Pharmacokinetics of high-dose cyclophosphamide for bone marrow transplantation.

BACKGROUND: Despite the fact that high-dose cyclophosphamide (CP) is currently used for both cancer treatment and bone marrow transplantation, its pharmacokinetics is not well defined. METHODS: Serum and urine concentrations of CP were determined in 19 patients who received 2 or more high doses of CP before bone marrow transplantation. RESULTS: Urinary recovery ranged between 1% and 32% and was essentially the same after the first and the second CP dose. In contrast, the pattern of disappearance from the serum of the two doses of CP was substantially different. The serum half-life of the first dose varied over a wide range (4.4 to 25.0 h, mean 8.7 +/- 4.6 h), while the half-life of the second dose was always shorter (1.7 to 6.0 h, mean 3.6 +/- 0.9 h). Accordingly, the CP area under the curve (AUC) of the first dose was much more variable and was always much higher than the CP AUC of the second dose. Therefore, prior administration of CP resulted in a very significant increase of CP metabolism. CONCLUSIONS: These differences can be relevant to the outcome of treatment, and suggest that the metabolism of CP can be manipulated and can be made more homogeneous, either by giving a priming dose of CP (leading to a lower CP AUC, to a faster conversion into activated metabolites and to the exposure of host cells to a higher concentration of the metabolites for a shorter time) or by giving the drug as a continuous infusion over a longer time, to obtain the opposite results.

Evidence for increased intracellular transport of m-sarcolysine (alkylating moiety) when combined with two amino acid analogs (PTT-119).

PTT-119 is an antineoplastic agent in which an alkylating moiety, m-sarcolysine, is linked to two amino acid analogs. Previous studies showed a higher "in vitro" cytotoxicity of PTT-119 when compared to free m-sarcolysine; the mechanisms of this enhanced activity are not completely understood. In this study we incubated peripheral blood cells from 8 chronic lymphocytic leukemia patients with both m-sarcolysine and equimolar concentrations of PTT-119, measuring the intracellular concentration of the alkylating moiety. We observed a significantly higher intracellular concentration of m-sarcolysine in cells incubated with the peptide-bound drug than with the free drug (58.3 +/- 39.6 versus 4.4 +/- 1.9 ng/10(6) cells; P = 0.013). This observation could explain the higher cytotoxic activity of PTT-119 and the lack of cross-resistance with melphalan.

An unusual case of Candida tropicalis sepsis in a patient submitted to allogeneic bone marrow transplantation.

We describe an exceptional case of Candida tropicalis sepsis in a patient submitted to allogeneic BMT; the diagnosis was made on a peripheral blood smear, when the pt was neutropenic and only mildly febrile. The combination of GM-CSF to accelerate hematological recovery and the possibility of administering large doses of a liposomal form of Amphotericin B were the contributing factors to the resolution of the infection.

Sensitivity of chronic myeloid leukemia hemopoietic progenitors to PTT-119 in combination with human recombinant interferon alpha and gamma.

PTT-119, a new synthetic alkylating compound, has shown a marked "in vitro" inhibitory effect on chronic myeloid leukemia (CML) granulo-monocytic precursors (CFU-GM) at doses greater than 5 micrograms/ml. Based on previous experiences of synergistic associations between alkylating drugs and biological modifiers, we tested the effects of low doses of PTT-119 (from 0.1 to 1 microgram/ml) in concert with alpha, gamma, or alpha + gamma interferons and compared to IFNs alone, in order to investigate an alternative choice for treatment of CML patients in chronic phase. Our results showed a significantly higher CFU-GM cloning inhibition after addition of 100 or 1,000 U/ml of alpha IFN to 0.1 microgram/ml PTT-119 (from 39.6% +/- 26.6 SD to 80.7% +/- 10 SD and 91.5% +/- 8 SD, respectively), while gamma IFN resulted in only a slight increase in colony growth inhibition when compared to the drug used alone. The association of alpha plus gamma IFN coupled with PTT-119 treatment did not significantly improve the results observed after exposure of leukemic progenitors to PTT-119 and alpha IFN alone. We conclude that a combined treatment with PTT-119 and IFN is probably worth testing both for purging methods before autologous bone marrow transplantation and for in vivo administration in chronic myeloid leukemia.

Cryopreserved autologous bone marrow transplantation in patients with acute nonlymphoid leukemia: chemotherapy before harvesting is the main factor in delaying hematological recovery.

We analyzed the kinetics of hematological recovery after autologous bone marrow transplantation in 13 patients with acute nonlymphoid leukemias (ANLL). A comparison was made with 31 patients with non-Hodgkin's lymphoma (NHL) whose bone marrow was harvested and cryopreserved, either at diagnosis or after intensive chemotherapy. Hematological recovery of ANLL patients was similar to that of pretreated NHL patients and significantly slower than that of untreated NHL patients. We suggest that chemotherapy before harvest (more than the possible decreased stem cell marrow potentiality resulting from the underlying disease) appears to be the main factor responsible for delayed recovery after autologous bone marrow transplantation in ANLL.

Systemic broad-spectrum antimicrobial prophylaxis in hematological patients after intensive antineoplastic chemotherapy.

We performed a pilot study on 13 heavily treated hematologic patients, in whom a systemic broad-spectrum antimicrobial prophylaxis was started after the end of the antineoplastic treatment. Results were compared to a historical control group of patients with similar characteristics, in whom antibody were started at the appearance of fever. We observed a remarkable reduction in infectious fevers (1 versus 7, p = 0.03) and a disappearance of bacterial sepsis (0 versus 7, p = 0.005). The length of treatment was longer (18.6 versus 12.0 days, p = 0.06); no side effects were seen. We conclude that this seems to be a promising and safe approach, whose role in the management of selected neutropenic patients could be evaluated with further, wider studies.

Phase II study of bisantrene in relapsed/refractory acute non lymphoid leukemias (ANLL).

The antileukemic activity of Bisantrene, a new anthracene derivative, has been evaluated in a phase II clinical study in 10 patients affected by refractory or primary relapsed ANLL. The patients received an induction course consisting of 250 mg/m2/day for 7 days followed, in case of CR, by 250 mg/m2/day for 3 days (consolidation treatment). In case of partial response a reinduction course (250 mg/m2/day for 3 days) was administered. Four out of the 10 patients obtained CR (3 of them after a single induction course). No significant toxic effect was noticed, apart from fever (due to myelosuppression) and hypotension in one patient who soon recovered without residual effects. These preliminary results could suggest further evaluation of Bisantrene in association with other drugs in both relapsed patients and those at onset of the disease.

Autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma: comparison of different parameters in predicting the kinetics of haematological recovery.

We analysed the kinetics of haematological recovery after autologous bone marrow transplantation (ABMT) in 31 patients with non-Hodgkin's lymphoma, of whom 14 had received chemotherapy and 17 had received no chemotherapy before marrow harvesting. The time for recovery of polymorph (PMN) and platelet numbers was assessed in relation to patient's sex, age, the numbers of mononuclear cells (MNC) and of granulocyte-macrophage colony-forming cells (CFU-GM) reinfused, the therapy before harvesting and the conditioning regimens. The results showed that the most important factor influencing the speed of haematological recovery was therapy before marrow collection; recovery was faster in patients not treated before harvesting than in those treated. The mean day for PMN recovery to 0.5 x 10(9)/l was 14.6 vs 21.8 (p less than 0.001); the mean day for platelet recovery to 50 x 10(9)/l was 16.5 vs 44.4 (p less than 0.00002). The other parameters assessed did not correlate with the kinetics of haemopoietic recovery. We conclude that NHL patients who undergo ABMT without chemotherapy prior to marrow harvest have rapid haematological recovery, which suggests that better timing of the harvest could be of value in the management of NHL patients for whom 'reinforcement' with ABMT is scheduled.

Hodgkin's disease (HD): a historical perspective.

Five hundred and seven patients with Hodgkin's lymphoma (HL), forming the basis of our 18 years experience, are retrospectively analyzed. Four therapeutic periods are recognizable: The 1966-1970 period was characterized by the absence of treatment and management policy. The 55 patients entered in this period experienced 70 and 56% survival at 5 and 10 yr, respectively, from diagnosis. The 1971-1974 period was characterized by the increasing knowledge of staging relevance and therapeutic approaches. The 153 patients who were treated in this period experienced 72 and 60% survival at 5 and 10 yr, respectively. The 1975-1980 period was characterized by a large combination of MOPP and radiotherapy. The 216 patients who entered this period observed 80 and 72.5% survival at 5 and 10 yr, respectively. The last therapeutic period (1980 to present time) is characterized by the increasing relevance of prognostic factors and alternating use of MOPP and ABVD as non-cross resistant regimen. The 83 patients who entered this period showed 90% survival at 5 yr. Both survival and disease-free survival were positively influenced by the change of therapeutic strategies during the four periods (P less than 0.005). Although better results have been recorded moving from one to the next therapeutic period, the present policy has been also based on the recognition of a high number of late complications due to the therapy. Preliminary results about the present therapeutic experience seem to indicate both a good remission rate and low incidence of complications.