Agnieszka Wierzbowska

Multicenter, Randomized, Open-Label, Phase III Trial of Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients With Newly Diagnosed Acute Myeloid Leukemia

PURPOSE This multicenter, randomized, open-label, phase III trial compared the efficacy and safety of decitabine with treatment choice (TC) in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics. PATIENTS AND METHODS Patients (N = 485) age ≥ 65 years were randomly assigned 1:1 to receive decitabine 20 mg/m(2) per day as a 1-hour intravenous infusion for five consecutive days every 4 weeks or TC (supportive care or cytarabine 20 mg/m(2) per day as a subcutaneous injection for 10 consecutive days every 4 weeks). The primary end point was overall survival (OS); the secondary end point was the complete remission (CR) rate plus the CR rate without platelet recovery (CRp). Adverse events (AEs) were recorded. RESULTS The primary analysis with 396 deaths (81.6%) showed a nonsignificant increase in median OS with decitabine (7.7 months; 95% CI, 6.2 to 9.2) versus TC (5.0 months; 95% CI, 4.3 to 6.3; P = .108; hazard ratio [HR], 0.85; 95% CI, 0.69 to 1.04). An unplanned analysis with 446 deaths (92%) indicated the same median OS (HR, 0.82; 95% CI, 0.68 to 0.99; nominal P = .037). The CR rate plus CRp was 17.8% with decitabine versus 7.8% with TC (odds ratio, 2.5; 95% CI, 1.4 to 4.8; P = .001). AEs were similar for decitabine and cytarabine, although patients received a median of four cycles of decitabine versus two cycles of TC. The most common drug-related AEs with decitabine were thrombocytopenia (27%) and neutropenia (24%). CONCLUSION In older patients with AML, decitabine improved response rates compared with standard therapies without major differences in safety. An unplanned survival analysis showed a benefit for decitabine, which was not observed at the time of the primary analysis.

International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts

This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.

Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study

PURPOSE The goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acute myeloid leukemia (AML). PATIENTS AND METHODS A cohort of 652 untreated AML patients with median age 47 years (range, 17 to 60 years) were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Postremission treatment was the same for all arms. RESULTS Complete remission rate in the DAC arm was higher compared with the DA arm (67.5% v 56%; P = .01) as a consequence of reduced incidence of resistant disease (21% v 34%; P = .004). There was no significant difference in early outcome between the DAF and DA arms. The probability of overall survival was improved for the DAC arm (45% ± 4% at 3 years) compared with the DA arm (33% ± 4%; P = .02), and leukemia-free survival was comparable. Long-term outcome did not differ significantly for the comparison of the DAF and DA arms. A survival advantage of the DAC arm over the DA arm was observed among patients age 50 years or older (P = .005), those with initial leukocyte count above 50 × 10(9)/L (P = .03), and those with unfavorable karyotype (P = .03). DAF revealed a significant advantage over DA in patients with adverse karyotype (P = .02). CONCLUSION The addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML.

Current and emerging therapies for acute myeloid leukemia

BACKGROUND Acute myeloid leukemia (AML) is a clonal disease characterized by the proliferation and accumulation of myeloid progenitor cells in the bone marrow, which ultimately leads to hematopoietic failure. The incidence of AML increases with age, and older patients typically have worse treatment outcomes than do younger patients. OBJECTIVE This review is focused on current and emerging treatment strategies for nonpromyelocytic AML in patients aged <60 years. METHODS A literature review was conducted of the PubMed database for articles published in English. Publications from 1990 through March 2009 were scrutinized, and the search was updated on August 26, 2009. The search terms used were: acute myeloid leukemia in conjunction with treatment, chemotherapy, stem cell transplantation, and immunotherapy. Clinical trials including adults with AML aged > or =19 years were selected for analysis. Conference proceedings from the previous 5 years of The American Society of Hematology, The European Hematology Association, and The American Society for Blood and Marrow Transplantation were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. RESULTS Cytarabine (AraC) is the cornerstone of induction therapy and consolidation therapy for AML. A standard form of induction therapy consists of AraC (100-200 mg/m(2)), administered by a continuous infusion for 7 days, combined with an anthracycline, administered intravenously for 3 days. Consolidation therapy comprises treatment with additional courses of intensive chemotherapy after the patient has achieved a complete remission (CR), usually with higher doses of the same drugs as were used during the induction period. High-dose AraC (2-3 g/m(2)) is now a standard consolidation therapy for patients aged <60 years. Despite substantial progress in the treatment of newly diagnosed AML, 20% to 40% of patients do not achieve remission with the standard induction chemotherapy, and 50% to 70% of first CR patients are expected to relapse within 3 years. The optimum strategy at the time of relapse, or for patients with the resistant disease, remains uncertain. Allogeneic stem cell transplantation has been established as the most effective form of antileukemic therapy in patients with AML in first or subsequent remission. New drugs are being evaluated in clinical studies, including immunotoxins, monoclonal antibodies, nucleoside analogues, hypomethylating agents, farnesyltransferase inhibitors, alkylating agents, FMS-like tyrosine kinase 3 inhibitors, and multidrug-resistant modulators. However, determining the success of these treatment strategies ultimately requires well-designed clinical trials, based on stratification of the patient risk, knowledge of the individual disease, and the drugs performance status. CONCLUSIONS Combinations of AraC and anthracyclines are still the mainstay of induction therapy, and use of high-dose AraC is now a standard consolidation therapy in AML patients aged <60 years. Although several new agents have shown promise in treating AML, it is unlikely that these agents will be curative when administered as monotherapy; it is more likely that they will be used in combination with other new agents or with conventional therapy.

Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group.

Objectives: Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2‐CdA) increase cytotoxic effect of Ara‐C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara‐C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi‐center phase II study evaluating the efficacy and toxicity of CLAG‐M salvage regimen in poor risk refractory/relapsed AML patients.

The inhibitor of apoptosis protein family and its antagonists in acute leukemias

The Inhibitor of Apoptosis Protein family (IAP) functions as inhibitors of apoptotic pathways, both death receptor- and mitochondrial mediated. We detail the current body of knowledge for the IAP family with regard to their structure and function, their expression in normal and leukemic cells, and their prognostic importance in acute leukemia. Although there is some evidence that IAPs play an important role in the chemoresistance of leukemia cell lines, little is known about their influence on this phenomenon in acute leukemia cells of human origin. IAPs are also explored as a specific target for new antitumor strategies, including antisense oligonucleotides of XIAP (X-chromosome-linked IAP) or survivin and small molecules of polyphenylurea-based XIAP inhibitors.Several proteins negatively regulate the function of the IAP family. One of those antagonists is Smac/DIABLO. Short peptides of Smac were found to enhanced apoptosis, induced by chemo- or immunotherapy, in the leukemic cells in vitro. Moreover, small-molecule agents, resembling Smac/DIABLO in function, were shown to potentiate cytotoxicity of chemotherapy in different malignancies.IAPs, exhibiting downstream influence on both external and intrinsic pathways as well as on some caspase-independent mechanisms of apoptosis, are potentially attractive target for anti-tumor therapy, although their role in the pathology and prognosis of acute leukemia has to be further elucidated.

Circulating endothelial cells in patients with acute myeloid leukemia.

Abstract:  Objectives: The circulating endothelial cells (CEC) are proposed to be a non‐invasive marker of angiogenesis. The level of CEC in peripheral blood (PB) of acute myeloid leukemia (AML) patients has not been investigated prior to this study. We evaluated the count of resting (rCEC), activated (aCEC) and endothelial progenitor cells (CEPC) in the PB of AML and healthy subjects. In addition we correlated the levels of CEC with disease status, known prognostic factors and response to treatment. Methods: CEC were quantified by utilizing four‐color flow cytometry procedures in 48 AML patients at the time of diagnosis and 29 healthy controls. Additionally, measurements were again taken after the first course of induction treatment in 12 of the patients. Results: The numbers of aCEC, rCEC and CEPC were significantly higher in the AML patients than in the controls (P < 0.0001, P < 0.0001 and P < 0.001, respectively). The CEC count was significantly higher in the AML patients with white blood cell count (WBC) >15 G/L, elevated lactic dehydrogenase (LDH) levels and a higher (over median) absolute blasts count (ABC) in PB than in the group with WBC <15 G/L (P < 0.03), a normal LDH level (P < 0.03) and a lower (

Circulating IL-6-type cytokines and sIL-6R in patients with multiple myeloma.

We investigated the serum concentration of interleukin‐6 (IL‐6) and four IL‐6 family cytokines — oncostatin M (OSM), leukaemia inhibitory factor (LIF), interleukin‐11 (IL‐11) and ciliary neurotrophic factor (CNTF) as well as IL‐6 soluble receptor (sIL‐6R) — using an enzyme‐linked immunosorbent assay (ELISA) in 67 patients with multiple myeloma (MM) and 24 healthy controls, for a possible association between the serum levels of these peptides with disease activity and known prognostic factors. sIL‐6R was detectable in all 67 and IL‐6 in 65 (97%) patients. Both peptides were measurable in all healthy controls. In contrast, OSM was detectable in 30 (44.8%) MM patients and in only four (16.6%) normal individuals. The serum levels of IL‐6, OSM and sIL‐6R were significantly higher in MM patients compared with control group (P < 0.001, P < 0.03 and P < 0.001 respectively). The highest concentrations of these cytokines were found in patients with progressive disease and the lowest in MM patients with stable disease and in healthy persons. LIF was detectable in four (6%), CNTF in 28 (41.8%) and IL‐11 in eight (11.9%) of the patients with MM. In the control group LIF, CNTF and IL‐11 were measurable in 8.3%, 33.3% and 8.3% respectively. The serum concentration of these cytokines did not correlate either with clinical stage or with the phase of disease and was similar to those in healthy individuals. We found significant positive correlation between IL‐6 levels and OSM (P < 0.001). We also observed positive correlation between β2‐M concentration and serum levels of IL‐6 (P < 0.002), sIL‐6R (P < 0.02) and OSM (P < 0.04) as well as a positive relationship between CRP and IL‐6 (P < 0.001) and OSM (P < 0.002). In conclusion, the serum levels of IL‐6, OSM and sIL‐6R, but not LIF, IL‐11 and CNTF, may be useful markers of MM activity.

A multicenter, open, non-comparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, and G-CSF as induction therapy in refractory acute myeloid leukemia - a report of the Polish Adult Leukemia Group (PALG).

Objectives: To evaluate the efficacy and toxicity of cladribine (2‐chlorodeoxyadenosine, 2‐CdA), cytarabine (Ara‐C), and granulocyte‐colony stimulating factor (G‐CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study.

Kinetics and apoptotic profile of circulating endothelial cells as prognostic factors for induction treatment failure in newly diagnosed acute myeloid leukemia patients

The circulating endothelial cells (CEC) are proposed to be a noninvasive marker of angiogenesis. Recent data suggest that endothelial cells may enhance the survival and proliferation of leukemic blasts and mediate chemotherapy resistance in acute myeloid leukemia (AML). We analyzed CEC count by the four-color flow cytometry in AML and healthy subjects. We evaluated the kinetics of mature CEC, both resting (rCEC) and activated (aCEC), as well as progenitor (CEPC) and apoptotic CEC (CECAnnV+) in AML patients treated with standard chemotherapy and their influence on response to treatment and overall survival. We found significantly higher numbers of aCEC, rCEC, CEPC, and CECAnnV+ in AML patients than in healthy controls. The elevated CEPC and absolute blood counts in peripheral blood as well as the low CECAnnV+ number were associated with higher probability of induction treatment failure. aCEC, rCEC, CEPC, and CECAnnV+ counts determined in complete remission (CR) were significantly lower than those found at diagnosis. In those CR patients, a significant decrease in the CEC count and increase in the number of CECAnnV+ were observed already 24h after the first dose of chemotherapy. In refractory AML, the aCEC, rCEC, CEPC, and CECAnnV+ counts assessed before and after induction chemotherapy did not differ significantly, and a significant decrease in CEC count and increase in CECAnnV+ number were noted only after the last dose of chemotherapy. The number of CEC is significantly higher in AML patients than in healthy subjects and correlates with response to treatment. The evaluation of CEC kinetics and apoptotic profile may be a promising tool to select AML patients with poor response to chemotherapy who may benefit from antiangiogenic therapies.