Showing papers by "Stefan Faderl published in 2008"

Phase II study of dasatinib in philadelphia chromosome - Negative acute and chronic myeloid diseases, including systemic mastocytosis

Abstract: Purpose: Molecular characterization of Philadelphia chromosome–negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro , significantly inhibiting wild-type KIT and platelet-derived growth factor receptor β TKs, and is active against cells carrying the mutant KIT-D816V gene. Experimental Design: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph− myeloid disorders, including SM ( n = 33; 28 KIT-D816V positive). Results: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. Conclusion: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.

Outcome of adults with acute lymphocytic leukemia after second salvage therapy

Abstract: BACKGROUND. The outcome of adults with acute lymphocytic leukemia (ALL) who undergo second salvage therapy has been characterized poorly. This is important with regard to investigational approaches aimed at helping this subset of patients. The objectives of the current study were to predict outcomes and determine the prognostic factors associated with second salvage therapy in patients with ALL. METHODS. In this study, 288 patients were analyzed who received second salvage therapy for ALL at the authors' institution. RESULTS. Overall, 53 patients (18%) achieved a complete response (CR). The median remission duration was 7 months and the median survival was 3 months. In multivariate analysis, prognostic factors that were associated independently with achieving CR were duration of first CR and platelet count. Patients with a first CR <36 months and platelet counts <50 × 109/L had an expected CR rate of 7%. In multivariate analysis, prognostic factors that were associated independently with survival were duration of first CR, percentage bone marrow blasts, platelet count, and albumin level. The expected 12-month survival rates for patients with 0 or 1, 2, 3, or 4 adverse factors were 33%, 14%, 8%, and 0%, respectively. A repeat multivariate analysis using landmark assessment at 6 weeks selected achievement of CR as adding significantly to the survival benefit (P = .0001; hazard ratio, 0.51). Only 22 patients (8%) were able to undergo allogeneic stem cell transplantation as second salvage therapy, and their 1-year survival rate was 18%. CONCLUSIONS. The outcome of adults with ALL undergoing second salvage therapy is poor. Novel effective therapies against ALL are needed in this subset of patients. Cancer 2008. © 2008 American Cancer Society.

Randomized Comparison of Cooked and Noncooked Diets in Patients Undergoing Remission Induction Therapy for Acute Myeloid Leukemia

Abstract: Purpose A neutropenic diet is often used to prevent infection in patients with acute myeloid leukemia (AML). Although such a diet potentially entails inconvenience, its value is uncertain. Patients and Methods One hundred fifty-three patients admitted to a high-efficiency particulate air–filtered room (protected environment [PE]) to receive induction therapy for newly diagnosed AML were randomly assigned to a diet containing no raw fruits or vegetables (cooked diet) or to a diet containing fresh fruit and fresh vegetables (raw diet). Stratification was based on the patients’ early risk of mortality (ERM) score. All patients received antibacterial and antifungal prophylaxis and remained on study until they were discharged from the PE. The outcomes of principal interest were major infection (pneumonia, bacteremia, or fungemia) and death; if the true probability of either event was 20% on the cooked arm and 40% on the raw arm, then the probability that the cooked arm would be selected as superior was 83%. Re...

Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia: need for new response definitions?

Abstract: BACKGROUND. Response rates in chronic myeloid leukemia (CML) are now reported based on the cumulative incidence of a single-time best response. The study aim was to examine the significance of different response criteria for CML on imatinib therapy. METHODS. In all, 276 patients with chronic phase CML on imatinib therapy were analyzed. Cytogenetic and molecular responses were coded as to single best response and response at specific intervals of treatment. RESULTS. The cumulative incidence of complete cytogenetic response (CGCR) with imatinib was 91%; however, the incidence of CGCR at 48 months into therapy was only 78%. Similarly, the incidence of major molecular responses (best cumulative vs landmark at 48 months) were 74% versus 62%, and of undetectable BCR-ABL transcripts 38% versus 24%. There was a strong association between achievement of major cytogenetic response (Philadelphia chromosome [Ph]-positivity ≤35%) at 6 months to 12 months and survival as well as progression-free survival (PFS). Achievement of major molecular response (vs lesser molecular response) in patients in complete cytogenetic response was not associated with significant differences in survival, but showed some association with PFS. Durable CGCR and major molecular responses (documented continuously for ≥12 months) were associated with longer PFS duration but not with survival duration differences. Of interest, major molecular responses documented at least twice were noted in 71% of patients on imatinib therapy; undetectable BCR-ABL transcripts documented at least twice were noted in 34%. CONCLUSIONS. Achievement and durability of CGCR and of major and complete molecular responses at landmark times predict outcome in CML, and may help in comparing the efficacy of different treatments. Cancer 2008. © 2007 American Cancer Society.

Results of the Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Regimen in Elderly Patients With Acute Lymphocytic Leukemia

Abstract: BACKGROUND. Understanding the causes of failure in older patients with acute lymphocytic leukemia (ALL) may help improve treatment strategies for patients in this particular age group. METHODS. The objectives of the current study were to define the causes of death in older patients (aged ≥60 years) with ALL during induction and consolidation-maintenance with a dose-intensive regimen of alternating 8 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) with high doses of methotrexate and cytarabine followed by maintenance with 6-mercaptopurine, vincristine, methotrexate, and prednisone and to compare their outcomes with the outcomes of older patients who received earlier, less intensive regimens and younger patients who received hyper-CVAD. One hundred twenty-two older patients who received hyper-CVAD were compared with 34 older patients who received less intensive regimens and with 409 younger patients who received hyper-CVAD. RESULTS. The complete response (CR) rates in older patients receiving hyper-CVAD, older patients receiving other regimens, and younger patients receiving hyper-CVAD were 84%, 59%, and 92%, respectively (P < .001); and the respective induction mortality rates were 10%, 12%, and 2% (P not significant in older patients). The incidence of disease resistance during induction was 5%, 27%, and 2%, respectively (P < .001). The majority of deaths were related to infections. Among patients who achieved a CR, death in CR was noted in 34%, 15%, and 7% of older patients receiving hyper-CVAD, older patients receiving other regimens, and younger patients, respectively (P < .001); and the respective rates of recurrence were 40%, 80%, and 48% (P = .004). The estimated 5-year survival rates were 20%, 9%, and 48%, respectively (P < .001). CONCLUSIONS. The results of the current study suggested that intensifying the chemotherapy in older patients with ALL reduced the incidence of leukemia resistance but increased the incidence of death in CR from myelosuppression-associated infections. The overall benefit:risk ratio was favorable. Identifying novel, low-intensity agents/regimens for older patients with ALL may improve the results further. Cancer 2008. © 2008 American Cancer Society.

Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine

Abstract: Azacitidine and decitabine are the two hypomethylating agents approved by the Food and Drug Administration for the treatment of patients with myelodysplastic syndrome (MDS). The efficacy of one agent post-failure of the other is unknown. Fourteen patients with MDS post-azacitidine failure/lack of response/intolerance were treated with decitabine. Overall three patients achieved a complete remission, and one patient had hematologic improvement, for an overall response rate of 28%. Of the responders, one stopped prior 5-azacitidine owing to disease progression, two for no response and one for severe skin toxicity. Grade 3-4 drug related side-effects were minimal. Global methylation studies in patient samples showed decrease of methylation after treatment with decitabine. As in our previous studies, there was no difference in hypomethylation between responders and nonresponders. We conclude that clinically significant responses with decitabine can be seen in patients post-azacitidine failure without significant toxicity.

Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years

Abstract: Major therapeutic progress has been accomplished in leukemia and myelodysplastic syndrome (MDS) over the past 40 years, which may not be fully appreciated by the larger medical community. The objective of this review was to briefly highlight the treatment breakthroughs in leukemia and MDS. Therapeutic progress happened through better understanding of disease pathophysiologies and rational development of targeted agents, like imatinib mesylate in chronic myeloid leukemia (CML), and through astute, empirical discoveries in the clinic, like all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia (APL) and chlorodeoxyadenosine in hairy cell leukemia (HCL). Today, the 5- to 10-year survival rates in patients with APL and HCL exceed 80%. In patients with CML, imatinib therapy has been associated with estimated 5- to 7-year survival rates from 85% to 90%. In patients with adult acute lymphocytic leukemia, modern intensive regimens have improved the 5-year survival rates from 20% up to 40%. In patients with chronic lymphocytic leukemia, chemoimmunotherapy recently produced high rates of quality responses and improved long-term outcome. In younger patients with acute myeloid leukemia (AML), the 5-year survival rates range from 40% to 50%, although elderly AML remains a therapeutic challenge. In patients with MDS, it was recently demonstrated that epigenetic therapy with hypomethylating agents improved survival. Much therapeutic progress has been witnessed in leukemia and MDS, and much more is expected to occur soon.

Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival

Abstract: BACKGROUND. Acute myelogenous leukemia (AML) associated with core-binding-factor (CBF) abnormalities is the type of leukemia most responsive to cytarabine (ara-C) therapy and is of relative favorable prognosis. In vitro and ex vivo observations suggest that increases in intracellular ara-C levels influenced by administration of fludarabine and granulocyte colony-stimulating factor (GCSF) increase the effect of ara-C, prompting us to clinically evaluate the efficacy of such combinations. METHODS. We analyzed the event-free survival of patients with newly diagnosed CBF AML treated with fludarabine and ara-C (FA) (N = 45) or with FA and GCSF (FLAG) (N = 22) and compared results to patients treated with regimens consisting of idarubicin and ara-C with or without GCSF (IA/IAG) (N = 47). RESULTS. After accounting for prognostic covariates other than treatment (including year in which treatment was administered), FA, and in particular FLAG, were associated with longer event-free survival than IA/IAG. CONCLUSIONS. Thus, our data lends clinical credence to the observed modulation of ara-C by fludarabine and GCSF. Cancer 2008. © 2008 American Cancer Society.

Clofarabine combinations as acute myeloid leukemia salvage therapy.

Abstract: BACKGROUND. Outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory. Clofarabine is a nucleoside analog with activity in adult AML. Combinations with cytarabine in AML are feasible and effective. Idarubicin is another active AML drug, which has not yet been tested with clofarabine. METHODS. The authors therefore designed a phase I study of clofarabinecytar- abine, plus idarubicin. Patients with primary refractory or first-relapse AML were assigned to either clofarabine plus idarubicin (CI) if previously exposed to cytara- bine with a response lasting <12 months, or clofarabine and idarubicin plus cytarabine (CIA) for responses � 12 months, or if never exposed to cytarabine. A standard ''3 1 3'' phase 1 design was followed to define maximum tolerated dose (MTD). Forty-four patients were treated (23 CI; 21 CIA). RESULTS. Dose-limiting toxicities were hyperbilirubinemia and hepatic transami- nase elevations for CI-treated patients in addition to mucositis and diarrhea for CIA-treated patients. MTD for CI was clofarabine 22.5 mg/m 2 intravenously daily 3 5 and idarubicin 10 mg/m 2 intravenously daily 3 3. MTD for CIA was clofara- bine 22.5 mg/m 2 intravenously 3 5, idarubicin 6 mg/m 2 intravenously 3 3, and cytarabine 0.75 g/m 2 intravenously 3 5 days.

Hematologic malignancies : acute leukemias

Abstract: Acute Myeloid Leukemia.- Therapy of AML.- Diagnosis and Classification of the Acute Myeloid Leukemias (with Discussion of the Role of the Myelodysplastic Syndromes in AML Pathogenesis).- Acute Myeloid Leukemia: Epidemiology and Etiology.- Relapsed and Refractory Acute Myeloid Leukemia.- Acute Lymphoblastic Leukemia.- Acute Lymphoblastic Leukemia: Epidemiology and Etiology.- Molecular Biology and Genetics.- Acute Lymphoblastic Leukemia: Clinical Presentation, Diagnosis, and Classification.- Diagnosis of Acute Lymphoblastic Leukemia.- General Approach to the Therapy of Adult Acute Lymphoblastic Leukemia.- Recent Clinical Trials in Acute Lymphoblastic Leukemia by the Cancer and Leukemia Group B.- Conventional Therapy in Adult Acute Lymphoblastic Leukemia: Review of the LALA Program.- ALL Therapy: Review of the MD Anderson Program.- Treatment of Adult ALL According to Protocols of the German Multicenter Study Group for Adult ALL (GMALL).- Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.- Burkitt's Acute Lymphoblastic Leukemia (L3ALL) in Adults.- Treatment of Lymphoblastic Lymphoma in Adults.- The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult Acute Lymphoblastic Leukemia (ALL).- The Role of Autologous Stem Cell Transplantation in the Management of Acute Lymphoblastic Leukemia in Adults.- Novel Therapies in Acute Lymphoblastic Leukemia.- Minimal Residual Disease Studies in Acute Lymphoblastic Leukemia.- Central Nervous System Involvement in Adult Acute Lymphocytic Leukemia.- Relapsed Acute Lymphoblastic Leukemia.- Emergencies in Acute Lymphoblastic Leukemia.- Erratum.- Erratum.

Potential role of novel nucleoside analogs in the treatment of acute myeloid leukemia.

Abstract: PURPOSE OF REVIEW Nucleoside analogs remain a cornerstone in acute myeloid leukemia therapy. As many new nucleosides are being investigated in clinical trials, this review aims to update the current state of experience with these new compounds and where they may fit into treatment strategies for acute myeloid leukemia. RECENT FINDINGS Many new nucleoside analogs are emerging with novel metabolic properties and mechanisms of action. Some have entered clinical trials and are actively investigated in the context of acute myeloid leukemia therapy. Clofarabine is the most-developed compound, and single-agent experience and combinations with other active agents in acute myeloid leukemia are being explored. Troxacitabine and sapacitabine are still in single-agent phases of their development and clinical experience is accumulating quickly. SUMMARY Nucleosides remain the most important class of drugs in acute myeloid leukemia and the interest in new compounds is strong. The plethora of new analogs continues to provide ample opportunity to expand the effectiveness of these drugs in acute myeloid leukemia therapy. Furthermore, their unique mechanisms of action provide possibilities for mechanism-based combinations.

Phase II study of single agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy

Abstract: 7025 Background: Studies have identified a population of older AML patients unlikely to benefit from standard combination induction therapy (“7+3”) based on adverse prognostic factors such as advanced age, poor performance status (PS), antecedent hematologic disorder (AHD), or intermediate/unfavorable risk karyotype. This study assessed the efficacy and safety of single agent clofarabine (CLO) in this population. Methods: Single arm, Phase II, open-label, 2-stage study; planned total enrollment of 109 patients. Eligible untreated AML patients included adults ≥60 years with ≥1 adverse prognostic factor: ≥70 years, AHD, PS 2, and/or intermediate/unfavorable risk karyotype. CLO given on days 1–5 as a 1-hr IV infusion: 30 mg/m2 during induction and 20 mg/m2 during re-induction/consolidation (6 cycles maximum). Primary endpoint was overall remission rate (ORR = CR + CRp). Preliminary Results: Enrollment completed with 116 patients. As of Aug 2007, safety data were available for 54 patients; efficacy data for 4...

The effect of interleukin 11 on thrombocytopenia associated with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia

Abstract: BACKGROUND. During therapy with tyrosine kinase inhibitors (TKIs), approximately 20% to 50% of patients with chronic myeloid leukemia (CML) develop grade ≥3 thrombocytopenia leading to treatment interruptions and dose reductions. Interleukin 11 (IL-11) reduces the incidence and the severity of thrombocytopenia in solid tumors. METHODS. The authors investigated the efficacy and safety of low-dose IL-11 for improving thrombocytopenia associated with TKI therapy in 14 patients with CML. The starting dose of IL-11 was 10 μg/kg 3 times weekly, and the dose was escalated by 1 dose level every 2 weeks if the patients had no sustained platelet increase. RESULTS. The median patient age was 52 years. The median platelet count at the time IL-11 was started was 37 × 109/L. All patients had prior TKI dose reductions. After the initiation of IL-11, 8 of 14 patients (57%) had an increase in platelet count with a median peak platelet count of 110 × 109/L. One additional patient had no platelet increase but was able to tolerate an imatinib dose increase. Eleven patients had a decrease in the number of days of TKI therapy interruption secondary to thrombocytopenia after the initiation of IL-11 (6% of total treatment time vs 34% of total treatment time before IL-11). Therapy was well tolerated. CONCLUSIONS. The current results indicated that IL-11 may correct thrombocytopenia associated with TKI therapy for patients with CML and that it has a favorable toxicity profile. Cancer 2008. © 2008 American Cancer Society.

A phase I and pharmacokinetic study of XK469R (NSC 698215), a quinoxaline phenoxypropionic acid derivative, in patients with refractory acute leukemia

Abstract: A phase I study was performed to determine the safety and pharmacokinetics of XK469R in patients with refractory acute leukemia. The study aimed to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of XK469R given intravenously over 30 to 60 min on days 1, 3, and 5 of a 21 day cycle. Patients were treated in successive cohorts of six until DLT was observed. Once the MTD was determined, an additional cohort of six patients was enrolled at the previous dose level and that dose was considered the recommended phase 2 dose (RPTD). Forty-six patients were treated at dose levels of 1,400, 1,750, 2,200, and 2,750 mg. The DLTs were: mucositis, colitis and hyperbilirubinemia. Reversible myelosuppression was noted at all dose levels. One (2%) of 42 patients achieved a complete remission and five patients (11%) had hematologic improvement. The half-life of the drug was long with a mean value of 48 h. The mean clearance was 206 mL/h with a coefficient of variation of 32%. No correlation was observed between the development of DLT and pharmacokinetics. The RTPD is 1,750 mg. XK469R induced hematological responses in patients with refractory leukemia at tolerable doses.

Pilot experience with continuous infusion alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia

Abstract: We evaluated the activity and tolerability of alemtuzumab given as a continuous infusion for 7 d followed by subcutaneous administration for 11 wk as salvage therapy for 10 patients with fludarabine-refractory chronic lymphocytic leukemia. The continuous infusion of alemtuzumab was well tolerated. The typical infusion reaction seen with intravenous alemtuzumab was abolished. Two patients achieved a partial response with an overall response rate of 20%. Alemtuzumab levels were measured in four patients and detectable levels were obtained in three. Clinical activity needs to be confirmed in a larger patient population.