Low-dose Ara-C Therapy Research Articles

Low-dose cytosine arabinoside-induced syptomatic bradycardia in a patient with acute myeloid leukemia

Cytosine arabinoside (Ara-C) is one of the critical agents for the treatment of acute myeloid leukemia (AML). The toxicity profile of Ara-C is highly dependent on the dose and schedule of administration. Cardiologic complications associated with Ara-C are rare. These side effects were reported with high doses of cytarabine (1–3g/m2, 6–12 doses) in the literature. Herein, we report a patient who developed symptomatic sinus bradycardia while receiving low-dose Ara-C therapy for AML. A 45-year-old female patient diagnosed with AML was treated with standard remission induction chemotherapy protocol that includes 3 days of anthracycline and 7 days of low-dose (100–200mg/m2 2–1) Ara-C. The same chemotherapy regimen was applied again on the 15th day of admission. During the second chemotherapy cycle, the patient developed symptomatic sinus bradycardia. All causes except Ara-C were excluded after required investigational procedures. Ara-C infusion was discontinued for a while and after her symptoms passed chemotherapy was completed with atropine support. Cardiac toxicity is scarce with Ara-C. We want to remind that clinicians should be aware of this potential toxic manifestation even in low doses of the medication, especially as Ara-C is widely used in the treatment of leukemia.<Learning objective: Cytosine arabinoside is one of the historic chemotherapeutics in hematology. It was widely used to treat many types of hematological malignancies in high doses and is commonly available in worldwide markets. Symptomatic sinus bradycardia is a rare type of cardiologic side effect, but it should be kept in mind during chemotherapy.>

Acute leukemic appendicitis

A 68-year-old woman was admitted to our hospital for the evaluation of right lower quadrant pain and constipation for 4 days. She had cytogenetic remission of acute myeloid leukemia (AML) with initial del 7(q22q32), diagnosed in April 2011 after the induction chemotherapy with idarubicin and Ara-C, and consolidation therapy with high-dose Ara-C and mitoxantrone. However, follow-up of peripheral blood smear and bone marrow cytology showed increased amounts of leukemic blasts, at around 5–7 %, without abnormal cytogenetics in January 2012. We believed that this suggested an early relapse of intramedullary or extramedullary origin. As she was ineligible for bone marrow transplantation and could not tolerate intensive chemotherapy again, low-dose Ara-C therapy was given in March 2012. No more increased leukemic blasts in peripheral blood smear were noted. However, she suffered from progressive abdominal pain and constipation during follow-up in June 2012. Physical examination showed right lower quadrant tenderness at McBurney’s point, with rebounding pain and muscle guarding. A full blood cell count showed a leukocyte count of 1.43 9 10/L with 28.4 % neutrophils, 63.5 % lymphocytes, 7.3 % monocytes, 0.3 % eosinophils, and 0.5 % basophils, a hemoglobin concentration of 87 g/L, and platelet count

Low-Dose Cytosine Arabinoside Therapy for Neonates with Down Syndrome (DS) and Transient Leukemia (TL).

AbstractAbstract 1074 Introduction:Transient leukemia (TL), which is also referred to as transient myeloproliferative disorder or transient abnormal myelopoiesis, occurs in approximately 10% of infants with Down syndrome (DS). This disorder is characterized by the appearance of blast cells with megakaryoblastic and/or erythroblastic characteristics in the peripheral blood. While most TL patients have a favorable clinical course and the blast cells disappear spontaneously, vital organ failure and early death occurs in some patients. In this group of patients, liver failure with hepatic fibrosis and cardiopulmonary failure are the major causes of death. Recently, low-dose cytosine arabinoside (Ara-C) therapy has been reported to be effective for improving the clinical outcome in TL patients with severe liver or cardiopulmonary disease. However, because the disease resolves spontaneously in most instances, it is not generally recommended that all patients receive antileukemic therapy. It is unknown whether the survival rate of certain TL patients could be improved by low-dose Ara-C. This study was conducted to clarify the safety and efficacy of low-dose Ara-C therapy for TL patients with DS. Patients and Methods:A retrospective questionnaire survey of patients diagnosed with DS between 2003 and 2009 was conducted to identify all DS neonates with TL. The eligibility criteria for the analysis were infants with DS who were younger than 3 months and had circulating blast cells in the peripheral blood. A total of 153 patients (81 male, 72 female) were identified. Results:Thirty-four of the 153 patients (22%) died. Early death occurred in 31 of 153 patients (20%); the median age at death was 47 days (range, 9–241 days). The covariates that were significantly correlated with early death were examined further. On univariate analysis, the following covariates were identified: early estimated gestational age, WBC ≥ 100 × 109/L, severe bleeding, and anasarca. On multivariate analysis, it was confirmed that WBC ≥ 100 × 109/L and anasarca were independent risk factors for early death. Twenty of the 121 patients (16.5%) who survived for more than 9 months after birth subsequently developed acute myeloid leukemia at a median age of 16 months (range, 3–45 months). All 21 patients were diagnosed as having acute megakaryoblastic leukemia (AMKL) and received low intensity chemotherapy specific for AMKL in DS patients. Eighteen of 21 (86%) patients achieved a complete remission, and they are alive and well; whereas 3 patients who had refractory or relapsed leukemia died.Twenty-eight of the 153 patients (18%) received low-dose Ara-C therapy. The median dose and duration of Ara-C were 0.95 mg/kg/day (range, 0.4–3.1 mg/kg/day) and 7 days (range, 2–15 days), respectively. The median duration of neutropenia (<0.5 × 109/L) was 0 days (range, 0–14 days). All patients recovered from myelosuppression and safely accomplished the treatment, except in 1 patient who had received 11 days of Ara-C treatment and died of prolonged neutropenia-induced sepsis. Sixteen of 28 (57%) patients were started to receive Ara-C within 10 days after diagnosis, whereas 12 patients received Ara-C later.While the median WBC count of early treated patients was significantly higher than that of other patients (133.5 × 109/L; range, 16.0–356.9 □L 109/L vs 31.9 × 109/L; range, 4.4–341.5 × 109/L.; p < 0.001), the probability of 1-year overall survival of patients who received low-dose Ara-C within 10 days after the initial diagnosis of TL was similar to that of patients who received Ara-C later or who did not receive Ara-C (69.4 ± 12.9%; n = 16 vs. 79.7 ± 3.5%; n = 137; p = 0.614). By subgroup analysis of patients with WBC ≥ 100 × 109/L, the probability of 1-year overall survival of patients who received early Ara-C treatment was significantly higher than that of others (66.1 ± 13.9%; n = 13 vs. 33.3 ± 8.6%; n = 30; p = 0.035). Conclusion:In summary, we found that low-dose Ara-C therapy for patients with TL and DS has a tolerable toxicity profile, and early intervention with this therapy could improve the clinical outcome of patients whose WBC count exceeds 100 × 109/L. We plan to confirm the efficacy of low dose Ara-C treatment in a prospective clinical trial for high-risk patients with DS and TL. Disclosures:No relevant conflicts of interest to declare.

Low Dose Ara-C for Myelodysplastic Syndromes: is it Still a Current Therapy?

The myelodysplastic syndromes (MDS) are characterized by hemopoietic insufficiency associated with severe cytopenias, leading to serious morbidity, and acute leukemia development. MDS typically occur in elderly people, with a median age at diagnosis ranging between 60 and 75 years. The patients' prognosis, estimated according to the International Prognostic Scoring System, age and performance status should be considered before choosing among the various treatment options. A therapeutic dilemma exists in MDS, due to the multifactorial pathogenetic features of the disease, the heterogeneous stage and the elderly age of patients at diagnosis. This is underlined by the absence of a Food and Drug Administration-approved agent with an indication for this disease. The therapeutic end-points vary from symptom management (using low-intensity treatment with biological targeted agents, or only supportive therapy), to attempts to change the natural history of the disease (generally using high intensity treatment, including intensive chemotherapy and hemopoietic stem cell transplantation). The main goal of low-intensity therapies is generally to induce hematological improvements and is mainly used for low-risk disease. On the other hand, high-intensity therapies generally aims to alter the disease's natural history (improving survival, and decrease progression to acute myeloid leukemia), and are mainly used for high-risk disease. This review will focus on the current role of low-dose Ara-C therapy in the management of MDS. In fact, there is evidence that low-dose chemotherapy with Ara-C can induce responses in patients with MDS. In particular, the use in combinations with growth factors, such as G-CSF or M-CSF, looks promising, suggesting further investigations about this old new therapeutic tool.

A randomized phase II trial of low-dose aclarubicin vs very low-dose cytosine arabinoside for treatment of myelodysplastic syndromes

We performed a randomized phase II trial comparing low-dose aclarubicin (LC-ACR) with very low-dose cytosine arabinoside (VLD-AC) in 39 consecutive untreated patients with myelodysplastic syndromes (MDS), including refractory anemia (RA), RA with excess of blasts (RAEB) and RAEB in transformation (RAEB-t). Nineteen patients received the VLD-AC therapy; 2 good responses (GR) and 2 partial responses (PR) were obtained in 11 patients with RAEB and RAEB-t, while 2 PR were obtained in 8 RA patients. Eighteen patients received the LD-ACR therapy; 2 GR and 4 PR were obtained in 11 RAEB/RAEB-t patients while 2 PR in 7 RA patients. There was no significant difference in the therapeutic effects and survival between these two groups of patients. These observations suggest that the LD-ACR therapy is effective in some patients with MDS and can be used as an alternative to the low-dose Ara-C therapy.

In vitro evidence for dose-dependent cytotoxicity as the predominant effect of low dose Ara-C on human leukemic and normal marrow cells.

To determine whether cytosine arabinoside (Ara-C) has a differentiating effect in vitro, marrow cells from nine patients with acute non-lymphocytic leukemia or myelodysplastic syndrome and eight non-leukemic controls were exposed to drug concentrations comparable to those achieved in vivo with low-dose Ara-C therapy. In soft agar cultures, the predominant effect of Ara-C at concentrations between 10(-8) M and 10(-6) M was cytotoxicity with a dose-dependent decrement in Colony Forming Unit of the granulocyte and monocyte lineage (CFUg/m) at 14 days. Growth in liquid cultures containing Giant Cell Tumor(GCT)-conditioned media without Ara-C resulted in a significant increment in the recovery of mature cells at day 10 from the non-leukemic cultures (P = 0.03), while only a minor increase was found in the leukemic cultures (P = 0.09). All liquid cultures exposed to greater than or equal to 10(-9) M Ara-C showed a marked reduction in the immature proliferating cell pool, with a concomitant increase in the percentage of mature non-dividing cells at 10 days. However, the absolute number of differentiated cells recovered remained constant or decreased in all non-leukemic and eight of nine leukemic cultures, compared with cultures without Ara-C. Enhanced recovery of differentiated cells was also never observed in any culture exposed to the relatively non-toxic 10(-9) M Ara-C. These in vitro findings support clinical observations suggesting that cytotoxicity rather than differentiation is the major mechanism involved in the therapeutic effect of low-dose Ara-C in acute leukemia and myelodysplasia.

Proto-oncogene expression in HL-60 cells exposed to ara-C.

To verify the reported differentiation/maturation-inducing effects of cytosine-beta-D-arabinofuranoside (ara-C, Sigma Chemical Corp, St Louis) on hematopoietic cells, we studied the morphologic changes and patterns of proto-oncogene expression in HL-60 cells that had been exposed to the drug. At the 1 X 10(-7) mol/L concentration of ara-C, approximately 10% of HL-60 cells became nitroblue tetrazolium (NBT) reduction test positive after four days exposure. However, no cells became nonspecific esterase-positive during the culture period. Doses less than 1 X 10(-8) mol/L had virtually no effect on maturation and proliferation of the target cells while doses greater than 1 X 10(-6) mol/L were lethal to HL-60 cells. Cells treated with 1 X 10(-7) mol/L and 1 X 10(-9) mol/L ara-C did not evidence any of the changes in c-myc, c-myb, c-fos, or c-fes that are noted when dimethyl sulfoxide (DMSO) or 12-0-tetradecanoyl phorbol 13-acetate (TPA, Sigma Chemical Corp, St Louis) are used to induce the differentiation of HL-60 cells. In both doses, temporary decreases of the S-phase specific and proliferation related histone H3 gene expression occurred. This phenomenon may be related to an increase in the tendency of these cells to spontaneously differentiate. Because of the possibility of drug inactivation during culture and because HL-60 cells have already matured to the promyelocytic stage, these kinds of experimental systems may be inadequate in in vitro models for low-dose ara-C therapy.

Sensitivity of stromal elements from human bone marrow cells to cytosine arabinoside in vitro.

Cytosine arabinoside (Ara-C) is one of the most effective agents in the treatment of acute myelogenous leukemia (AML). Recently, low-dose Ara-C therapy has been the subject of topical interest in view of its differentiation-inducing effect on leukemic blast cells. Many patients, however, develop severe aplasia with low-dose Ara-C therapy [1, 6, 10, 11]. The aim of our study was to obtain some information about causes of this aplasia, i.e., to determine whether the lesion is primarily in the hemopoietic stem cells or whether there is any additional damage done to stromal elements.

Low-dose cytosine arabinoside (Ara-C) therapy in the myelodysplastic syndromes and acute leukemia.

Twenty-two patients with either a myelodysplastic syndrome or acute nonlymphocytic leukemia were treated with 10-21 days of subcutaneous cytosine arabinoside (Ara-C) (5-10 mg/m2 every 12 hours). There were two complete remissions and ten partial responses. Clinically significant improvements in peripheral blood counts persisted for periods of 8 weeks to greater than 21 weeks. Responses were seen even in patients who had previously proven refractory to conventional induction regimens or high-dose Ara-C. The toxicity, however, was considerable. Nearly all patients developed significant thrombocytopenia. Platelet and red cell transfusion support was required in many cases. The response to low-dose Ara-C therapy seen in patients with the leukemic and myelodysplastic disorders may be mediated by the induction of cell differentiation or a direct cytotoxic effect on a sensitive population of cells. Low-dose Ara-C may provide an alternative therapy in the selected patient with acute nonlymphocytic leukemia or a myelodysplastic syndrome.