The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML

Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma

We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mR and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction treatment in patients who were scheduled to receive high-dose therapy. 139 patients (86 male, 53 female; median age 53 years, range 32-65 years; Durie and Salmon stage IIA: 42, IIB: one, IIIA: 89, IIIB: seven) were included in a prospective multicentre study in which VAD was administered as remission induction treatment and was followed by intensified treatment. The response was evaluated according to the criteria of the Eastern Cooperative Oncology Group (ECOG). The results of treatment were evaluable in 134 patients. Five patients died before evaluation. 86 patients (62%) achieved a partial response (PR) and seven patients (5%) achieved a complete response (CR), which equates to a response rate of 67%. The main side-effect was mild neurotoxicity, which was observed in 18% of the patients. Fever or infections were reported in 27% of the patients. VAD administered as an outpatient regimen, based on rapid intravenous infusion, is an effective induction regimen for untreated myeloma with a 67% response rate and acceptable toxicity

Darbepoetin alfa administration in patients with non-Hodgkin lymphoma and chemotherapy-induced anemia receiving (±R)CHOP

IMPACT NHL was a multicenter, observational study in adults with non-Hodgkin lymphoma receiving CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy with or without rituximab. Erythropoietin-stimulating agent treatment was given according to routine clinical practice and physician preference. In a subanalysis, outcomes were evaluated in 207 patients who received darbepoetin alfa (DA). The most common reason (81%) for initiating DA was low/declining hemoglobin (Hb) concentration. Mean (±standard deviation) duration of DA exposure was 8.8 ± 6.9 weeks (mean number of doses, 5.1 ± 4.6). Overall, 23% of patients had chemotherapy and DA treatment synchronized more than 75% of the time. At the time of DA initiation, 67% of patients had Hb concentrations in the guideline-recommended range (9-11 g/dl). Of 89 patients with Hb concentrations <10 g/dl at DA initiation and still receiving DA 5 weeks later, 92% (Kaplan-Meier) achieved Hb concentrations 10-12 g/dl between week 5 and at the end of treatment

Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: A phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)

Optimal dose and timing of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy for aggressive non-Hodgkin lymphoma (NHL) is still an unresolved issue. We assessed whether dose intensifications with cyclophosphamide and doxorubicin mi

High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients

The proto-oncogene EVI1 encodes a DNA binding protein and is located on chromosome 3q26. The gene is aberrantly expressed in acute myeloid leukemia (AML) patients carrying 3q26 abnormalities. Two mRNAs are transcribed from this locus: EVI1 and a fusion of EVI1 with MDS1 (MDS1-EVI1), a gene located 5' of EVI1. The purpose of this study was to investigate which of the 2 gene products is involved in transformation in human AML. To discriminate between EVI1 and MDS1-EVI1 transcripts, distinct real-time quantitative polymerase chain reaction (PCR) assays were developed. Patients with 3q26 abnormalities often showed high EVI1 and MDS1-EVI1 expression. In a cohort of 319 AML patients, 4 subgroups could be distinguished: EVI1(+) and MDS1-EVI1(-) (6 patients; group I), EVI1(+) and MDS1-EVI1(+) (26 patients; group II), EVI1(-) and MDS1-EVI1(+) (12 patients; group III), and EVI1(-) and MDS1-EVI1(-) (275 patients; group IV). The only 4 patients with a 3q26 aberration belonged to groups I and II. Interestingly, high EVI1 and not MDS1-EVI1 expression was associated with unfavorable karyotypes (eg, -7/7q-) or complex karyotypes. Moreover, a significant correlation was observed between EVI1 expression and 11q23 aberrations (mixed lineage leukemia [MLL] gene involvement). Patients from groups I and II had significantly shorter overall and event-free survival than patients in groups III and IV. Our data demonstrate that high EVI1 expression is an independent poor prognostic marker within the intermediate- risk karyotypic group

High-dose daunorubicin in older patients with acute myeloid leukemia

BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P = 0.002); the rates of remission after the first cycle

Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: A randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl)