The estimated 4-year survival rate was 86%. Multivariate analysis for survival identified hematologic resistance to IFN-alpha (P =.01), splenomegaly (P =.03), and lack of any cytogenetic response after 3 months of therapy (P =.01) to have independent poor prognostic significance. Patients could be divided into good (no adverse factors), intermediate (1 adverse factor), and poor-risk groups (2 or 3 adverse factors; 12% of patients) with estimated 4-year survival rates of 96%, 86%, and 49%, respectively (P <.00001). The 4-year cumulative major molecular response (quantitative reverse transcriptase-polymerase chain reaction [Q-PCR] = BCR-ABL/ABL less than 0.05%) rate was 43% and complete molecular response rate (BCR-ABL undetectable) 26%. Compared with a historical group of 251 similar patients treated with nonimatinib therapies, imatinib mesylate was associated with a better 4-year survival rate (86% versus 43%; P <.0001); the survival advantage was confirmed by multivariate analysis (hazard ratio, 0.19; P <.0001).

Aged↗
PubMed2004

Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma.

Therapy of lymphoblastic lymphoma (LL) has evolved with use of chemotherapy regimens modeled after those for acute lymphocytic leukemia (ALL). We treated 33 patients with LL with the intensive chemotherapy regimens hyper-CVAD (fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone) or modified hyper-CVAD used for ALL at our institution. Induction consolidation was administered with 8 or 9 alternating cycles of chemotherapy over 5 to 6 months with intrathecal chemotherapy prophylaxis, followed by maintenance therapy. Consolidative radiation therapy was given to patients with mediastinal disease at presentation. No consolidation with autologous or allogeneic stem cell transplantation was performed. At diagnosis, 80% were T-cell immunophenotype, 70% were stages III to IV, 70% had mediastinal involvement, and 9% had central nervous system (CNS) disease. Of the patients, 30 (91%) achieved complete remission, and 3 (9%) achieved partial response. Within a median of 13 months, 10 patients (30%) relapsed or progressed. Estimates for 3-year progression-free and overall survival for the 33 patients were 66% and 70%, respectively. Estimates for the patients with known T-cell immunophenotype were 62% and 67%, respectively. No parameters (eg, age, stage, serum lactate dehydrogenase [LDH], beta(2) microglobulin) appeared to influence outcome except for CNS disease at presentation. Modification of the hyper-CVAD regimen with anthracycline intensification did not improve outcome. Other modifications of the program could include incorporation of monoclonal antibodies and/or nucleoside analogs, particularly for slow responders or those with residual mediastinal disease.

Adolescent↗
PubMed2004

Phase I study of bortezomib in refractory or relapsed acute leukemias.

Bortezomib (Velcade, formerly PS-341) is proteasome inhibitor with documented antitumor activity in multiple myeloma and other lymphoid malignancies. We performed a Phase I study to investigate the maximum tolerated dose and dose-limiting toxicity of bortezomib in patients with acute leukemias refractory to or relapsing after prior therapy. Fifteen patients were treated with 0.75 (n = 3), 1.25 (n = 7), or 1.5 (n = 5) mg/m(2) bortezomib administered twice weekly for 4 weeks every 6 weeks. Dose-limiting toxicity included orthostatic hypotension (n = 2), nausea (n = 2), diarrhea (n = 1), and fluid retention (n = 1), all at 1.5 mg/m(2) bortezomib. Proteasome inhibition was dose dependent and reached 68% at 1.5 mg/m(2) bortezomib. Peak inhibition was observed 1 h after treatment and returned to near baseline levels by 72 h after treatment. Incubation of blast cells with bortezomib in vitro showed induction of apoptosis in three of five patients investigated. We conclude that the maximum tolerated dose of bortezomib in patients with acute leukemia is 1.25 mg/m(2), using a twice-weekly for 4 weeks every 6 weeks schedule. The in vitro evidence of antileukemia and transient hematological improvements observed in some patients warrants further investigation of bortezomib in acute leukemias, probably in combination with other agents.

Adolescent↗
PubMed2004

A Phase I and pharmacokinetic study of VNP40101M, a novel sulfonylhydrazine alkylating agent, in patients with refractory leukemia.

PURPOSE: VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS). EXPERIMENTAL DESIGN: VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m(2) was escalated by approximately 33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8. RESULTS: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m(2) for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m(2) was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m(2) and 1 with acute myeloid leukemia treated with 600 mg/m(2), achieved complete remission. CONCLUSIONS: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.

Acute Disease↗