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Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8may affect imatinib trough levels. This study investigates the effect of common CYP2C8polymorphisms [*1B(rs7909236), *1C(rs17110453), *3(rs11572080 and rs10509681), and *4(rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors. Standardized imatinib trough levels did not show a significant difference between wild-type and variant groups for any of the tested SNPs, but an association with age was found, with older patients having higher trough levels. This suggests that common CYP2C8SNPs have no effect on the pharmacokinetics of imatinib.

Objective--To quantify the effect of selection of relatively healthy women in studies reporting reduced relative risk for cardiovascular disease in postmenopausal women taking hormone replacement therapy. Design--Review of the follow [...]

Lugtenburg: Genmab: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Honoraria; Janssen Cilag: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Kersten:Gilead: Honoraria; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Miltenyi: Honoraria; Kite Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria.

Introduction

Introduction.Since publication of the pivotal CLL011 phase 3 trial, combination of chlorambucil and anti-CD20 MAb has become the standard first-line CLL treatment for patients unfit for FCR. Lenalidomide (Len) has been proven effective both as monotherapy and in combination with rituximab. Although recent studies in CLL suggest that Len is mostly beneficial as consolidation treatment, the exact place and duration of this drug is still not optimized. Moreover, Len has shown a distinct and more difficult to manage toxicity profile in the context of CLL, potentially hampering combination treatment with this drug. We therefore conducted a phase 2 study to evaluate efficacy and safety of a combination of chlorambucil, rituximab and individual dosed Len (induction-I) followed by 6 months of Len monotherapy (induction-II).

Introduction

Imatinib and dasatinib modulate immune responses in vitroand in vivo. Immunological surveillance in the MRD-situation might be of particular relevance for long-term control or even elimination of CML-repopulating stem cells. Little is known about potential immune-modulatory effects of nilotinib in vivo. The ENEST1st study (NCT01061177) is focused on examining the role of firstline nilotinib therapy in CML-CP - this ENEST1st substudy involves a comprehensive immunological monitoring program.

NT-proBNP is emerging to be of great importance in risk assessment of patients with acute pulmonary embolism (PE), by identifying both high and low-risk patients. The aim of the present management study was to investigate the safety of out of hospital treatment of patients with acute PE based on a NT-proBNP < 500 pg/ml.Hemodynamically stable outpatients with objectively diagnosed acute PE and a NT-proBNP level < 500 pg/ml, were considered eligible for participation in this multicenter prospective study. Patients were discharged immediately from the emergency room or within the first 24 hours of admission. The primary objective was the 10-days mortality rate. Secondary objectives were the incidence of re-admission to hospital due to PE or its treatment, the patient's satisfaction during the first ten days of treatment and the incidence of serious adverse events in a 3-month follow-up period.Approximately 40 percent of all patients presenting at the emergency room with acute PE fulfilled the inclusion criteria. In total, 152 patients (mean age 53.4 ± 14.3 years; 51% female) with PE were treated as outpatients. No deaths, major bleedings or recurrent venous thromboembolism occurred during the first 10 days or in a follow-up period of 3 months. Seven patients required readmission. Three patients were admitted because of complaints of their PE: two patients with anxiety and pain and one patient with dyspnoea and low oxygen saturation. There were no signs of progression of PE in these 3 patients. Four patients were re-admitted because of an illness unrelated to PE. According to the PSQ18 and anxiety score, patients were satisfied with their out of hospital treatment; they had no progression of anxiety during the first ten days of treatment.Out of hospital treatment is safe in a group of low risk patients with non-massive PE, based on NT-proBNP levels < 500 pg/ml. Approximately 40 percent of PE-patients can be treated in an outpatient setting. Patients consider out of hospital treatment as comfortable and have no increase in anxiety scores.No relevant conflicts of interest to declare.

In this study we analyzed 40 patients with AML who received donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation (alloSCT). Patients with a median age of 42 (range, 11–66) were transplanted with an in vitro T-cell depleted (Campath in the bag) graft from an HLA matched sibling following a myeloablative (n=35) or a nonmyeloablative conditioning regimen (n=5). Patients received DLI for relapsed AML (n=28) or for mixed chimerism (n=12). All patients with relapsed AML were treated with a cytarabine-containing chemotherapy regimen or with gemtuzumab ozogamycin immediately prior to DLI treatment and received daily 3 x 106 U α-IFN sc. The DLI dose administered was depending on the protocol used. Fourteen relapsed patients received high dose DLI with a median of 50 x 106 CD3+ cells/kg and 14 low dose DLI with a median of 5 x 106 CD3+ cells/kg. Ten of 28 patients with relapsed AML obtained a complete remission after the combination of chemotherapy and DLI. One patient obtained a partial remission and fourteen patients showed no response. Three patients were not evaluable. No effect of cell dose was observed on the clinical response after DLI. The median percentage of donor chimerism in patients with relapsed AML before DLI was 74% (range, 5–96%) and increased after DLI to 97% (range, 5–100%). Six patients with relapsed AML became complete chimera after DLI. DLI caused in 12 of 28 relapsed patients grade 3–4 GVHD. cGVHD was observed in 3 patients of whom 2 developed extensive GVHD. With a median follow up of 11 months only 1 pt in the high dose and 4 pts in the low dose group are alive in CR and 23 have died due to progressive disease (16) or GVHD (7). Due to this low rate of long-term survival of relapsed AML patients treated with DLI, we recently developed a new DLI protocol for AML patients. Twelve patients with mixed chimerism at 6 months after T-cell depleted alloSCT were pre-emptively treated with 3 x 106 CD3+ cells/kg. Complete chimeric response was observed in 6 of these 12 patients. Two patients showed increasing mixed chimerism and three patients showed no response. Two of 12 patients treated for mixed chimerism developed aGVHD gr 1–2. No severe aGVHD was observed in this group. Two patients developed chronic GVHD, both after nonmyeloablative conditioning. Incidence of GVHD was significantly lower in this group compared to the relapsed patients. Currently, 7 patients are alive in CR. In conclusion: 1) Long term survival of patients with overt relapse AML after alloSCT treated with DLI remains poor 2) High dose DLI appeared to be less effective than low dose DLI due to increased toxicity 3) DLI for AML may be more successful when it is administered pre-emptively for mixed chimerism after T-cell depleted alloSCT.

Transplantation of stem cells that are T-cell depleted using Campath 1H incubation following non-myeloablative (NM-alloSCT) conditioning leads to durable donor engraftment with minimal GVHD using HLA-identical family sibling and unrelated donors. The high levels of donor chimerism allow the subsequent use of DLI to treat residual disease (Exp. Hematol. 2003; 31: 865–872). Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. We analyzed 12 patients with advanced CLL (9), PLL (1) or M. Waldenstrom (2) treated with NM-alloSCT. Median age was 56 years. Recipient conditioning consisted of fludarabine (30 mg/m2, 6 days), ATG (10 mg/kg, 4 days) and busulphan (3.2 mg/kg, 2 days). High numbers of G-CSF mobilized peripheral blood CD34+cells from 11 related and 1 unrelated donors were collected (median 12 x 106/kg). The graft was T-cell depleted by 30 minutes incubation with 20 mg Campath 1H. No post-transplant GVHD prophylaxis was administered. The transplant procedure was very well tolerated. All patients engrafted rapidly. Only 1 patient experienced GVHD gr I (skin) after alloSCT. Sequential chimerism studies of bone marrow showed sustained mixed chimerism with a median donor percentage at 3 months after alloSCT of 86% (range 8–100%). At a fixed time period of 6 months after NM-alloSCT, low dose DLI was administered (5 x 106CD3+cells/kg) in 8 patients (3 pts too early after alloSCT and one pt died before DLI). The disease status pre-DLI was persistent disease in 4 pts and CR in 4 pts. After DLI, four patients experienced severe aGVHD (≥ grade 2) and 1 limited cGVHD. Importantly, the observed GVHD after low dose DLI was well managable. One patient received a second transplant from the original donor after myeloablative conditioning due to progressive disease with concommitant decreasing mixed chimerism. Donor chimerism increased after DLI with a median donor percentage of 98% (range, 3–100%) at 3 months after DLI. Presently at a median follow-up of 423 (range 46–1572) days, 9 patients are alive. Four patients are in complete remission, 3 with partial remission and 2 with progressive disease. Three patients have died, two due to infection and one by unknown cause.