Low Dose Arabinosyl Cytosine Research Articles

Long‐term experience with imatinib therapy in chronic phase chronic myelogenous leukemia—Remarkable activity with room for improvement

Long‐term experience with imatinib therapy in chronic phase chronic myelogenous leukemia—Remarkable activity with room for improvement

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Treatment modalities in hematology: Imatinib mesylate as therapy for chronic myeloid leukemia

Imatinib mesylate (GlivecR/GleevecR) represents a truly new concept in the treatment of chronic myeloid leukemia (CML) and a breakthrough in the therapy of hematological malignancies in general. It blocks the CML specific tyrosine kinase BCR-ABL. This fusion gene product of the BCR-ABL t(9;22) translocation represents the hallmark of the disease, is constitutively activated and thereby directly involved in the pathological regulation of cell growth. Imatinib is a potent and selective inhibitor in vitro. In phase I and II studies it induced durable hematological responses in more than 90% of all patients with chronic phase CML and in a large proportion of patients even in advanced disease with remarkably few side effects. In a prospective randomised phase III study it was compared in 1,106 patients with newly diagnosed patients with CML to the standard approach for CML, interferon-a combined with low-dose arabinosyl cytosine. At median follow up of 14 months, 84% of patients with imatinib showed a major cytogenetic response (68% complete) compared to 30% (7% complete) in the control arm. Survival rate at 12 months without progression to accelerated phase or blast crisis was 98.5% compared to 93.1% in the control arm (P=0.001). Tolerance to imatinib was significantly better than the interferon based regimen with nausea and fluid retention as main side effects in the imatinib arm. This study illustrates the superiority of imatinib in inducing hematological and cytogenetic remissions, in tolerability and in preventing progression to advanced phase compared to previous therapy. It can be considered as initial treatment for newly diagnosed CML patients. Imatinib sets the standard for future specific tumor therapies to come. *** DIRECT SUPPORT *** A00RC002 00003

Vitamin D<sub>3</sub> Administration and Multidrug Resistance in Acute Nonlymphoblastic Leukemia

This article reports preliminary results from a pilot study started in 1986 on patients with acute myeloblastic leukemia treated for several months with low-dose arabinosylcytosine and 1(OH)D3. During treatment or at the time of relapse, a monoblastic component was frequently found. A high percentage of patients were P-170-positive. In 2 patients it was possible to show that blasts, previously P-170-negative, became positive after treatment. In these 2 patients, failure of clinical response to antileukemic therapy was associated with this phenotype. The addition of the revertant drug nicardipine to the previously inactive treatment induced a partial response. Thus, previously reported in vitro observations on the differentiating activity of vitamin D3 metabolites, possible induction of multidrug chemoresistance by differentiating agents and the revertant activity of the Ca++ antagonist nicardipine appear to be confirmed in vivo in the reported patients.

Cell kinetic effect of low dose arabinosyl cytosine.

Low dose arabinosyl cytosine (ARA-C) is effective for treatment of acute non-lymphocytic leukaemia (ANLL). The mechanism of action is not clearly understood and it was suggested that low doses of the drug could induce leukaemic cells to differentiate. We investigated the effect of low dose ARA-C (20 mg/m2/d, divided into two doses s.c. at 12 h intervals, x 20 d) on the cell cycle distribution of leukaemic cells in four cases of ANLL. By comparison, four other cases of ANLL were studied during treatment with standard dose ARA-C (200 mg/m2/d as a continuous i.v. infusion x 7 d). Both treatments induced an accumulation of leukaemic cells in post G1 phases, at a variable extent and rate. During treatment by low dose ARA-C, the mitotic index (MI) fell slowly to zero in two patients who achieved a complete remission (CR), while it fell but recovered during treatment in the patients who did not achieve a CR. The MI fell rapidly to zero in the four cases treated by standard dose, who achieved a CR. These data are consistent with the known cytotoxic activity of ARA-C, via inhibition and slowing of DNA synthesis leading to defective cell proliferation and to cell death.

In vitro exposure of leukemic cells to low concentration Arabinosyl Cytosine: no evidence of differentiation inducing activity.

Low dose Arabinosyl Cytosine (LD ARA-C) is widely used for treatment of acute non-lymphocytic leukemia (ANLL) and myelodysplastic syndrome (MDS) in the elderly, based on a favorable response rate and on the hypothesis that LD ARA-C can induce differentiation or maturation of leukemic cells. We investigated the effect of low concentration of ARA-C on the growth of marrow cells that were obtained from 6 cases of MDS and from 11 cases of ANLL by using the in vitro culture system for normal granulo-monocyte precursors (CFU-GM). At ARA-C concentrations equal to or higher than 1 ng/ml cell growth was inhibited in a dose-dependent manner. At ARA-C concentration of 0.1 ng/ml cell growth was slightly affected, but colony number and colony cell composition were identical to control cultures. This experiment did not support the hypothesis that ARA-C can induce leukemic cells to recover any normal growth patterns but confirmed that even very low ARA-C concentrations can inhibit or slow down leukemic cell proliferation.

Low-dose Ara-C can cause complete remission of acute non-lymphocytic leukemia: Differentiation induction?

Fourteen patients with acute nonlymphocytic leukemia were treated with low-dose arabinosylcytosine (LDAC). Thirteen patients received subcutaneous injections at a dose of 10 mg/M 2 every 12 h. One patient received 25 mg intramuscularly daily. All cases received one to three courses with each course lasting 10–60 days (median 19). Complete remission was achieved in 6 (or 43%) of the patients. Three patients had only cytoreduction and 5 patients did not respond. During the therapy severe thrombocytopenia occurred in all patients while prominent other cytopenias occurred in 10. Two-thirds of the patients achieving a remission had significant myelosuppression. There was one treatment-related death. During therapy 11 patients demonstrated a decrease in leukemia cells with an associated increase in differentiated granulocytes. This included 3 of the 4 complete remitters, and 3 of the 5 nonresponders. These results seem to suggest that the therapeutic effect of low-dose Ara-C may result from a combination of differentiation induction, cytotoxicity and unusual sensitivity of the leukemic cells to this agent.

Low-dose arabinosyl cytosine in acute leukemia after a myelodysplastic syndrome and in elderly leukemia.

Low-dose arabinosyl cytosine (ARA-C) was tested in 15 patients with acute leukemia after a myelodysplastic syndrome (MDS) and in six elderly patients with acute nonlymphoid leukemia (ANLL). The drug was given subcutaneously at 10 mg/m2, every 12 hr for 2 weeks, every 28 days. The overall response rate was 19% (one complete remission, three partial responses), and the median duration of response was 4 months. No particular features at diagnosis were predictive of response. Pancytopenia and marrow hypoplasia occurred after 44 (78%) of 56 courses of therapy and were more severe in nonresponders. Four patients died during the aplasia following ARA-C therapy. Subcutaneous low-dose ARA-C was of limited benefit and bore a noticeable hematologic toxicity.

Treatment of acute myeloid leukemia developing after a myelodysplastic phase with low dose arabinosyl cytosine

Patients with acute myeloid leukemia (AML) secondary to myelodysplastic phase respond poorly to standard chemotherapy designed for AML. As arabinosyl cytosine (Ara-C) at low-dose has been reported to achieve promising results in certain forms of AML, we have applied the low-dose (10 mg m −2/12h subcutaneously for 14–24 days) regimen in 11 patients with AML secondary to myelodysplastic syndromes. Though a complete remission could be achieved in 2 patients and a short partial remission in 2 further patients, complications are severe and often life threatening. The amount of hematological supportive care required often exceeded that needed for patients treated by conventional TAD regimen. Moreover, survival of the responders did not seem to be longer than that of non-responders. A review of the literature showed that the results of this low-dose Ara-C regimen might be more promising in patients in the myelodysplastic phase and in those with de novo acute leukemia.

Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia

Several agents, including arabinosyl cytosine (ARA-C) at a low concentration, can induce leukemic myeloblasts to mature to a variable extent. The therapeutic implications of this observation are worth investigating. A few case-reports have shown that low dose ARA-C can be useful for treatment of the myelodysplastic syndromes (MDS) and of acute myeloid leukemia (AML). However, no information is available yet on the proportion of patients who can be expected to respond. We treated by low dose ARA-C (20–30 mg/sqm/day i.v. or i.m. for 7–10 days) 20 consecutive patients. A complete remission of 5 months was obtained in one of nine cases of subacute myeloid leukemia (SAML). A partial remission (complete normalization of blood counts with a slight excess of marrow blast cells) was obtained twice in one of 11 cases of MDS. An increase of Hb level (more than 11.5 g/dl) was obtained and maintained for 12 months in a case of MDS. A short-lasting increase of granulocyte count was obtained in another two cases of MDS and SAML respectively. It is suggested that low dose ARA-C can advantageously modify the proliferation to maturation imbalance of leukemic cells by slowing down cell proliferation rate. However, the proportion of patients who respond is probably low. This treatment is at a very early experimental stage and should be probably limited to selected cases of MDS and subacute or acute myeloid leukemia.