High-Dose Cytosine Arabinoside in Chronic Lymphocytic Leukemia: A Clinical and Pharmacologic Analysis

Abstract

Twenty-seven patients with B-cell chronic lymphocytic leukemia (CLL) or a related lymphoid malignancy were treated with high-dose cytosine arabinoside (ara-C) at a dosage of 3 gm/m2 administered over 2 hours every 12 hours at one to four doses per course, which were repeated at 4-week intervals. Median patient age was 60 years. Fifty-four percent of CLL patients had Rai stage III or IV disease and the median number of prior therapies was three. Two patients achieved a complete response, five had a partial response, and two had clinical improvement for an overall response rate of 33%. The median duration of response was 9 months. Myelosuppression and infection were the main toxicities. Intracellular levels of the active metabolite ara-C triphosphate varied among patients, but comparisons of pharmacokinetic parameters revealed no significant differences between responders and non-responders. We conclude that high-dose ara-C has modest activity in CLL and that its use in combination with other agents in the treatment of CLL is warranted.

Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H

“…Although cytoreductive efficacy of ID Ara-C in CLL has been demonstrated when used in combination, 17 the drug alone has been investigated only in few poor prognosis cases with disappointing results concerning the antileukemic effect. 16 However, as already mentioned the in vivo purging efficacy of high-dose Ara-C has been reported in patients with mantle cell and indolent lymphomas. 14 In our study, three patients switched from a monoclonal rearrangement for IgH gene to polyclonal collections after ID Ara-C þ G-CSF mobilization, and three patients switched from a polyclonal rearrangement for IgH gene to a monoclonal collection after ID Ara-C þ G-CSF.…”

“…The rationale of using ID Ara-C for mobilization in our study was based on the observations that the drug at high doses proved to be highly effective in PBPC harvesting and in vivo purging in indolent lymphomas, 14 and that it demonstrated some cytoreductive efficacy in CLL. [15][16][17] Furthermore, ID Ara-C has not been included in any phase of our debulking CLL program and in our conditioning regimen for ASCT.…”

Therapeutic potential of purine analogue combinations in the treatment of lymphoid malignancies

“…50 The potentiation of araCTP formation which results from pre-exposure of cells tō udarabine can be demonstrated in CLL cells 47 but although this approach has been utilized in the treatment of patients with CLL there is very little clinical activity. 51 Because there is good in vitro evidence that¯udarabine might also have a synergistic action with cisplatin as a result of inhibition of the repair of cisplatin-induced DNA cross-links, 52,53 this agent has been incorporated into combination therapy with¯udarabine and cytarabine.…”

Rational design of a new cytarabine-based prodrug for highly efficient oral delivery of cytarabine

“…1-(b-D-Arabinofuranosyl) cytosine (cytarabine, Ara-C) is a clinically widely used anticancer agent, especially for the treatment of both acute and chronic leukemia, which is a dangerous cancer with an estimated 62 130 new cases and 24 500 deaths in the United States in 2017. [1][2][3][4] As a potent chemotherapeutical anti-metabolic drug, Ara-C will go through activation and inactivation in vivo. On the one hand, aer intravenous injection into the blood circulation, part of the cytarabine crosses the cell membrane with the help of nucleoside transporters, and is then converted to a major active metabolite, 1-b-D-arabinofuranoside 5 0 -triphosphate (Ara-CTP), which forcefully inhibits the production of DNA polymerase and is nally also incorporated into the DNA to exert anticancer therapeutic effects.…”