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© 2001 American Society for Clinical Oncology Experience With 2-Chlorodeoxyadenosine in Previously Untreated Children With Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic DiseasesFrom the Departments of Hematology-Oncology, Pathology, Pharmaceutical Sciences, Biostatistics and Epidemiology, and Pharmacology, St Jude Children’s Research Hospital; and Colleges of Medicine and Pharmacy, The University of Memphis Health Sciences Center, Memphis, TN. Address reprint requests to Robert Krance, MD, Texas Children’s Hospital MC3-3320, 6621 Fannin St, Houston, TX 77030; email: rakrance{at}bcm.tmc.edu
PURPOSE: To develop more effective chemotherapy regimens for childhood acute myelogenous leukemia (AML). PATIENTS AND METHODS: Between June 1991 and December 1996, we administered the nucleoside analog 2-chlorodeoxyadenosine (2-CDA) to 73 children with primary AML and 20 children with secondary AML or myelodysplastic syndrome (MDS). Patients received one or two 5-day courses of 2-CDA (8.9 mg/m2/d) given by continuous infusion. All patients then received one to three courses of daunomycin, cytarabine, and etoposide (DAV) remission induction therapy. RESULTS: Seventy-two patients with primary AML were assessable for response. Their rate of complete remission (CR) was 24% after one course of 2-CDA, 40% after two courses of 2-CDA, and 78% after DAV therapy. Of the 57 patients who entered CR, 11 subsequently underwent allogeneic bone marrow transplantation (BMT), and 40 underwent autologous BMT. Twenty-nine patients remain in continuous CR after BMT. Two patients remain in CR after chemotherapy only. The 5-year event-free survival (EFS) estimate was 40% (SE = 0.080%). Patients with French-American-British (FAB) M5 AML had a higher rate of CR after treatment with 2-CDA (45% after one course and 70.6% after two courses) than did others (P = .002). In contrast, no patient with FAB M7 AML (n = 10) entered CR after treatment with 2-CDA. Similarly, no patient with primary MDS (n = 6) responded to 2-CDA. Seven patients with secondary AML or MDS (n = 14) had a partial response to one course of 2-CDA. CONCLUSION: This agent was well tolerated, and its toxicity was acceptable. Future trials should examine the effectiveness of 2-CDA given in combination with other agents effective against AML.
THE OUTCOME OF treatment for childhood acute myeloid leukemia (AML) has improved during the recent decade.1,2 In part, this advance may be attributed to dose-intensive regimens that include anthracycline and high-dose cytarabine and to the widespread use of allogeneic and autologous bone marrow transplantation (BMT). Recognition of the relationship between cytogenetic subtypes of AML and sensitivity to specific drugs has also contributed to improved survival.3 However, despite this progress, only half of the children with AML experience long-term disease-free survival. There is a clear need to improve the treatment of children with this disease. Defining new chemotherapeutic agents that are active against AML is important in achieving this goal. In 1988, we initiated the first of several sequential clinical trials that used 2-chlorodeoxyadenosine (2-CDA) in the treatment of children with leukemia.4 In the study described here, the effectiveness of 2-CDA was investigated by administering it to children with newly diagnosed AML or myelodysplastic syndrome (MDS) in an up-front window before other treatment was given. The responses of the first 22 patients enrolled onto this protocol suggested that 2-CDA is active against primary AML.5 The data presented here confirm those preliminary findings and further define the activity of 2-CDA against specific phenotypic and cytogenetic subtypes of AML.
Patients Between June 1991 and December 1996, 93 patients were enrolled onto the AML-91 protocol: 73 patients with primary AML, six patients with primary MDS, and 14 patients with secondary AML or MDS. Patients who had French-American-British (FAB) M3 AML with chromosomal rearrangements involving the RAR  gene were not treated on this protocol. The institutional review board of St. Jude Children’s Research Hospital approved the protocol, and informed consent was obtained from patients, parents, or guardians, as appropriate. Patients’ demographic data appear in Table 1.
Treatment All patients began therapy with 2-CDA, which was given at 8.9 mg/m2/d by continuous intravenous infusion for 5 consecutive days. This dosage was based on the results of our previous phase I and II studies.4,6 Fourteen days after the course of 2-CDA began, a bone marrow aspirate and biopsy were obtained to evaluate response. Further therapy depended on the bone marrow findings. Patients who entered complete remission (CR, defined as trilineage hematopoietic recovery and fewer than 5% leukemic blast cells in the bone marrow) resumed treatment when their platelet counts increased to more than 30,000/µL and their absolute neutrophil counts increased to more than 300/µL. Patients who had a partial response (PR, defined as bone marrow cellularity > 10%, trilineage hematopoietic recovery, and a reduction of blast cells by 50% or more) or who had no response (any findings not indicating CR or PR) proceeded immediately to the second course of chemotherapy. Patients who had less than 10% bone marrow cellularity received no chemotherapy for 7 days, after which time the bone marrow examination was repeated. After treatment with 2-CDA, all patients received daunomycin 30 mg/m2/d by continuous infusion for 3 days (days 1 to 3); cytarabine (ara-C) 250 mg/m2/d by continuous infusion for 5 days (days 1 to 5); and etoposide 200 mg/m2/d by continuous infusion for 2 days (days 6 and 7) (DAV). Patients who were in CR after one course of DAV received a second course as consolidation therapy. Patients who were not in remission also received a second course of DAV. If they entered CR, they received a third course. If they did not enter CR, they were removed from the study (Fig 1).
The protocol originally called for a single course of 2-CDA. After 23 patients with primary AML had been enrolled onto the study, the treatment protocol was modified. Patients received a second course of 2-CDA if their response to the first course was a CR or a PR. Twenty-nine of the subsequent 50 patients with primary AML received a second course of 2-CDA. Those who entered CR with the second course of 2-CDA received one course of DAV as consolidation therapy. Patients who were not in CR after the second course of 2-CDA received two courses of DAV. To prevent CNS leukemia, intrathecal (IT) methotrexate, hydrocortisone, and ara-C (MHA) were administered monthly, with age-adjusted dosages in a 1:2:3 ratio. IT chemotherapy began with the second course of chemotherapy (DAV or 2-CDA) and continued until BMT was performed. Asymptomatic CNS leukemia (CSF with five or more cells/µL and detection of leukemic blast cells after cytocentrifugation) required weekly IT-MHA therapy, beginning with the second course of chemotherapy and continuing until the CNS was clear of leukemic cells. IT-MHA was withheld during the first course of 2-CDA to allow assessment of the effects of 2-CDA against CNS leukemia; the 2-CDA dosage administered was expected to achieve cytotoxic concentration in the CNS.5 Patients who had symptomatic CNS disease (meningismus, cranial nerve palsy) began receiving IT-MHA immediately with the initiation of 2-CDA therapy. These patients also received 12 Gy cranial irradiation. Patients who were in CR after completing chemotherapy and who had an HLA-identical sibling donor were eligible for allogeneic BMT. Autologous BMT was provided to patients with primary AML who entered remission but had no sibling donor. Patients with MDS or secondary AML were eligible for allogeneic BMT if a suitable related or unrelated donor was identified. One patient with secondary AML did not undergo BMT because of the lack of a suitable donor. As preparation for allogeneic BMT, patients with HLA-identical sibling donors received ara-C (six doses, each 3 g/m2), cyclophosphamide (two doses, each 45 mg/kg), and 12 Gy total-body irradiation given in eight fractions. Cyclosporine was administered with either methotrexate or pentoxifylline to prevent graft-versus-host disease.7 The preparatory regimen was similar for patients whose donor was mismatched or unrelated, except that the marrow graft was T-cell depleted, the total-body irradiation dose was 14.4 Gy, three doses (20 mg/kg each) of antithymocyte globulin were administered before transplantation, and only cyclosporine was given after transplantation.7 The preparatory regimen for autologous BMT combined busulfan (16 doses, 1 mg/kg each) and cyclophosphamide (four doses, 50 mg/kg each).
Pharmacokinetic Testing and Analysis Plasma 2-CDA concentration was measured in samples from the first 13 patients by radioimmunoassay as previously described.6 All other samples were measured by high-pressure liquid chromatography on a Beckman System Gold analyzer with a 5-µm reversed-phase Ultrasphere ODS column, 4.6 mm x 25 cm (Beckman, Fullerton, CA). The mobile phase gradient consisted of Mobile Phase A (0.1 mol/L NH4OAc pH 6.2 with 5% methanol and 5% acetonitrile, running for 6.5 minutes) followed by a 20-minute linear gradient to Mobile Phase B (0.1 mol/L NH4OAc pH 6.2 with 15% methanol and 15% acetonitrile). The total run time was 47 minutes, and the flow rate was 1.5 mL/min. Plasma (0.5 mL) was added to a glass tube containing 2 mL of phosphate buffer (pH 7.0) and 100 pmol of the internal standard, 6-dimethylaminopurine 9-riboside (Sigma Chemical Co., St. Louis, MO). The solution was mixed and applied to a 3-mL phenyl solid-phase extraction column (Varian, Harbor City, CA) preconditioned with 2 mL of methanol and then 2 mL of phosphate buffer. The columns were washed twice with 3 mL of water, dried for 10 minutes under vacuum (Vacman; Promega, Madison, WI), and eluted three times with 1 mL of 3% ammonia in ethyl acetate. The eluate was dried under 100% nitrogen at 40°C (Reacti-Therm; Pierce, Rockford, IL), reconstituted with 200 µL of Mobile Phase A, and centrifuged; 150 µL of the supernatant was injected into the high-pressure liquid chromatography system. The column eluate was monitored for ultraviolet absorbance at 264 nm. The retention time was 12.5 minutes for 2-CDA and 18.5 minutes for the internal standard. The range of the standard curve was 5 to 120 nmol/L; the assay’s interday percentage coefficient of variation was less than 15.9% across this range. The accuracy of the assay was within 13% of target concentrations. A two-compartment open model was fit to the 2-CDA concentration-versus-time data by nonlinear regression with a Bayesian algorithm as previously described (ADAPT II software, Biomedical Modeling and Simulation Resource, Los Angeles, CA).7,8 The area under the plasma concentration-versus-time curve (AUC) through hour 48 after infusion was calculated by using the log-linear trapezoidal method.
Statistical Analysis
Patients With Primary AML Seventy-three patients with primary AML were enrolled onto the AML91 protocol; 72 patients were assessable for response to therapy. One patient died of pulmonary hemorrhage and complications of leukocytosis (initial WBC count, 374,000/µL) during the first day of 2-CDA treatment. Fifty-seven patients (78%) entered CR. Table 2 shows responses and current patient status according to FAB type and cytogenetic subtype. The 10 patients with FAB M7 AML had a significantly lower frequency of CR (20%) than did other patients (87.1%; P < .0001). Patients whose leukemic cells had the favorable karyotypic features t(8;21) inv(16) or t(9;11) had a rate of CR that was not significantly different from that of other patients.
Of the 57 patients who entered CR, 51 underwent BMT (11 received allogeneic and 40 received autologous transplants). Twenty-nine of the 51 remained in continuous CR (CCR). Of the 11 patients who underwent allogeneic transplantation, six remained in CCR, four had relapses, and one died of infection. After autologous transplantation, 21 of 40 patients remained in CCR, 15 had relapses, three died of infection, and one died of regimen-related toxicity. Six patients entered CR but did not undergo BMT; two of these remain in CCR after receiving only chemotherapy, three had relapses before BMT could be carried out, and one died of fungal infection. The estimated probability of 5-year EFS was 40% (SE = 0.08%) (Fig 2).
Table 3 shows the responses of the 72 assessable patients with primary AML to courses 1 and 2 of 2-CDA according to FAB type and cytogenetic features. The initial course of 2-CDA induced a CR in 24% of patients and a PR in 36%. Of the 50 patients with primary AML who were treated after the amendment of the protocol, 29 received a second course of 2-CDA. Among these patients, 2-CDA induced a CR in 40% (20 of 50 patients). One patient who had a CR to the first course of 2-CDA developed progressive disease after completing the second course of 2-CDA. Eleven of the 19 patients who had a PR to the first course of 2-CDA and received a second course entered CR (Table 4).
Patients with FAB M5 AML had significantly better responses to 2-CDA alone than did other patients, whether one course or two courses were given (Table 5). Even when patients with FAB M7 AML, who had the poorest responses, were excluded from the analysis, the difference between FAB M5 and other subtypes of AML remained significant among patients who received two courses of 2-CDA. Among those who received a single course of 2-CDA, there was a trend toward a higher rate of CR among patients with FAB M5 AML.
Patients With MDS or Secondary AML None of the six patients who had primary MDS had a response to 2-CDA; however, three of these patients entered CR after DAV chemotherapy. Only one patient with primary MDS remains in CCR; this patient underwent allogeneic BMT. Seven of the 14 patients who had secondary AML or MDS had a PR to the first course of 2-CDA; however, only one of the five patients who received a second course had a CR. One patient from this group who entered CR after DAV chemotherapy remains in CCR after allogeneic BMT. Although eight of these 14 patients had a CR, only four remained in initial CR long enough to undergo transplantation while in initial remission.
Pharmacokinetics of 2-CDA
Toxicity Nine patients experienced 18 episodes of grade 3 or 4 nonhematologic toxicity after the first course of 2-CDA, and one patient died. Grade 4 toxicity included pulmonary hemorrhage in two patients, one of whom died less than 24 hours after starting therapy. The other patient had pulmonary hemorrhage while experiencing tumor lysis syndrome with grade 4 hypocalcemia and grade 3 renal and cardiac toxicity. Four patients experienced grade 4 infectious complications (three bacterial and one yeast). Infection or its sequelae were responsible for most grade 3 toxicity. Four patients experienced six episodes of grade 3 or 4 nonhematologic toxicity with the second course of 2-CDA. All of these episodes were caused by fungal infection or related complications. Cycles of DAV, as expected, were associated with infectious complications and mucositis. Four patients died of infection after prolonged pancytopenia; three of these patients had FAB M7 primary AML and one had MDS. A median of 13 days elapsed between the start of the first course of 2-CDA chemotherapy and the start of the second course of chemotherapy (either 2-CDA or DAV). A median of 24 days elapsed between the start of the second 2-CDA course and the start of subsequent DAV chemotherapy. Among patients with primary AML, a median of 81 days elapsed between CR and transplantation from HLA-matched sibling donors; a median of 85 days elapsed between CR and autologous transplantation.
As in our previous studies, 2-CDA demonstrated activity against primary AML.4-6 This group of patients had a 24% rate of CR after one course and a 42% rate of CR after two courses of 2-CDA. These responses compare favorably with those achieved with ara-C or daunomycin given as single agents.13-15 The overall rate of CR, 78%, is similar to those reported by others treating childhood AML2,16-19
After entering CR, all but six patients with primary AML underwent either allogeneic or (in the absence of a matched sibling donor) autologous BMT. The estimated probability of 5-year EFS for all patients with primary AML was 40%. These results are similar to those achieved in other contemporary studies.16,19,20 The exclusion from this treatment protocol of patients with primary AML FAB M3, characterized by RAR As noted in our earlier report, patients with primary FAB M5 AML had a significantly higher rate of CR to 2-CDA than did other patients, whether one or two courses of 2-CDA were given.24 The reason for this finding is unknown but, as most patients with FAB M5 AML showed rearrangements of 11q23, commonly the t(9;11), it remains to be determined whether particular 11q23 translocations are specifically sensitive to 2-CDA therapy. Our findings are consistent with in vitro assays which show that FAB M5 leukemic cells are 6.7-fold more sensitive to 2-CDA than FAB M1/M2 leukemic cells and seven-fold more sensitive than FAB M4 leukemic cells.25 Our previous pharmacokinetic studies found 2-CDA transport, retention, and phosphorylation to be similar in several pediatric AML FAB subtypes.4 However, other factors, including incorporation into nascent DNA, interactions with the apoptosis cascade, and inhibition of DNA synthesis and repair, have not been compared in different subtypes of AML.26
Patients who had FAB M7 AML were significantly less likely to have a CR to treatment than were patients with other types of primary AML (P = .0001). Other investigators have reported that children with FAB M7 AML who do not have Down’s syndrome have a relatively poor rate of response to therapy.16,20,27 In this study, a single patient with primary FAB M7 AML had Down’s syndrome. This patient had a PR to the first course of 2-CDA but had no response to the second course. Two other patients with FAB M7 AML had PRs to 2-CDA, but no patient with FAB M7 primary AML entered remission after treatment with 2-CDA. Two of these 10 patients had a CR after further treatment with DAV. The single patient who had FAB M3 AML without a characteristic RAR The responses obtained in this study are consistent with those of our phase II trial in which eight of 17 patients with AML in first or subsequent relapse entered CR after one or two courses of 2-CDA.6 In older patients, 2-CDA seems to be less active. Most adults with leukemia who were treated with 2-CDA had a response, but sustained responses were uncommon. In two phase II studies, zero of 27 and three of 36 patients had a CR.28,29 A possible explanation for this age difference may be the status of patients’ disease. Previous MDS, cytogenetic features, length of first remission, number of prior remissions, and prior therapies influence responses in phase II studies.29 In the St. Jude phase II study, all nine patients who had a CR were treated during the first relapse. The adult trials included a large proportion of patients whose AML had unfavorable features, including multiple relapses, refractory primary disease, preceding MDS, or a combination of these. Pharmacokinetic or pharmacodynamic differences between patients who did and did not have responses may be another possible explanation for the disparate responses to 2-CDA. We observed wide variation between children in 2-CDA systemic clearance and systemic exposure, as measured by AUC. Similar variability in children with acute leukemia has been reported previously.30 We found no relationship between plasma drug disposition and response. This finding is not surprising, because no direct relationship has been found between 2-CDA plasma systemic exposure and intracellular exposure to 2-CDA nucleotides, the active metabolites. Therapeutic response to 2-CDA is probably more dependent on the intrinsic sensitivity of malignant cells to the drug than on plasma systemic exposure. Albertioni et al31 recently reported finding no correlation between cellular cladribine nucleotides and either plasma 2-CDA concentration or deoxycytidine kinase activity; this result suggests that the cytotoxicity of 2-CDA is related to factors other than its intracellular activation. Until such a relationship is identified, it will not be possible to adjust a 2-CDA dose based on plasma pharmacokinetic results for an individual patient. Factors that determine 2-CDA cytotoxicity in AML may be inherent in the specific mechanisms underlying leukemogenesis, as in the relationship between the efficacy of all-trans-retinoic acid or high-dose ara-C and the rearrangement of specific transcription factor genes. Given the favorable therapeutic balance between the activity and toxicity of 2-CDA for the treatment of childhood AML, we have initiated a study combining 2-CDA with ara-C. Preliminary clinical and preclinical data suggest that 2-CDA can promote the antileukemic activity of ara-C.32 Other studies have demonstrated that combining 2-CDA with other chemotherapeutic agents enhances their activity.33-35 Further, as previously reported, 2-CDA penetrates the blood-brain barrier and helps to control CNS leukemia in patients with no symptoms of CNS disease.5 If 2-CDA proves to be effective against specific genetic variants of AML, it may become a particularly important adjunct to current therapy. Most toxicity is immediate, and, to date, patients have shown no long-term adverse effects after treatment with 2-CDA.
Supported in part by grant nos. P30-CA-21765 and PO1-CA-20180 from the National Institutes of Health, by a Center of Excellence grant from the State of Tennessee, and by the American-Lebanese-Syrian Associated Charities. We thank Mary Heim-Green for management of protocol data and Sharon Naron for editorial assistance.
1. Stevens RF, Hann IM, Wheatley K, et al: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: Results of the United Kingdom Medical Research Council’s 10th AML trial—MRC Childhood Leukaemia Working Party. Br J Haematol 101: 130-140, 1998[Medline] 2. Creutzig U, Ritter J, Zimmermann M, et al: Improved treatment outcome results after risk-adapted intensification of chemotherapy in children with AML: Results of study AML-BFM 93. Blood 94: 629a, 1999 (abstr, suppl 1)
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Lange BJ, Kobrinsky N, Barnard DR, et al: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group Studies 2861 and 2891. Blood 91: 608-615, 1998
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Burnett AK, Grimwade D, Solomon E, et al: Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: Result of the Randomized MRC Trial. Blood 93: 4131-4143, 1999
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Fenaux P, Chastang C, Chevret S, et al: A randomized comparison of all trans retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia: The European APL Group. Blood 94: 1192-1200, 1999
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Woods WG, Neudorf S, Gold S, et al: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: A report from the Children’s Cancer Group. Blood 97: 56-62, 2001 24. Ribeiro RC, Santana VM, Head D, et al: Factors associated with hematologic response to 2-chloro-deoxyadenosine in de novo pediatric acute myeloid leukemia. Blood 88: 219a, 1996 (abstr, suppl 1) 25. Zwaan CHM, Kaspers GJL, Pieters R, et al: Circumvention of cytarabine resistance by 2-chloro-deoxyadenosine in pediatric acute myeloid and acute lymphoblastic leukemia: An in vitro study. Blood 96: 307a, 2000 (abstr, suppl 1)
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Kearns CM, Blakley RL, Santana VM, Crom WR: Pharmacokinetics of cladribine (2-chlorodeoxyadenosine) in children with acute leukemia. Cancer Res 54: 1235-1239, 1994 31. Albertioni F, Lindemalm S, Eriksson S, et al: Relationship between cladribine (CdA) plasma, intracellular CdA-5'-triphosphate (CdATP) concentration, deoxycytidine kinase (dCK), and chemotherapeutic activity in chronic lymphocytic leukemia (CLL). Adv Exp Med Biol 431: 693-697, 1998[Medline]
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Gandhi V, Estey E, Keating MJ, et al: Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: Pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 87: 256-264, 1996 33. Tefferi A, Levitt R, Li CY, et al: Phase II study of 2-chlorodeoxyadenosine in combination with chlorambucil in previously un- treated B-cell chronic lymphocytic leukemia. Am J Clin Oncol 22: 509-516, 1999[Medline] 34. Van Den NE, Bontemps F, Delacauw A, et al: Potentiation of antitumor effects of cyclophosphamide derivatives in B-chronic lymphocytic leukemia cells by 2-chloro-2'-deoxyadenosine. Leukemia 13: 918-925, 1999[Medline] 35. Maranda E, Szmigielska A, Robak T: Additive action of gemcitabine (2',2'-difluorodeoxycytidine) and 2-chlorodeoxyadenosine on murine leukemias L1210 and P388. Cancer Invest 17: 95-101, 1999[Medline] Submitted January 8, 2001; accepted March 13, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
