Patients with CLL responding to initial chemotherapy with fludarabine alone (F) or in combination with cyclophosphamide (FC) were randomized for treatment with alemtuzumab (30 mg i.v. TIW, 12 weeks) or observation. Of 21 evaluable patients, 11 were randomized to alemtuzumab before the study was stopped due to severe infections in seven of 11 patients. These infections (one life-threatening pulmonary aspergillosis IV; four CMV reactivations III requiring i.v. ganciclovir; one pulmonary tuberculosis III; one herpes zoster III) were successfully treated and not associated with cumulative dose of alemtuzumab. In the observation arm, one herpes zoster infection II and one sinusitis I were documented. At 6 months after randomization, two patients in the alemtuzumab arm converted to CR, while three patients in the observation arm progressed. After alemtuzumab treatment, five of six patients achieved a molecular remission in peripheral blood while all patients in the observation arm remained MRD-positive (P ¼ 0.048). At 21.4 months median follow-up, patients receiving alemtuzumab showed a significant longer progression-free survival (no progression vs mean 24.7 months; P ¼ 0.036). In conclusion, a consolidation therapy with alemtuzumab is able to achieve molecular remissions and longer survival in CLL, but a safe treatment regimen needs to be determined.

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The XE-2100 trade mark was evaluated in a multicentre study following a previously established protocol. In this paper, we demonstrate the results of analytical performance studies, including comparison of the leucocyte differential with the NCCLS H20-A method and evaluation of flagging sensitivity. Linearity of the leucocyte count over a wide clinical range, low imprecision in clinically important ranges and no measurable carry over were confirmed. For comparability studies, 4 x 200 cell microscopic differential leucocyte counts were correlated with the automated five-part-differential counts. No significant differences were detected in (1) a group without morphological abnormality and in (2) a leukopenic group. The sensitivity of flags for the detection of immature granulocytes and myeloid blasts was very good. Only few samples containing blast cells remained unrecognized but these would have been examined microscopically in any event because of other abnormalities indicated by the instrument. Atypical/abnormal lymphocytes/and lymphoblasts were detected very reliably when the total lymphocyte count and the flags were evaluated in combination. A similar procedure is recommended for the detection of left shift. When the neutrophil count is elevated, the sensitivity of the left shift flag is improved. The absolute immature granulocyte (IG) count by the instrument correlates well with that of myeloid precursor cells by microscopy.

Expression and functional activity of P-glycoprotein (P-gp) were measured in 182 acute myelogenous leukemia (AML) patients: 136 patients were treated with the AML-6 protocol (EORTC), containing daunorubicin, vincristine, and conventional-dose cytarabine (ara-C), and 21 patients received idarubicin, vepeside, and conventional-dose ara-C (ICE-AML-10 protocol/EORTC). An additional 25 patients were treated with a dose of idarubicin and ara-C, modified as compared with the ICE protocol, but with the same dose of etopside (ICE-I protocol). P-gp was determined using monoclonal antibody 4E3.16 and functional activity using the rhodamine 123 accumulation test. P-gp positivity was defined as a Kolmogorov Smirnov (KS) D value > or = 0.15, P-gp negativity as a KS D value < 0.15. P-gp activity was defined as a ratio of mean rhodamine 123 accumulation with/without verapamil. In AML patients at primary diagnosis and early relapse/refractoriness a significant (p < 0.05) difference between P-gp-positive and P-gp-negative patients was ascertained using the AML-6 protocol; the difference corresponded to the complete remission rate. For ICE- and ICE-I-treated AML patients at primary diagnosis this significance was not shown. Compared with AML patients at primary diagnosis and patients at early relapse or refractoriness, a significantly (p < 0.05) increased incidence of non-pumping P-gp and a trend (p = 0.054) to a higher percentage of non-P-gp-related mechanisms in AML patients at late relapse was determined. When the AML-6 protocol is used, age, activated P-gp, and CD34 expression are independent prognostic factors in AML patients. A test system which determines a functional P-gp overexpression is a major tool for identifying a group of AML patients with a poor prognosis. In order to effectively use so-called P-gp modulator substances, the degree of P-gp expression, the activated or nonactivated P-gp condition, and detection of non-P-gp-related resistance mechanisms are of utmost interest for optimal design and analysis of P-gp modulator trials and for understanding the complexity of chemotherapy-related resistance mechanisms in patients.