Complete hematologic remissions induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia

Abstract

The majority of children with acute myeloid leukemia (AML) who are treated exclusively with chemotherapy die of progressive disease. Improvement in outcome will likely require new active drugs capable of eradicating resistant blast cells early in the clinical course. We therefore assessed the cytoreductive potential of 2- chlorodeoxyadenosine (2-CdA), a halogenated purine analogue, in 22 consecutive children with newly diagnosed AML. The drug was administered as a single 120-hour continuous infusion (8.9 mg/m2 of body surface area per day) before the introduction of standard remission induction therapy. Six patients (27%) had complete hematologic remissions by a median of 21 days after treatment with the nucleoside (range, 14 to 33 days). Seven others had partial responses, yielding a total response rate of 59%. The drug also eliminated leukemic cells from cerebrospinal fluid in 4 of the 6 patients tested. Concentrations of 2-CdA in cerebrospinal fluid on day 5 after the initiation of treatment ranged from 12.4% to 38.0% (mean, 22.7%) of the steady-state plasma concentrations. Severe but reversible myelosuppression and thrombocytopenia developed in all patients. Analysis of factors that may have influenced the complete remission rate suggested a better outcome in patients with myeloblastic leukemia (M0-M2 subtypes in the revised French-American-British classification system). These results demonstrate clinically significant activity by 2- CdA against previously untreated AML in children, including leukemic blast cells in the central nervous system. Its use in combination chemotherapy may improve the outlook for patients with this often fatal hematologic cancer.

Increased remissions from one course for intermediate‐dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population‐based phase II study

“…Single-drug therapy with cladribine was shown to induce complete remission (CR) in eight of 17 (47%) paediatric patients with AML in first or later relapse (four of them after one course) (Santana et al, 1992). In a subsequent study, cladribine was given as a single-drug therapy to 22 consecutive patients with newly diagnosed AML, and six (27%) achieved CR by a median of 21 d after the start of treatment, and seven others had a partial response, yielding an overall response rate of 59% (Santana et al, 1994). In 72 newly diagnosed paediatric AML patients, 24% achieved CR with one single-drug course of cladribine and 40% obtained CR after two courses (Krance et al, 2001).…”

Revisiting the role of cladribine in acute myeloid leukemia: An improvement on past accomplishments or more old news?

“…1. However, it is important to note that even in myeloid cell lines highly resistant to ara-C, CdA retains clinical activity in vitro [29] and has demonstrated single agent efficacy in adult [30] and pediatric patients [31][32][33]. Favorable interactions (additive or synergistic) between CdA and other chemotherapeutic agents have been described, such as daunorubicin [34], idarubicin [35], doxorubicin [35], mitoxantrone [35], interferon-a [13,36], and interferon-g [13].…”

“…CR was observed in 27% after a single cycle while nonresponders proceeded to get standard AML induction therapy. Interestingly, single agent CdA eliminated meningeal leukemia in four of six evaluable patients [31]. In the AML-91 trial, Krance et al studied single agent CdA 8.9 mg/m 2 /day CIVI for 5 days before DAV (daunorubicin, ara-C, etoposide) induction in 72 pediatric patients with ND-AML [47].…”

“…Overall, outcomes obtained from single agent CdA for management of ND pediatric AML are somewhat disappointing given the higher CR rates demonstrated in the RR-AML setting. Such differences may be related to the use of only a single CdA induction cycle in the treatment na€ ıve setting [31], compared with two CdA induction cycles in the RR-AML studies [32,33]. The absolute benefit of CdA "window treatment" before conventional AML induction remains unknown as a randomized trial comparing cohorts receiving and not receiving such pretreatment has not been published.…”

Long‐term follow‐up of Cladribine, high‐dose Cytarabine, and Idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review

“…13,14 In contrast to fludarabine, cladribine has been shown to be effective as monotherapy in AML, particularly as complete remissions could be achieved in children. 15,16 In the adult setting, cladribine monotherapy showed disappointing results, 17,18 but when combined with cytarabine and/or anthracyclines in the 1st-line setting response rates improved up to 50%-70%. 7,19,20 Efforts were made to use cladribine-based regimen in relapsed AML, and high remission rates were achieved (about 50%).…”