Fludarabine and cytosine-arabinoside for poor-risk acute myeloid leukemia.

Thirteen relapsed or refractory AML patients were treated with the FLA regimen. A complete remission was observed in 54% of cases but the median duration of remission was short (4 months). These results suggest that the FLA regimen is not able to induce a durable complete remission in the poor-risk AML patients.

All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase.

Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously.

Time-Dependent Kinetics of Tretinoin in Chronic Myelogenous Leukaemia during Intermittent Dose Scheduling: 1 Week On/1 Week Off.

OBJECTIVE: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with Ph1+ chronic myelogenous leukaemia (CML) in the chronic phase. PATIENTS: Eighteen patients with CML were treated with tretinoin 80 mg/m(2)/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). RESULTS: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean +/- SD) 678.3 +/- 498.1 to 258.7 +/- 272.4 microg/L.h. In about 40% of the patients the decline in plasma concentrations was >/=80%, while 17% of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15%) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62% of patients showed an increase in the AUC, which was 40% higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C(max)) was strongly correlated to the corresponding AUC. No significant change in the time to observed C(max) (t(max)) and in the elimination half-life (t((1/2))) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the noninduced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. CONCLUSION: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable.

Clinical experience of antibodies to interferon-alpha during treatment of chronic myeloid leukemia.

Interferon-alpha (IFN-alpha) remains the only viable alternative to bone marrow transplantation for patients with chronic myeloid leukemia (CML) and is the treatment of choice in many circumstances. IFN-alpha can induce hematologic remissions in most patients with CML and suppresses the Philadelphia chromosome-positive cell clone in 30%-40% of hematologically responsive patients. IFN-alpha can also prolong the length of the chronic disease phase and survival time in patients who achieve a karyotypic response. A third of patients, however, never respond to IFN-alpha, and a proportion of the initial responders will later become resistant. It has been suggested that the induction of anti-IFN-alpha antibodies might be one of the reasons for resistance to IFN-alpha. It is difficult to evaluate the factors that influence antibody induction and the effects of these antibodies on clinical results. The source of IFN-alpha product, trial design, and differences in the sensitivity of the assays used to measure antibodies are all factors that need to be considered.

Response to sequential treatment with lymphoblastoid interferon-alpha in patients with Ph+ chronic myeloid leukemia unresponsive to recombinant interferon-alpha (rIFN alpha 2a) and neutralizing-rIFN alpha 2a antibodies negative.

Nine Ph+ CML patients in chronic phase who were hematologically and/or karyotypically unresponsive to recombinant-IFN alpha 2a (rIFN alpha 2a) and neutralizing-rIFN alpha 2a Abs negative were shifted from rIFN alpha 2a to lymphoblastoid-IFN alpha (IFN alpha-Ly) therapy. After 3 months of IFNa-Ly treatment, the hematologic response was reinduced in 3 out of the 6 pts who were resistant to previous rIFN alpha 2a therapy, and was maintained in 2 out of 3 patients who were hematologically but not karyotypically responsive to rIFN alpha 2a. After 6 and 12 months, the hematologic response was progressively lost, being present only in 3 out of 7 and in 2 out of 3 evaluable patients respectively. None of the hematologically responsive patients achieved a karyotypic response (Ph neg. metaphases-0%). One patient, who was hematologically responsive, continued being treated with IFN alpha-ly for 36 months but he did not achieve any karyotypic response. The results of this study suggest that in the unresponsive and neutralizing-rIFN alpha 2a Abs negative CML patients a change in therapy, by using a non cross-reactive type of IFN alpha, would not be advantageous.