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Stefan Faderl

Publications and source records attributed to Stefan Faderl.

At least 91 records · Page 5Linked to original sources
PubMed2003

Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia.

PURPOSE: Bortezomib is a peptide boronic acid inhibitor of the proteasome developed for cancer therapy. The compound is being evaluated currently in Phase II and III clinical trials. Here we characterized the effects and mechanisms of action of bortezomib in cells obtained from patients with chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: We exposed isolated CLL lymphocytes from >100 patients to various concentrations of bortezomib or other proapoptotic stimuli, and measured DNA fragmentation by propidium iodide staining and flow cytometry. We characterized the effects of bortezomib on release of apoptosis-associated mitochondrial factors and measured downstream effects on caspase activation using a fluorogenic substrate cleavage assay. We assessed potential effects of the drug on inhibitor of apoptosis protein family apoptosis inhibitors by immunoblotting. Finally, we quantified the effects of bortezomib on apoptosis in 5 patients on a Phase II clinical trial. RESULTS: Bortezomib stimulated apoptosis more rapidly than positive controls (glucocorticoid and fludarabine), although substantial heterogeneity was noted with respect to the concentration of drug required to induce cell death. Bortezomib-induced apoptosis was associated with release of SMAC, apoptosis-inducing factor, and cytochrome c from mitochondria, but the drug did not affect levels of inhibitor of apoptosis protein family cell death inhibitors. Levels of apoptosis were marginally elevated in CLL cells obtained from 2 of 5 fludarabine-refractory patients treated with bortezomib in vivo. CONCLUSION: Our data confirm that bortezomib, like other proteasome inhibitors, has proapoptotic activity in CLL cells.

Antineoplastic Agents↗
PubMed2003

Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

BACKGROUND: Older age is a consistent poor prognostic factor in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Whether this is related to an intrinsic worse disease biology or to inadequate drug delivery or excessive treatment-associated toxicity is unknown. The availability of imatinib mesylate, a selective, Bcr-Abl-targeted therapy that is administered orally with minimal side effects, may clarify whether older age would remain an adverse factor (thus, implying a different age-related CML biology). METHODS: Seven hundred forty-seven patients in different phases of Ph-positive CML who were treated with imatinib from 1999 until the time of last follow-up were evaluated. Among them, 187 patients had newly diagnosed, early chronic phase CML; 351 patients had chronic phase CML after interferon alpha (IFN) failure; 133 patients had accelerated phase CML; and 76 patients had blastic phase CML. The imatinib daily dose varied from 400 mg to 800 mg orally, according to the protocol design. Patients were categorized into a group of older patients (age 60 years or older) or younger patients (age younger than 60 years). Their characteristics, responses to therapy, and survival were compared by univariate and multivariate analyses. RESULTS: One hundred eighty-seven patients had newly diagnosed CML, and 49 patients (26%) were in the older age group. Older patients had similar cytogenetic response rates and survival compared with younger patients. Among 351 patients with late chronic phase CML after IFN failure, 120 patients (34%) were in the older age group. Although the older patients had a lower incidence of achievement of complete cytogenetic response (Ph, 0%) by univariate analysis (56% vs. 44%; P = 0.05), age was not found to be an independent poor prognostic factor in the multivariate analysis. Similarly, older age was not an adverse poor prognostic factor for survival. Forty-two of 133 patients (32%) with accelerated phase CML were older. The incidence of any cytogenetic response was lower in older patients (53% vs. 33%; P = 0.04), but age was not significant in the multivariate analysis. Older patients also had a trend toward worse survival (P = 0.09) that was not significant in the multivariate analysis. Twenty-eight of 76 patients (37%) evaluated in blastic phase were older. Older age was not a significant prognostic factor either for achieving response or for survival. CONCLUSIONS: With imatinib therapy, older age appears to have lost much of its prognostic relevance. This suggests that the previous poor prognosis observed with older age was related to treatment-associated factors (e.g., toxicity with allogeneic transplantation or with IFN therapy) rather than to an intrinsic, different disease biology of CML in older patients.

Administration, Oral↗
PubMed2003

Mylotarg, fludarabine, cytarabine (ara-C), and cyclosporine (MFAC) regimen as post-remission therapy in acute myelogenous leukemia.

PURPOSE: Mylotarg, a humanized anti-CD33 antibody linked to an antitumor antibiotic, is approved for the treatment of patients with relapsed acute myeloid leukemia (AML). Its role as a component of post-remission therapy in AML has not been established. The Mylotarg, fludarabine, cytarabine, and cyclosporine (MFAC) regimen was evaluated in patients in complete remission following Mylotarg-containing regimens. METHODS: The MFAC regimen comprised: Mylotarg 4.5 mg/m2 intravenously (i.v.) over 2 h after a loading dose of cyclosporine A (CSA) on day 1; fludarabine 15 mg/m2 i.v. over 30 min every 12 h for six doses on days 2 through 4; ara-C 0.5 g/m2 over 2 h every 12 h for six doses on days 2 through 4, 4 h after fludarabine started; CSA 6 mg/kg over 2 h, followed by 16 mg/kg continuous i.v. infusion on days 1 and 2. Patients in complete remission (CR) commenced idarubicin and ara-C (IA) alternating with MFAC or vice versa for 9 months from the date of CR. Idarubicin was administered at 8 mg/m2 on days 1 and 2 and ara-C at 1.5 g/m2 on days 1 and 2. RESULTS: A total of 22 patients received 76 courses of MFAC (35 courses) alternating with IA (41 courses) or vice versa. The interval between courses, and degrees of myelosuppression, were equivalent in the alternating regimens. Failure-free and 12-month survival rates of were 32% and 55%, respectively. Grade 3/4 toxicities, including sepsis, neutropenic fever, and nausea/vomiting, were equivalent with MFAC and IA. CONCLUSIONS: Post-remission therapy with MFAC is feasible and well tolerated in patients with AML.

Acute Disease↗
PubMed2003

Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase.

BACKGROUND: Before the discovery of imatinib mesylate, a Bcr-Abl selective tyrosine kinase inhibitor, three agents, interferon-alpha (IFN-alpha), cytarabine (ara-C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN-alpha, ara-C, and HHT in newly diagnosed Ph-positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis. METHODS: Ninety patients with Ph-positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m(2) IFN-alpha subcutaneously (s.c. daily, ara-C 10 mg s.c. daily, and HHT 2.5 mg/m(2) by continuous infusion over 24 hours daily x 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily. RESULTS: With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to < or = 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN-alpha dose was 1.6 MU/m(2) daily, the median ara-C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow-up time of 46 months for the total study group, the estimated 5-year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase. CONCLUSIONS: The sequence of IFN-alpha, ara-C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5-year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML.

Adult↗
PubMed2003

Phase II study of alemtuzumab in chronic lymphoproliferative disorders.

BACKGROUND: Pilot studies showed that alemtuzumab is active in lymphoproliferative disorders. The authors conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in advanced or refractory chronic lymphoproliferative disorders. METHODS: Seventy-eight patients were enrolled. The most common diagnoses were chronic lymphocytic leukemia (n = 42 patients) and T-cell prolymphocytic leukemia (n = 18 patients). Before entering the study, the patients had received multiple therapies (median, three therapies) and the median time from diagnosis was 7 years. Alemtuzumab was given intravenously at doses of 3 mg, 10 mg, and 30 mg on 3 consecutive days, after which 30 mg was administered 3 times a week. Patients were treated for 4-12 weeks depending on disease response. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir. RESULTS: The overall response rate was 35%, the complete response (CR) rate was 13%, and the partial response (PR) rate was 22%. The median duration of response was 18 months for patients achieving a CR and 7 months for patients achieving a PR. The median duration of survival was 25 months for patients who had a response and 12 months for the entire population. Normalization of the lymphocyte count was observed in 84% of patients and resolution of bone marrow involvement was observed in 49% of patients. The most common infusion-related adverse events were fever, rigors, skin rash, nausea, and dyspnea. These were most common during the first week of therapy. Hematologic toxicity was comprised of long-lasting lymphocytopenia and transient neutropenia and thrombocytopenia. Thirty-six patients (46%) experienced at least one episode of fever or infection. CONCLUSIONS: Alemtuzumab has a high response rate in patients with chronic lymphoproliferative disorders.

Adult↗
PubMed2003

Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia.

BACKGROUND: General and site-specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti-CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML. METHODS: One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)-positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph-negative CML. Decitabine was given at 100 mg/m(2) over 6 hours every 12 hours x 5 days (1000 mg/m(2) per course) in the first 13 patients, 75 mg/m(2) in the subsequent 33 patients, and 50 mg/m(2) in the remaining 84 patients. RESULTS: A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph-negative CML, four (57%) had objective responses. There was no evidence of a dose-response effect. The estimated 3-year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50-75 mg/m(2), the median time to granulocyte recovery above 0.5 x 10(9)/L was about 4 weeks. Myelosuppression-associated complications included febrile episodes in 37% and documented infections in 34%. CONCLUSIONS: Decitabine appears to have significant anti-CML activity. Future studies should evaluate lower-dose, longer-exposure decitabine schedules alone in imatinib-resistant CML, as well as combinations of decitabine and imatinib in different CML phases.

Adolescent↗
PubMed2003

Rituximab in relapsed or refractory hairy cell leukemia.

The purpose of this study was to investigate the efficacy and safety of the monoclonal antibody, rituximab, in relapsed or refractory hairy cell leukemia (HCL). Fifteen patients with relapsed or primary refractory HCL after nucleoside analogs received rituximab 375 mg/m2 weekly for a total of 8 planned doses. An additional 4 doses could be administered to responders who had not achieved complete response (CR). The overall response rate was 80%. Eight patients (53%) achieved CR, 2 (13%) attained CR by hematologic parameters with residual marrow disease (1% to 5% marrow hairy cells), and 2 (13%) had a partial response. Of the 12 responders followed for a median of 32 months (range, 8 to 45+ months), 5 patients (42%) had progression of disease 8, 12, 18, 23, and 39 months from the start of therapy. Three patients failed to respond (after 4, 6, or 8 doses). Reductions in serum interleukin-2 receptor (sIL-2R) levels correlated with response. Toxicity was minimal, and no infectious episodes were observed. Rituximab has significant activity and minimal toxicity in HCL and warrants further study. Rituximab should be explored further in HCL with regard to eradication of minimal residual disease and in combination with nucleoside analogs.

Adult↗
PubMed2003

Treatment of Philadelphia chromosome-positive chronic myelogenous leukemia with weekly polyethylene glycol formulation of interferon-alpha-2b and low-dose cytosine arabinoside.

BACKGROUND: To evaluate the activity and toxicity of weekly Schering 54301, a polyethylene glycol formulation of interferon- alpha-2b (PEG-IFN-alpha-2b), with cytosine arabinoside (ara-C) in patients with chronic myelogenous leukemia (CML). METHODS: Seventy-six patients with Philadelphia chromosome (Ph)-positive early chronic-phase CML were treated with the combination of PEG-IFN-alpha-2b and ara-C (10 mg daily subcutaneously [s.c.]). The starting dose of PEG-IFN-alpha-2b was 6 microg/kg s.c. weekly in the first 24 patients but was reduced to 4.5 microg/kg in the next 52 patients. RESULTS: Overall, 73% of patients had a complete hematologic response, 35% of patients had a major cytogenetic response (Ph < 35%), and 21% of patients had a complete cytogenetic response (Ph = 0%). With a median follow-up of 19 months, the estimated 2-year survival rate was 89%. Therapy was discontinued in 24% of patients due to Grade III-IV toxicity. Frequent severe side effects that required dose reductions included neutropenia (49%), fatigue (43%), and neurologic toxicity (17%). The median PEG-IFN-alpha-2b and ara-C doses delivered were 3 microg/kg weekly and 7.5 mg daily, respectively, at 12 months of therapy. The activity and toxicity profiles of this combination was similar to those observed in historical patients treated with IFN-alpha and cytarabine. CONCLUSIONS: The combination of PEG-IFN-alpha-2b and ara-C is active but has significant toxicity in patients with chronic-phase CML at the dose schedule used. The recommended dose of PEG-IFN-alpha-2b in future combination studies is 3 microg/kg or less.

Adult↗
PubMed2003

Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia.

In a phase 2 study, 62 patients with relapsed and refractory acute myeloid leukemia (AML; n = 31), myelodysplastic syndrome (MDS; n = 8), chronic myeloid leukemia in blastic phase (CMLBP; n = 11), and acute lymphocytic leukemia (ALL; n = 12) received 40 mg/m2 clofarabine intravenously over 1 hour daily for 5 days, every 3 to 6 weeks. Twenty patients (32%) achieved complete response (CR), 1 had a partial response (PR), and 9 (15%) achieved CR but without platelet recovery (CRp), for an overall response rate of 48%. In AML, responses were noted in 2 (18%) of 11 patients in first salvage with short first CR (</= 12 months), in 7 (87%) of 8 patients with longer first CR, and in 8 (67%) of 12 patients in second or subsequent salvage. Responses were observed in 4 of 8 patients with high-risk MDS (50%), in 7 (64%) of 11 with CML-BP, and in 2 (17%) of 12 with ALL. Severe reversible liver dysfunction was noted in 15% to 25%. After the first clofarabine infusion, responders accumulated more clofarabine triphosphate in blasts compared with nonresponders (median 18 vs 10 microM; P =.03). This increased only in responders (median, 1.8-fold; P =.008) after the second clofarabine infusion. In summary, clofarabine is active in acute leukemias and MDS; cellular pharmacokinetics may have prognostic significance.

Adenine Nucleotides↗
PubMed2003

Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders.

BACKGROUND: Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl, bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). METHODS: The authors investigated the efficacy of imatinib in patients with these disorders. Forty-eight patients with AML (n = 10), MDS (n = 8), myelofibrosis (n = 18), atypical chronic myeloid leukemia (CML; n = 7), chronic myelomonocytic leukemia (CMML; n = 3), or polycythemia vera (n = 2) were treated with imatinib 400 mg daily. RESULTS: None of the patients with AML or MDS responded. Among patients with myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had erythroid hematologic improvement, and 1 had improvement in platelet count. One patient with atypical CML had erythroid hematologic improvement. Both patients with polycythemia vera needed fewer phlebotomies (from 2-3 per year to none during the 8 months of therapy and from 3-6 per year to 1 during 9 months of therapy). None of the three patients with CMML responded. Treatment was well tolerated. The side effects were similar to those observed in patients with CML. CONCLUSIONS: Within these small subgroups of disease types, single-agent imatinib did not achieve a significant clinical response among patients with AML, MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on polycythemia vera are promising and deserve further investigation. Responses among myelofibrosis patients were minor. Therefore, a combination treatment regimen including imatinib may be more effective.

Adult↗
PubMed2003

Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia.

PURPOSE: Troxacitabine has activity in refractory myeloid leukemia, either as a single agent or when combined with cytarabine (ara-C) or with idarubicin. A prospective, randomized study was conducted in patients aged 50 years or older with untreated, adverse karyotype, acute myeloid leukemia (AML) to assess troxacitabine-based regimes as induction therapy. PATIENTS AND METHODS: Patients were randomized to receive idarubicin and ara-C (IA) versus troxacitabine and ara-C (TA) versus troxacitabine and idarubicin (TI). A Bayesian design was used to adaptively randomly assign patients to treatment. Thus, although there was initially an equal chance for randomization to IA, TA, or TI, treatment arms with a higher success rate progressively received a greater proportion of patients. RESULTS: Thirty-four patients were treated. Randomization to TI stopped after five patients and randomization to TA stopped after 11 patients. Defining success as complete remission (CR) that occurred within 49 days of starting treatment, success rates were 55% (10 of 18 patients) with IA, 27% (three of 11 patients) with TA, and 0% (zero of five patients) with TI. Because three CRs occurred after day 49, final CR rates were 55% (10 of 18 patients) with IA, 45% (five of 11 patients) with TA, and 20% (one of five patients) with TI. The probability that TA was inferior to IA was 70%, with a 5% probability that TA would have a 20% higher CR rate than IA. Survival was equivalent with all three regimens. CONCLUSION: Neither troxacitabine combination was superior to IA in elderly patients with previously untreated adverse karyotype AML.

Acute Disease↗
PubMed2003

Clinical relevance of the expression of the CD31 ligand for CD38 in patients with B-cell chronic lymphocytic leukemia.

BACKGROUND: CD31 (platelet endothelial cell adhesion molecule-1 [PECAM-1]) is the ligand for CD38, a transmembrane glycoprotein that is expressed on the surface of leukemic cells in many patients with B-cell chronic lymphocytic leukemia (B-CLL). In a previous study, the authors showed that CD38 expression was correlated with a poor prognosis in patients with B-CLL. In the current study, blood samples from patients with B-CLL were examined to identify CD31 surface marker expression, and CD31 expression was correlated with several other known prognostic variables, including CD38. METHODS: Using flow cytometry, peripheral blood samples from 120 patients with B-CLL were analyzed for CD31 and CD38 expression on CD19 positive leukemic B cells. RESULTS: Thirteen of 120 patients (11%) had CD31 expression on < 20% of their B cells, and the remaining patients had various levels of CD31 expression. The median expression of CD31 was 76% of leukemic, CD19 positive cells. Levels of CD31 expression were not correlated with survival outcomes or with any of the known prognostic parameters when all patients were considered. Patients who had high CD38 expression (>or= 20%), as expected, had significantly shorter survival (P = 0.001) compared with patients who had low CD38 expression (< 20%). However, in patients with low CD38 expression, a subgroup with low CD31 expression (< 76%) had significantly longer survival compared with the survival for the entire group (P = 0.0001). Moreover, the survival pattern of patients with low CD38 expression and high CD31 expression was not significantly different from the survival pattern seen in patients with high CD38 expression. CONCLUSIONS: CD31 expression further defined a subgroup of patients with B-CLL who had a different survival outcome. Defining the interaction between CD31 expression and CD38 expression in patients with CLL will require further exploration.

ADP-ribosyl Cyclase↗
PubMed2003

Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells.

Resveratrol, an edible polyphenolic stilbene, has been reported to possess substantial antileukemic activities in different leukemia cell lines. We investigated whether resveratrol is active against fresh acute myeloid leukemia (AML) cells and its mechanism of action. Because interleukin 1beta(IL-1beta) plays a key role in proliferation of AML cells, we first tested the effect of resveratrol on the AML cell lines OCIM2 and OCI/AML3, both of which produce IL-1beta and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 microM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1beta partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1beta in OCIM2 cells. It also suppressed the IL-1beta-induced activation of transcription factor nuclear factor kappaB (NF-kappaB), which modulates an array of signals controlling cellular survival, proliferation, and cytokine production. Indeed, incubation of OCIM2 cells with resveratrol resulted in apoptotic cell death. Because caspase inhibitors Ac-DEVD-CHO or z-DEVD-FMK partially reversed the antiproliferative effect of resveratrol, we tested its effect on the caspase pathway and found that resveratrol induced the activation of the cysteine protease caspase 3 and subsequent cleavage of the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase. Finally, resveratrol suppressed colony-forming cell proliferation of fresh AML marrow cells from 5 patients with newly diagnosed AML in a dose-dependent fashion. Taken together, our data showing that resveratrol is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.

Acute Disease↗
PubMed2003

Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia.

BACKGROUND: Therapy for patients with Richter syndrome (RS) or fludarabine-refractory chronic lymphocytic leukemia (CLL) is unsatisfactory. A Phase II study was conducted to evaluate an alternating combination cytotoxic regimen given with rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) in these patients. METHODS: Fludarabine-refractory CLL was defined as failure to respond to most recent prior fludarabine-containing regimen. Patients received up to six cycles of fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone (hyper-CVXD) plus rituximab and GM-CSF alternating with methotrexate and cytarabine plus rituximab and GM-CSF. Response, toxicity, and survival data were compared with data from prior therapy with hyper-CVXD alone in this patient group. RESULTS: Forty-nine patients with RS (n = 30 patients) or refractory CLL (n = 19 patients) were treated on study. Nine patients (18%) achieved a complete remission, and 11 patients achieved a partial remission (22%), for an overall objective response (OR) rate of 41%. With a median follow-up of 7.5 months and a maximum follow-up of 15.2 months, the 12-month failure free survival (FFS) rate was 27%, and the overall survival (OS) rate was 39%. Nine patients (18%) died during the first cycle of therapy, and two patients (4%) died during the second cycle. There were no significant differences between the rates of OR, OS, and FFS in the current study and those obtained with hyper-CVXD alone on a prior study. CONCLUSIONS: The study regimen had activity and significant toxicity in patients with RS or fludarabine-refractory CLL. It was not clearly better compared with hyper-CVXD alone in this patient population.

Adult↗
PubMed2003

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia.

High levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF-responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5'-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)-Stat inhibitor AG490 abrogated GM-CSF-induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat-dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.

Acute Disease↗
PubMed2003

Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes.

BACKGROUND: Gemtuzumab is used to treat patients with previously untreated or recurrent acute myelogenous leukemia (AML). The fludarabine and cytarabine (ara-C) regimen is active in these patients. Resistance to gemtuzumab is associated with blast multidrug resistance (MDR). The objectives of this study were to evaluate the efficacy and toxicity of a combination regimen of gemtuzumab, fludarabine, ara-C, and the MDR modifier (cyclosporine [CyA]) in patients with previously untreated AML, refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEBT). METHODS: The MFAC regimen was comprised of gemtuzumab (Mylotarg trade mark ) (6 mg/m(2) intravenously [i.v.] on Day 1); fludarabine and ara-C (15 mg/m(2) and 0.5 g/m(2), respectively, twice daily on Days 2-6); and CSA (6 mg/kg loading dose before gemtuzumab, followed by 16 mg/kg continuous i.v. infusion on Days 1 and 2). RESULTS: Fifty-nine evaluable patients were treated: 39 patients (66%) had AML and 20 patients (34%) had RAEB/RAEBT. Their median age was 57 years (range, 27-76 years). The MFAC regimen induced complete remission (CR) in 27 patients (46%) and CR with incomplete platelet recovery (CRp) in 1 patient (2%). The median survival period is 8 months. At 12 months, the survival rate is 38% and the event-free survival rate in patients with CR/CRp is 27%. Infections complicated 38% of the courses of chemotherapy. Grade 3/4 toxicity included hyperbilirubinemia in 31% and transaminitis in 7% of the patients. Four patients (7%) developed hepatic venoocclusive disease (VOD). CONCLUSIONS: The MFAC regimen may merit further study in patients with AML if measures to avoid and/or treat VOD can be incorporated into the regimen.

Adult↗
PubMed2003

Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias.

PURPOSE: Troxacitabine has significant single-agent activity. This study was conducted to define the dose-limiting toxicities (DLTs) of its combination with cytarabine (ara-C), idarubicin, or topotecan. PATIENTS AND METHODS: Patients with refractory acute myeloid leukemia (AML), advanced myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were initially randomly assigned to receive troxacitabine 5.0 mg/m(2) by intravenous (IV) infusion over 30 minutes on days 1 to 5 with ara-C 1.0 g/m(2)/d IV [DOSAGE ERROR CORRECTED] over 2 hours on days 1 to 5, idarubicin 12 mg/m(2) by 5 minute IV infusion on days 1 to 3, or topotecan 1.0 mg/m(2) as an continuous IV infusion on days 1 to 5. Doses were then adjusted to define DLT for each combination. RESULTS: Eighty-seven patients (68 AML, eight MDS, 11 CML-BP) were treated. DLTs were hepatic transaminitis, hyperbilirubinemia, and hand foot syndrome (HFS) on the troxacitabine plus ara-C combination. The recommended phase II doses were 6 mg/m(2) once a day for 5 days and 1.0g/m(2) once a day for 5 days, respectively. DLTs were diarrhea, rash, and mucositis on the troxacitabine plus topotecan combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 0.75 mg/m(2) once a day for 5 days, respectively. DLTs were HFS, rash, and mucositis on the troxacitabine plus idarubicin combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 9 mg/m(2) once a day for 3 days, respectively. Among 74 evaluable patients with AML or MDS, 10 (13%) achieved complete remission and four (5%) had hematologic improvement. Two of 11 (18%) evaluable patients with CML-BP returned to chronic phase. CONCLUSION: Troxacitabine-based combinations had significant antileukemic activity.

Adolescent↗