Roquinimex (Linomide) vs placebo in AML after autologous bone marrow transplantation.

Roquinimex, Linomide, a quinoline derivative with pleiotropic immunomodulatory activity, has previously been shown to enhance natural killer (NK) cell number and activity after ABMT in patients with AML. In this study 278 AML patients in remission were randomized to receive Roquinimex 0.2 mg/kg body weight or placebo twice weekly for 2 years following ABMT. Out of 139 patients in each group, 109 Roquinimex patients and 108 placebo patients were in their first CR. Median age at inclusion was 41 years for Roquinimex patients and 39 years for placebo patients. Twelve patients in each group had their marrow purged prior to reinfusion. Relapse and death were study endpoints. Surviving patients were followed for 2.6 to 6. 9 years. The total number of relapses was 60 in the Roquinimex group and 63 in the placebo group (not significant). Leukemia-free and overall survivals were similar in the two groups. Recovery of platelet counts was significantly delayed in the Roquinimex group as compared to placebo. No other significant differences regarding toxicity parameters were recorded. In conclusion, previous findings on NK cells could not be confirmed and the study showed no benefit for Roquinimex over placebo regarding relapse or survival following ABMT for AML in remission.

Treatment of chronic myelogenous leukemia with autologous bone marrow transplantation followed by roquinimex.

Unmanipulated autologous bone marrow transplant (ABMT) offers patients with chronic myelogenous leukemia (CML) a long-term survival of 10%, at best. Immunotherapy has a role in the myeloid leukemias, and there is increasing evidence that of all hematopoietic neoplasms, CML may be the most susceptible to immune regulation. Roquinimex is known to enhance T cell, NK cell and macrophage activity. A phase II study was initiated in March 1992 to evaluate the role of roquinimex in Ph chromosome-positive CML post ABMT. Patients were conditioned with busulfan/ cyclophosphamide followed by reinfusion of unmanipulated Ph-positive bone marrow stem cells (>1 x 108 NBC/kg). When engraftment of neutrophils (ANC) reached 100/microl, patients received oral roquinimex twice weekly, escalating to a maximal dose of 0.2 mg/kg in 2 weeks. Seventeen patients have entered the study; 11 in first chronic phase (CP1); two in second chronic phase (CP2) and four in accelerated phase (AP). All required significant myelosuppressive therapy prior to ABMT to maintain stable blood counts and most had also received prior interferon therapy. All patients survived the transplant. Subsequent toxicity consisted mainly of musculoskeletal aches and peripheral edema. Additionally, specific skin changes were observed including graft-versus-host-like disease and eccrine sweat gland necrosis. Eight out of 17 patients are alive 28-60 months post ABMT. Of the nine patients who died, two were in CP2 and three in AP. All patients in CP1 went into a complete hematological remission post ABMT and seven of the 11 patients had at least a major cytogenetic response (greater than 65% Ph-negative metaphases) at 1 year or beyond and four of the 11 patients had a complete cytogenetic response at 2 years or beyond. Cytogenetic response post transplant often developed over time and did not simply represent post ABMT engraftment with Ph-negative cells. The clinical and cytogenetic data in these patients are encouraging and suggest that roquinimex may have significant activity when given post ABMT to patients with Ph-positive CML.

The first clinical pilot study of roquinimex (Linomide) in cancer patients with special focus on immunological effects.

Roquinimex (Linomide) has been demonstrated to suppress tumor growth in animal models. The effect is at least in part related to enhanced numbers and activity of natural killer (NK) cells. In this clinical pilot study, roquinimex was given at increasing doses (0.05 mg/kg to 0.6 mg/kg) to 13 patients (performance status 0-3) with various malignant disorders. Immunology parameters were followed and side effects were observed during the study. The plasma pharmacokinetics of roquinimex was studied at the 0.2 mg/kg dose level. The clinical side effects were dominated by musculoskeletal discomfort, nausea, and pain. No significant hematological or biochemical toxicity was observed. Pharmacokinetic analysis at the 0.2 mg/kg dose level revealed a Cmax of 4.0 mumol/L at tmax of 1.2 hr and an elimination half-life of 42 hr. Increased numbers of phenotypic NK cells, activated T (DR+CD4+) cells, and monocytes were observed after administration of roquinimex compared with pretreatment values. Roquinimex seems to be an active immunomodulator with manageable toxicity. Further exploration of therapeutic efficacy is warranted.

Leucocyte doubling time is a useful predictor of progression-free survival in chronic lymphocytic leukaemia.

OBJECTIVE: To assess leucocyte doubling time (LDT) in relation to progression-free survival in patients with chronic lymphocytic leukaemia (CLL). In addition, to define the impact of a second LDT in both untreated and treated patients. DESIGN: Retrospective study of LDT in previously untreated patients with CLL. SUBJECTS AND SETTING: Sixty patients diagnosed over a 13-year period at a county hospital. In forty-five of the 60 patients, an LDT could be defined. These patients were included in the final analysis. MAIN OUTCOME MEASURES: LDT below and above 12 months, progression-free and overall survival. RESULTS: Patients in Binet stages B and C had a median LDT of 4 months as compared to 26 months in stage A patients (P < 0.01). The projected progression-free survival at 3 years was 24% in patients with an LDT of < 12 months. The corresponding figure for the remaining patients was 68% (P < 0.01). The overall 5-year survival did not differ significantly between patients with an LDT below and above 12 months, respectively. In seven untreated patients, a second LDT could be calculated which was shorter than the first recorded LDT. A second LDT was also identified in five patients post treatment that was consistently shorter than their first LDT. CONCLUSIONS: Measurement of LDT is a simple complement in predicting progression-free survival in patients with CLL. Thus, monitoring of LDT may add to the clinical evaluation and therapeutic decision making for the many elderly patients with this often indolent disease.

Treatment of minimal residual disease in myeloid leukemia--the immunotherapeutic options with emphasis on Linomide.

It is now known that syngeneic transplantation, T lymphocyte depletion and absence of graft-versus-host disease all increase the risk of relapse following allogeneic transplantation for the myeloid leukemias, both acute and chronic. Leukemia-specific immune responses appear to play a major role in the therapy of the myeloid leukemias. In recent years attempts have been made to better characterize and effectively utilize these antileukemic immune responses, concentrating on clinical states of minimal residual disease. This review will discuss the role of such immunotherapy following autologous bone marrow transplantation for myeloid leukemias, and will focus on recent experience and ongoing clinical trials using the novel immunomodulator Linomide.

Relationship between interdigestive gallbladder emptying, plasma motilin and migrating motor complex in man.

The aim of this study was to elucidate the importance of biliary output for the regulation of migrating motor complex and the release of plasma motilin. Gallbladder emptying was monitored by hepatobiliary scintigraphy, plasma motilin concentration by radioimmunoassay and gastrointestinal motility by a perfused catheter system. During a total recording time of 46 h and 20 min in 16 volunteers, we observed 29 episodes of gallbladder emptying, 27 plasma motilin peaks and 23 activity fronts (phase 3 activity) of the migrating motor complex (MMC). Twelve episodes of gallbladder emptying started in phase 1 and continued into phase 2 of the MMC. The remaining 17 episodes of gallbladder emptying started in phase 2, and three of these continued into phase 3 of the MMC. Biliary output was associated with a significant rise in plasma motilin concentration, whereas plasma motilin significantly decreased after the activity fronts. These observations may explain the well-known fluctuations of plasma motilin concentration in the fasted state. Motilin is released into the circulation as a result of biliary output, while the ensuing activity front of the MMC removes this stimulant from the proximal small bowel, resulting in a fall in plasma motilin. In conclusion, we have confirmed a temporal relationship between biliary output into the duodenum and the release of plasma motilin. The observed transition from phase 1 to phase 2 and from phase 2 to phase 3 of the MMC during gallbladder emptying episodes suggests that biliary output stimulates gastrointestinal motility in the fasted state.

Phase I study in malignancy of LS 2616, a new immunomodulator: methodological considerations.

LS 2616 (Linomide) is a new immunomodulator that enhances natural killer (NK)-cell activity, delayed-type hypersensitivity reaction, mitogen responsiveness of T cells, and antibody production. It suppresses tumor growth and reduces metastases in animal experiments. In a phase I clinical trial, the maximal tolerated dose will not necessarily be the maximally effective dose, so both effect and toxicity parameters have to be monitored. Because of the pleiotropic function of the drug, several biological responses have to be analyzed. Furthermore, different malignancies are associated with different immunologic disturbances both qualitatively and quantitatively, necessitating the use of normal controls and baseline assessments as well as a range of different malignancies. The pharmacokinetic features will differ from the kinetics of the biological responses, and thus both drug concentration and effect parameters will be followed over time. Repeated doses will give information needed for tailoring of optimal schedules for administration.