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© 2001 American Society for Clinical Oncology Evaluation of the Combination of Nelarabine and Fludarabine in Leukemias: Clinical Response, Pharmacokinetics, and Pharmacodynamics in Leukemia CellsFrom the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC. Address reprint requests to Varsha Gandhi, PhD, Department of Experimental Therapeutics, Box 71, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: vgandhi{at}mdanderson.org
PURPOSE: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. PATIENTS AND METHODS: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m2) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg/m2) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days. RESULTS: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P = .001) in responders (890 µmol/L, n = 6) and nonresponders (30 µmol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27). CONCLUSION: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.
THE SUCCESS OF purine nucleoside analogs such as cladribine,1,2 pentostatin,3,4 and fludarabine5,6 in a diverse group of indolent hematologic malignancies has provided a rationale for the clinical evaluation of the arabinosyl analog of deoxyguanosine, 9-ß-D-arabinosylguanine (ara-G). Although the synthesis of ara-G was reported in 1964,7 its low solubility and difficulty in synthesis dampened enthusiasm for clinical development. Nelarabine (compound 506U78 or 2-amino-6-methoxypurine arabinoside), was synthesized enzymatically from diaminopurine arabinoside.8 The purpose of this synthesis was to provide a clinically useful water-soluble prodrug of ara-G.9 Although not active itself, demethoxylation of nelarabine by adenosine deaminase converts it to biologically active ara-G. Nelarabine is a poor substrate for adenosine deaminase, having a substrate efficiency of less than 1% of that of adenosine, however, the high specific activity of this enzyme in RBCs and body organs has been shown to result in the rapid conversion of nelarabine to ara-G in monkeys.9 Consistent with this observation, plasma pharmacokinetic studies in humans during a phase I trial suggested that peak ara-G levels are quickly achieved after nelarabine infusion.10 Although the ara-G peak levels were dependent on the dose of nelarabine, even at the lowest dose, 20 µmol/L ara-G was achieved in plasma. Based on in vitro data9 and the kinetic values for phosphorylation by deoxyguanosine (dGuo) kinase11,12 and deoxycytidine (dCyd) kinase,9,13 it could be predicted that such levels would result in cytotoxic concentrations of ara-G triphosphate (ara-GTP) in the circulating leukemia cells. Cellular pharmacokinetics showed a trend of dose-dependent accumulation of cellular ara-GTP; however, a major finding of this study14 was the diagnosis-specific accumulation of ara-GTP.15 Patients having T-cell lymphoblasts generally had a higher level of ara-GTP than did those having myeloblasts or B-cell lymphoblasts. Importantly, the clinical response to this analog14 was directly related to the peak level of ara-GTP, which was three-fold greater in leukemia cells of patients who achieved complete or partial remission in comparison with patients who failed this therapy.15 Also, using human leukemia cell lines, it has been shown that the marked cytotoxicity of ara-G to T cells16,17 is associated with greater accumulation and more prolonged retention of the cytotoxic triphosphate ara-GTP.18,19 Consistent with this observation, greater accumulation of ara-GTP was also evident in ex vivo cultures of primary T-acute lymphoblastic leukemia (T-ALL) cells.20 These in vitro,16-19 ex vivo,20 and in vivo15 data indicated that the clinical success of nelarabine may be related to the cellular accumulation of ara-GTP. Although, the clinical responses (overall response rate = 31%) observed in this phase I investigation14,15 generally occurred in patients with T-cell lymphoblastic diseases (21 of 39 patients, 54%), the lone patient having B-cell chronic lymphocytic leukemia (B-CLL) achieved partial remission.14,15 This clinical result encouraged us to test nelarabine in indolent leukemias, and the pharmacologic data prompted us to develop strategies that would result in an increase in the cellular accumulation of ara-GTP.21 One of the approaches was biochemical modulation of ara-GTP accumulation by the ribonucleotide reductase inhibitor, fludarabine. Clinically achievable levels of fludarabine triphosphate (F-ara-ATP)22 can mediate a decrease in deoxynucleotides, especially deoxycytidine triphosphate and deoxyguanosine triphosphate (dGTP) pools, that may result in decreased feed-back inhibition of dCyd and dGuo kinase, respectively.23,24 Each of these kinases are involved in the initial phosphorylation of ara-G to ara-G monophosphate, which is the rate-limiting step in the synthesis of ara-GTP.11-13 Such biochemical modulation strategies combining fludarabine with cytarabine have previously been tested and validated during therapy for acute myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia (CLL).25,26 Based on these pharmacokinetic, clinical, and biochemical rationales, a pilot protocol was designed to combine fludarabine with nelarabine. Here we report the clinical outcome, pharmacologic and pharmacokinetic end points, biochemical modulation, and comparison of the metabolism of these two purine nucleoside analogs in leukemia cells.
Patients Thirteen adult patients having hematologic malignancies received treatment at the University of Texas M.D. Anderson Cancer Center from August 1997 to January 1998 ( Table 1). The majority of the patients had indolent leukemias, however, two patients had T-ALL, one had chronic myelogenous leukemia in blast crisis (myeloid), and one had mycosis fungoides (MF) in blastic transformation. All patients were included in the pharmacology investigations for the first course (days 1 to 5). One patient (patient no. 11) was studied only for few hours on day 1 because of development of a pulmonary infection.
Protocol Design This was a pilot protocol designed to test efficacy of fludarabine with nelarabine and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. Each patient received a 2-hour intravenous infusion of 1.2 g/m2 nelarabine over 1 hour on day 1. On days 3 and 5, the same dose of nelarabine was administered; however, 4 hours before the nelarabine infusion, 30 mg/m2 fludarabine was infused over a half an hour. Blood samples for pharmacokinetic analyses were obtained before treatment and for 5 days. This schedule permitted evaluation of the plasma and cellular pharmacology when nelarabine was infused alone (day 1) or in combination with fludarabine (days 3 and 5). The 5-day therapy course was repeated every 21 to 28 days. The protocol design and pharmacologic investigations were approved by the institutional review board. Patients were informed about the investigational nature of this program in accord with the institutional policies.
Drug and Other Chemicals
Criteria for Response and Toxicity
Blood Samples for Clinical Pharmacology
Plasma Pharmacology
Cellular Pharmacology
Determination of Intracellular dATP and dGTP Pools
Calculations and Statistical Analysis
Patient Characteristics and Clinical Responses The 13 patients entered on this pilot protocol had a median age of 62 years and a variety of hematologic malignancies although the majority had indolent leukemias (Table 1). All of the patients had previously received treatments; 10 of them more than once. Generally, the patients having indolent leukemias had received treatments using other purine analogs, such as fludarabine and cladribine. Patients having greater than or equal to 5% prolymphocytes were considered to have CLL in transformation (patient nos. 5, 6, and 11). Seven patients (54%) had an objective response to this combination regimen. In addition, there were six responders among the nine patients having indolent leukemias; five had a complete or partial remission, whereas one had stable disease. Interestingly, among the six purine (fludarabine or cladribine) analog-refractory patients, four achieved remission and one had stable disease. Also one of the two T-ALL patients had a complete remission.
Toxicity
Plasma Pharmacology
Cellular Pharmacology of ara-GTP Leukemia cells isolated from blood samples obtained during therapy from the 12 patients having leukemia and peripheral-blood mononuclear cells obtained from the patient having MF were analyzed for cellular accumulation and retention of ara-GTP on days 1 through 4. On day 1, the time of the peak ara-GTP level in the circulating peripheral-blood cells varied among the patients; in five patients the peak occurred within 3 hours after the end of the infusion, but in the other seven, it ranged from 7 to 40 hours after the end of the infusion (data not shown). Although the median peak concentration of ara-GTP was 84 µmol/L (range, 22 to 1,420 µmol/L; Table 3), the distribution of these values seemed to be bimodal; less than 100 µmol/L in six patients and more than 350 µmol/L in the other six. These values will be discussed further under accumulation of ara-GTP and relationship to response.
Circulating peripheral-blood leukemia cells obtained from 11 patients with leukemia and normal peripheral-blood mononuclear cells (patient no. 8) obtained from patients with MF were also evaluated for retention of ara-GTP after the ara-GTP peak ( Table 4). The data presented in Fig 1 were selected to illustrate the extremes in the elimination kinetics of ara-GTP in leukemia cells. For example, a component of the population exhibited only minor elimination of ara-GTP, with a similar increment in ara-GTP accumulation occurring after the second nelarabine infusion (Fig 1A). Such elimination kinetics, which challenge the ability to accurately compute the rate of elimination, were observed in patient nos. 2, 3, 5, 9, 10, and 12 and did not seem to be lineage-specific (Table 4). In contrast, there was a separate cohort with more rapid elimination of ara-GTP, t1/2 values ranged from 18 to 27 hours (eg, Fig 1B). Nevertheless, the leukemia cells in these patients all retained a significant concentration of ara-GTP before the infusion of the second nelarabine dose (Table 3). For instance, cells having an ara-GTP elimination t1/2 of more than 35 hours retained between 45% and 100% of the peak ara-GTP concentration, whereas those having more rapid ara-GTP elimination kinetics (t1/2 = 18 to 27 hours) had 17% to 27% of the peak ara-GTP concentration at 48 hours. In addition, the ara-GTP t1/2 values after the first and second nelarabine infusions were similar within patients, regardless of the absolute rate of elimination. In all leukemia cases, ara-GTP elimination seemed to be linear in the leukemia cells. Additionally, peripheral-blood mononuclear cells obtained from the MF patient in transformation had the fastest rate of ara-GTP elimination, with a t1/2 of 13 hours and undetectable level of ara-GTP before the second infusion of nelarabine.
The cellular pharmacokinetic profile of ara-GTP described above was compared with that on day 3, ie, when fludarabine and nelarabine were infused as a couplet with a 4-hour interval between the two drugs. Although there was an increase in the peak level of ara-GTP in the majority of cases on day 3 compared with that on day 1, the pharmacokinetic characteristics of ara-GTP made it difficult to directly attribute this increase to a biochemical modulation mechanism. This was because of the fact that there was substantial residual ara-GTP at the time of the second nelarabine infusion in the majority of the patients’ cells, (ie, 48 hours after the start of therapy, Table 3). For example, the residual ara-GTP at 48 hours ranged from 17% to 100% of the peak value in leukemia cells and was related to the elimination rate of ara-GTP. Of the six patients in which the residual ara-GTP concentration was below 20 µmol/L, three had a greater than 10% increase in ara-GTP compared with the additive value (the ara-GTP peak on day 1 plus the residual ara-GTP at 48 hours) suggesting biochemical modulation.
Cellular Pharmacology of F-ara-ATP
Relationship Between ara-GTP and F-ara-ATP Accumulation
Comparison of ara-GTP and F-ara-ATP Pharmacokinetics and Their Ratios With Competing dNTPs The dominant cytotoxic action of these nucleoside analogs is associated with their incorporation into DNA. Thus, the ratio of the cellular concentration of the analog triphosphates to that of the normal deoxynucleoside triphosphate with which they compete for incorporation by DNA polymerases is a key indicator of this function. Adequate leukemia cells were obtained from 12 patients for analysis of endogenous dGTP levels, and 10 patients for quantitation of the dATP pools. In all cases, the levels of these dNTPs were determined in pretreatment samples and on day 3 before the fludarabine infusion. In most cases, samples were also analyzed after the end of the first nelarabine infusion and 2 or 3 hours later for longitudinal studies. There were no significant changes in the levels of these dNTPs within individual patients during the first 40 hours (not shown). However, the cellular levels of dGTP and dATP varied greatly among patients even those having a similar diagnosis (Table 4). Specifically, the concentrations of dGTP were generally low with a median value of 1.6 µmol/L (range 0.7 to 35 µmol/L). Relative to the dGTP pool, the endogenous levels of dATP were greater, with a median value of 15 µmol/L (range, 3.9 to 368 µmol/L). In addition, there was a higher concentration of dATP in leukemia cells as well as a relatively lower level of intracellular F-ara-ATP (compare F-ara-ATP with ara-GTP, Table 4). Therefore, the ratio of analog triphosphate to competing dNTP, was significantly (P = .0002, Mann-Whitney nonparametric unpaired t test) lower for F-ara-ATP/dATP (median = 2.2, n = 10) than that for ara-GTP/dGTP (median = 42, n = 12). This would seem to favor the action of the deoxyguanosine analog over that of the deoxyadenosine analog.
Relationship Between Cellular Pharmacology and Clinical Responses
The response of a patient having B-cell CLL to nelarabine in the initial phase I trial provided the incentive to further explore the efficacy of this agent alone and in combinations against indolent leukemias.14 A second phase I investigation of nelarabine as a single agent on an alternate-day schedule is being evaluated and will be reported elsewhere.30 The present investigation of fludarabine and nelarabine in a sequential combination therapy was based on previous clinical results using combination of fludarabine and ara-C against leukemias.25,26 Furthermore, in vitro studies using human leukemia cell lines23 and ex vivo investigations using primary acute and chronic leukemia cells demonstrated that a similar biochemical modulation strategy could be successfully applied to the fludarabine and ara-G combination.21 Based on these preclinical rationales and the activity of fludarabine against indolent leukemias,5,6 the present protocol was designed to infuse these agents as a couplet. Nelarabine was infused alone on day 1 as a design strategy to facilitate the evaluation of fludarabine action on the cellular ara-GTP pharmacokinetics on administration of the couplet. Consistent with earlier studies of monkeys9 and humans,10,15 the short elimination half-life of nelarabine in plasma (median = 16 minutes, Table 2) and the concomitant increase in the level of ara-G suggested a rapid metabolic conversion of the prodrug to ara-G. Furthermore, the similar peak plasma concentrations of ara-G during the first infusion when nelarabine was given alone and the second infusion when fludarabine and nelarabine were administered as a couplet (Table 2) suggested that fludarabine did not affect this metabolic conversion profile (P = .16). This was expected because fludarabine is neither a substrate nor an effective inhibitor of adenosine deaminase,31 the enzyme responsible for demethoxylation of nelarabine to generate ara-G.9 Thus, fludarabine does not interfere with the ability of nelarabine to serve as an effective prodrug for rapid formation of ara-G in plasma. Comparison of the plasma pharmacokinetics with diagnosis and response to therapy demonstrated that neither the peak levels of nelarabine, ara-G, nor the plasma elimination kinetics of ara-G were related to these clinical parameters (data not shown). However, ara-G concentrations are important regarding cellular accumulation of ara-GTP. This is based on the fact that linear relationships between the ara-G concentrations at different nelarabine doses and the accumulation of ara-GTP by leukemia cells have been observed both in vitro21 and in vivo.15 For this reason, in the present trial, we selected the daily dose to be the maximum-tolerated dose of nelarabine (1.2 g/m2/d) on a 5-day schedule in combination with fludarabine. However, instead of giving five infusions, the prodrug was infused on days 1, 3, and 5 to accommodate the addition of fludarabine doses on days 3 and 5. Furthermore, the alternate-day schedule was based on the prolonged intracellular retention (t1/2, > 24 hours) of ara-GTP observed in our original investigation15 indicating that cytotoxic levels of ara-GTP may be retained for as long as 48 hours, thereby avoiding the need for daily nelarabine infusions. Finally, the alternate-day schedule of administering nelarabine as a single agent has demonstrated clinical efficacy in the setting of indolent leukemias.30 In the present study, there was a wide variation in the peak levels of ara-GTP. Consistent with our previous phase I investigation with nelarabine,15 peripheral-blood mononuclear cells (patient no. 8), myeloid leukemia cells (patient no. 4), and T-CLL cells (patient no. 3) accumulated less than 50 µmol/L ara-GTP. Among other diseases, there was interpatient heterogeneity in the ability to accumulate ara-GTP in cells obtained from patients with T-ALL, T-prolymphocytic leukemia, and B-CLL, and there was a strong relationship between ara-GTP accumulation and clinical response (Fig 3). As this was also observed in our previous phase I trial of nelarabine administered alone to patients with a variety of hematologic malignancies,15 it will be important to prospectively evaluate the prognostic potential of triphosphate levels determined in vitro and during therapy. The 70-fold variation in the ara-GTP levels in the leukemia cells of these patients is likely to reflect heterogeneity in ara-G phosphorylation. For instance, the variation may be because of the differences in the cellular levels of dCyd kinase and dGuo kinase available for phosphorylation of ara-G. Importantly, F-ara-A is also phosphorylated by dCyd kinase.13 Because dCyd kinase is present at a relatively high specific activity in lymphoid cells, it may be expected that this enzyme may also predominate for the accumulation of ara-GTP. Hence, among individuals a proportional accumulation of these two purine analog triphosphates may be expected. In general, such a relationship was observed in the 12 assessable patient samples (r = 0.85). Nonetheless, these data also show that ara-GTP accumulation was bimodal in the leukemia cells (< 100 µmol/L, n = 6; > 350 µmol/L, n = 6, Fig 2). Additionally, in a cohort of individuals having low ara-GTP peak values, F-ara-ATP levels were quantitatively similar (Fig 2), indicating the phosphorylation of both analogs by dCyd kinase. In the other group, the peak levels of ara-GTP were 10-fold greater than those of F-ara-ATP (Fig 2), suggesting an additional contribution of dGuo kinase in ara-G phosphorylation. Prospective evaluation of the expression of each of these kinases in primary leukemia cells may provide a biochemical basis for the pharmacologic differences in the accumulation of ara-GTP. As an experimental approach, the role of each kinase in phosphorylation of ara-G is being explored using stable transfection and expression of the dCyd or dGuo kinase genes in a cell line lacking dCyd kinase and expressing a low level of dGuo kinase.32,33 As observed before in T-ALL patients, there was a strong direct relationship between accumulation of ara-GTP and clinical response using nelarabine plus fludarabine combination therapy (Fig 3). Most of the responding patients had indolent leukemias, a finding that extends the potential utility of nelarabine to these diseases. Because two infusions of fludarabine were given during each course, the role of fludarabine in the observed responses using this protocol cannot be ruled out. Analysis of the role of F-ara-ATP in modulating the accumulation of ara-GTP was complicated by substantial residual ara-GTP at the time of the second nelarabine infusion (Table 3). Even in the absence of a biochemical modulation benefit with this combination, F-ara-ATP may provide a molecular advantage at the DNA level. Such interactions between two nucleoside analog triphosphates have been demonstrated before, albeit in an in vitro setting.34 One observation that favors the effectiveness of nelarabine alone against indolent leukemias is that four of the six patients whose disease was refractory to prior fludarabine therapy had a response to the nelarabine plus fludarabine combination regimen (Table 1). This observation raises the postulate that these two purine analogs are not cross-resistant. Although data are available from only a limited number of patients, the pharmacokinetics and pharmacodynamics with each of these purine analogs (Table 4) may explain the observed superiority of nelarabine. The predominant locus of action of nucleoside analogs is at the level of DNA synthesis as a consequence of analog incorporation into DNA. Cytarabine,35,36 fludarabine,37,38 and gemcitabine39 are examples of nucleosides in which incorporation into the DNA is strongly correlated with cytotoxicity. Although data regarding the site and extent of incorporation of ara-GTP into DNA of intact cells are not available, published evidence demonstrates that the incorporation of ara-GTP into the replicating DNA of whole cells is necessary for the inhibition of DNA synthesis, execution of high-molecular-weight DNA fragmentation, and apoptosis.40 Using an in vitro DNA primer assay, we and others have demonstrated that the molecular basis for ara-GTP–induced inhibition of DNA synthesis is due in part to incorporation of the nucleoside analog.41-43 This depends on the ratio of the concentrations of the available analog triphosphate to the natural substrate, dGTP. A similar scenario has been proposed for F-ara-ATP and dATP in both an in vitro assay38 and whole cells.44 In addition, a comparison of the ratio of the peak analog triphosphate level with the endogenous competing dNTP level in the leukemic lymphocytes of the fludarabine-refractory patients indicated that this ratio was significantly (P = .005, Mann-Whitney t test) greater for ara-GTP/dGTP (median, 60.5; n = 6; patient nos. 1, 2, 5, 10, 11, and 12) than for F-ara-ATP/dATP (median, 1.5; n = 4; patient nos. 2, 5, 10, and 12). Although the ara-GTP to dGTP ratio is favorable for a pharmacodynamic and clinical response to nelarabine, this postulate needs to be investigated further using either cell lines or primary patient samples. In conclusion, the present investigation identifies the therapeutic potential of the combination of nelarabine and fludarabine against indolent leukemias, which is effective and well tolerated. Furthermore, the study also provides a compelling pharmacokinetic basis for the activity of nelarabine; determination of ara-GTP levels in the target tumor population may provide a prognostic test for that activity. The response of patients with a variety of hematologic malignancies to nelarabine provides an indication for further exploration of this agent alone and in combinations. In particular, responses in fludarabine-refractory patients suggest the utility of nelarabine in diseases that are refractory to other purine analogs.
We thank Carol Bivins and Susan Lerner for patient data management and coordination and Don Norwood for critically editing the manuscript. Supported in part by grant nos. CA32839, CA57629, and CA81534 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.
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ABSTRACT
INTRODUCTION
) in cells obtained from two patients with B-CLL: (A) slow elimination profile (patient no. 2) for ara-GTP; (B) fast-elimination profile (patient no. 1) for ara-GTP. The solid squares on the abscissa represent the first and second infusions of nelarabine; the arrow on the abscissa denotes the infusion of fludarabine.
: Affinity, interaction, and consequences. Clin Cancer Res 3: 1347-1355, 1997
