Vancomycin serum concentration during febrile neutropenia in patients with acute myeloid leukemia.

BACKGROUND: Adult leukemia patients with febrile neutropenia have a higher volume of distribution requiring increased drug doses. We performed a survey of vancomycin use in that population to assess the accuracy of our dosing guidelines. METHODS: We retrospectively reviewed the charts and laboratory results of vancomycin prescription and monitoring in adult acute myeloid leukemia patients with febrile neutropenia in a teaching hospital. RESULTS: Fifty-four patients received 67 vancomycin courses between January 2005 and April 2007. A loading dose was used in 97% of cases dosed at a mean 15.5±3.3mg/kg. It was followed by a continuous infusion of an average 35.4±6.9mg/kg per day maintenance dose. Serum monitoring yielded serum levels above the 20mg/L target in only 12% of cases. Despite higher dose, the target concentration was only reached in 32% of cases, after a mean 1.5 dose adjustment. The mean final maintenance dose was 42.1±9.4mg/kg per day. Vancomycin was well tolerated and induced only two temporary increases in serum creatinine. The treatment was microbiologically justified in only two cases. The mean length of therapy was 7.7±4.4 days and 41 over 65 (63%) non-documented infections were treated for more than five days despite local guidelines recommending a maximum 5-day course without bacterial documentation. Overall, only seven (10%) vancomycin courses complied with all defined criteria. CONCLUSIONS: Vancomycin use was not optimal. We updated our guidelines after the study to dramatically reduce vancomycin indications in leukemia patients. When it is indicated, following the loading dose, we more closely monitor vancomycin serum levels to allow for an earlier dose adjustment when necessary.

Invasive fungal infections: epidemiology and analysis of antifungal prescriptions in onco-haematology.

WHAT IS KNOWN AND OBJECTIVE: Invasive fungal infections (IFI) are associated with high rates of morbidity and mortality, particularly in onco-haematology patients. We aimed to study the epidemiology of IFI in neutropenic patients and estimate the economic impact of treatment of those infections. METHODS: All patients hospitalized in onco-haematology, and treated with antifungal agents, in 2005 were investigated. Four features were studied: the diagnosis for each patient, the antifungal drugs used, the thoracic densitometry reports and the sero-mycological data. Infectious episodes were stratified according to the EORTC 2008 classification criteria (10). RESULTS AND DISCUSSION: Of the 1130 patients surveyed, 192 patients received systemic antifungal agents. Of these 46% had acute leukaemia, 29% bone-marrow allografts, 7% lymphoma and 18% other malignant haemopathies. Using the EORTC 2008 criteria (10), there were 8 proved IFI (3 aspergillosis, 3 candidosis and 2 other IFI), 17 probable IFI (11 aspergillosis, 6 candidosis) and 16 possible aspergillosis. The incidence of IFI was 2·1%. Eighty patients (41·7%) had received prophylaxis: 56 with fluconazole and 24 with voriconazole. Treatment was most often empirical (n = 127, 66·1%). Combination of two antifungals was used in 17 cases. The mean duration of prophylactic, empirical, proved/probable aspergillosis-directed, candidaemia-directed and combination treatment was 19, 19, 46, 32 and 27 days, respectively. The cost of antifungal treatment in 2005 reached almost 2,000,000 €, including 427,000 € for documented infections (proved and probable), 1,246,000 € for empirical treatment and 58,300 € for prophylaxis. WHAT IS NEW AND CONCLUSION: The incidence of IFI is low but the pharmacoeconomic impact is extremely high. Improved strategies are required to reduce the frequency and duration of empirical treatment without compromising beneficial outcome.

Fluorescence in situ hybridization characterization of ider(20q) in myelodysplastic syndrome.

Isochromosome of the long arm of chromosome 20 with loss of interstitial material [ider(20q)] is a variant of deletion of chromosome 20q and a rare abnormality in myelodysplastic syndrome (MDS). We studied seven cases with an ider(20q) in MDS. Fluorescence in situ hybridization (FISH) studies showed all proximal breakpoints to be consistently located in 20q11.21 band whereas distal breakpoints were variable. Amplification of HCK, TNFRSF6B and DIDO1 genes included in retained regions associated with loss of tumour suppressor genes in deleted regions could explain cell tumour progression and possibly the less favourable prognosis of ider(20q) compared with del(20q).

Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase.

Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03-20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in

Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib.

Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism.

Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL(+) leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K+T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.

Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP).

The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3-67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.