Based on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol).

Summary:Although several studies have demonstrated the efficacy of large volume leukapheresis (LVL) to yield high numbers of peripheral blood progenitor cells (PBPC), the mechanisms of stem cell release into circulation and the postulated phenomenon of PBPC recruitment during apheresis have not been investigated in detail. Therefore, we analyzed the kinetics of stem cell enrichment in a total of 34 standardized LVL for patients with hematologic malignancies (lymphoma, multiple myeloma) and solid tumors (breast cancer, rhabdomyosarcoma). LVL was started 2 h after administration of G-CSF processing six times the patient's blood volume. Cells were sequentially collected into six bags and the numbers of leukocytes, mononuclear cells (MNC), CD34 ؉ cells and colony-forming cells (CFU-GM) in each collection bag were analyzed. The numbers of PBPC collected demonstrated a continuous decrease starting after an early maximum during the second processed blood volume (P ‫؍‬ 0.001). Interestingly, these kinetics of decreasing stem cell yields during LVL were similar for both entities of patients with hematologic malignancies as well as for both groups of patients with solid tumors. In summary, a recruitment phenomenon, defined as a timedependent and LVL-induced increase of PBPC, could not be demonstrated in any of the diseases investigated. Bone Marrow Transplantation (2001) 28, 13-20.

Background: Titanocene dichloride (TD) is an organometallic compound with antiproliferative properties in vitro and promising antitumor activity in preclinical in vivo models. The drug interferes with DNA, blocks the S/G₂ phase of the cell cycle and shows antiangiogenic properties. The purpose of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a ‘split’ dose administration schedule (days 1, 3, 5 q 3 weeks). Patients and Method: Patients with progressive advanced cancer and a creatinine clearance > 60 ml/min qualified for a treatment with TD after standard therapies (radio-, chemo-, hormone therapy) failed. A total of 10 patients (4 females, 6 males) with a median age of 58 (range 49–68) years were treated with 80 mg/m² TD at days 1, 3 and 5 (repeated at day 22). The drug was administered as light-protected infusion within 1 h. Results: Significant side effects were as follows: nausea/vomiting, appetite loss, renal toxicity (elevation of serum creatinine and proteinuria) and liver toxicity (bilirubin and alkaline phosphatase elevation), but no myelosuppression. At the starting dose (3 x 80 = 240 mg/m² TD), renal (3 patients) or liver toxicity (1 patient) of grade 3 was judged as DLT. No further dose escalation was possible. No objective tumor remission was observed. Conclusion: The tolerability of TD cannot be improved by splitting the total dose in to three treatments every other day. Compared to previous phase I data using a 3-weekly and a 1-weekly schedule, the ‘split’ dose administration allowed no further increase of the total drug dose per treatment cycle. Thus, dose intensification by alterations of the application mode does not seem to be possible.

From July 1983 to January 1991 a total of 622 patients were randomized (585 eligible) to compare the effects of hydroxyurea, interferon alpha (IFN), and busulfan on the duration of chronic phase, and survival. Further goals included the determination of prognostic parameters. 598 CML patients were documented and 575 evaluable. The Ph-status was known for 547 patients. 89.4% of the patients were Ph-positive (+). 11% had additional chromosome aberrations. The median survival of Ph+ patients by now is 4.2 years, that of Ph-patients 1.4 years. Ph-negative patients are older, tend to have lower cell counts and, as a group are more ill at diagnosis. A survival difference of about one year is expected between busulfan and hydroxyurea treated patients. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, number of erythroblasts and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined which was superior to Sokal's score in the study population. 164 patients were randomized to receive IFN. In 54 patients (33%) IFN had to be terminated because of adverse effects, therapy resistance or other reasons. Clinically relevant neutralizing antibodies were detected in 9 cases. Most frequent adverse events were flu-like symptoms in 74%, gastrointestinal symptoms in 52%, and neurologic-psychiatric symptoms in 30% of patients. Reduction of the Ph-chromosome was observed in 13% of evaluable patients (10 of 75). In 4 patients complete cytogenetic remissions were observed, in three of these ongoing. Cytogenetic responders have a survival advantage. Interferon treated Philadelphia-negative CML patients have no survival disadvantage. The study is expected to allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.

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