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Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: pp. 1098-1105 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.1986 Phase I Trial of Nelarabine in Indolent Leukemias
From the Departments of Experimental Therapeutics and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoSmithKline, Research Triangle Park, NC Corresponding author: Varsha Gandhi, PhD, Department of Experimental Therapeutics, Box 71, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: vgandhi{at}mdanderson.org
Purpose To test whether nelarabine is an effective agent for indolent leukemias and to evaluate whether there is a relationship between cellular pharmacokinetics of the analog triphosphate and clinical responses. Patients and Methods Thirty-five patients with relapsed/refractory leukemias (n = 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic leukemia) were entered onto three different protocols. For schedule A, patient received nelarabine daily for 5 days, whereas for schedule B, nelarabine was administered on days 1, 3, and 5. Schedule C was similar to schedule B except that fludarabine was also infused. Plasma and cellular pharmacokinetics were studied during the first cycle. Results Responses were achieved in 20%, 15%, and 63% of patients receiving schedule A, B, and C, respectively. Histologic category, number of prior therapies, and fludarabine refractoriness did not influence the response rate. The most common nonhematologic toxicity was peripheral neuropathy. Grade 4 neutropenia and thrombocytopenia complicated 23% and 26% of courses respectively, and were significantly more frequent among patients with pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were similar in the two groups of diagnoses, and the elimination of ara-GTP from leukemia cells was slow (median, > 24 hours). The median peak intracellular concentrations of ara-GTP were significantly different (P = .0003) between responders (440 µmol/L; range, 35 to 1,438 µmol/L; n = 10) and nonresponders (50 µmol/L; range, 22 to 178 µmol/L; n = 15). Conclusion Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.
The success of purine nucleoside analogs such as cladribine,1,2 and fludarabine,3,4 either as single agents or in combination with alkylating agents in a diverse group of indolent hematologic malignancies, has been associated with favorable cellular pharmacokinetics of the analog triphosphates. The half-life of fludarabine triphosphate is 7 hours in acute leukemia cells,5 and that of cladribine phosphorylated metabolites is 11 hours in immature myeloblasts or lymphoblasts,6 whereas, these triphosphates are eliminated with a long life (> 24 hours) from circulating leukemic lymphocytes.7-9 Similar to purine nucleoside analogs, normal purine nucleosides are also effective in indolent setting of hematologic malignancies. Deoxycoformycin results in accumulation of plasma deoxyadenosine and cellular plasma deoxyadenosine triphosphate, because of a robust inhibition of adenosine deaminase. The drug was originally synthesized to tackle immature T-cell diseases; however, the inhibitor has been successfully used in indolent leukemias with an associated accumulation of cellular plasma deoxyadenosine triphosphate in primary lymphocytes.10,11 A rare genetic disorder that results in inactivation of purine nucleoside phosphorylase suggested that deoxyguanosine (dGuo) or analogs might act as drug specifically for patients with immature T-cell disorder.12 Recently, forodesine, a potent inhibitor of purine nucleoside phosphorylase,13 enabled the accumulation of dGuo in plasma and dGou triphosphate (dGTP) in T-ALL cells.14 It was also efficacious in indolent B- and T-cell diseases in vitro and during therapy,14,15 further suggesting utilization of purine nucleosides by these quiescent malignancies.15 Collectively, these investigations suggest that the inherent biologic properties of indolent leukemia cells make them susceptible to purine nucleosides and their analogs. On the basis of these observations, we hypothesized that arabinosylguanine (ara-G), should provide clinical benefit for patients with mature cell leukemias.16 Although the synthesis of ara-G was reported in 1964,17 its low solubility and difficulty in synthesis hampered clinical development. Nelarabine (compound 506U78 or 2-amino-6-methoxypurine arabinoside), was synthesized enzymatically from diaminopurine arabinoside.18 The purpose of this synthesis was to provide a clinically useful, water-soluble prodrug of ara-G.16 Several investigations were initiated to test clinical efficacy of nelarabine in hematologic malignancies and conversion of nelarabine to ara-G, and its accumulation as triphosphate in leukemia cells.19,20 As expected from the earlier in vitro investigations, the drug was highly effective in immature T-cell diseases for adult and pediatric populations.21 These phase I studies were extended to cooperative group phase II investigations to fully and formally evaluate this new analog for pediatric22 and adult patient populations.23 On the basis of the clinical results, nelarabine received an accelerated approval in the United States for patients with T-cell acute leukemias and lymphomas.24,25 Pharmacokinetic studies demonstrated efficient conversion of nelarabine to ara-G26 and its phosphorylation to the triphosphate, which was effectively retained by leukemia cells during therapy.19,20 On the basis of these pharmacokinetic, clinical, and biochemical rationales, and successes of purine nucleoside analogs in quiescent leukemias, we decided to enter patients with indolent hematologic malignancies onto protocols containing nelarabine. Here, we report the clinical outcome and pharmacokinetic end points.
Patients Thirty-five patients with indolent leukemia were treated with nelarabine at the University of Texas M.D. Anderson Cancer Center (Houston, TX) from August 1995 to January 1998 (Table 1). Patients were informed about the investigational nature of this program in accord with the institutional policies. They signed separate informed consent forms for treatment protocols and for pharmacologic investigations.
Protocols Patients were treated with one of the three protocols. For schedule A, the first phase I study, they (n = 5) received 20, 30, 40, or 60 mg/kg of nelarabine over 1 hour daily for 5 days. After this phase I study, doses were converted to mg/m2 (for adult, 40 mg/kg = 1.2 g/m2). Nelarabine (1,500 to 2,900 mg/m2) was administered on days 1, 3, and 5 for schedule B (n = 21), whereas in schedule C, patients received 1,200 mg/m2 nelarabine over 2 hours on days 1, 3, and 5, but on days 3 and 5, 30 mg/m2 fludarabine was infused over 30 minutes (n = 9) 4 hours before the nelarabine. The course of therapy was repeated every 21 to 28 days. Clinical and pharmacokinetic studies from schedules A and C with respect to protocol design, dose response pharmacology, and biochemical modulation in the total cohort have been reported previously19,20; the present investigation focuses on patients with prolymphocytic leukemia (PLL) or chronic lymphocytic leukemia (CLL) to interrogate the utility of nelarabine in this population and the associated pharmacokinetics in quiescent leukemia cells.
Drug and Other Chemicals
Criteria for Response and Toxicity
Blood Samples for Clinical Pharmacology
Plasma Pharmacology
Cellular Pharmacology
Calculations and Statistical Analysis
Patient Characteristics and Clinical Responses The majority of patients were male with a median age of 66 years (Table 1). Twenty-four patients had B-cell chronic lymphocytic leukemia (B-CLL), and 11 had T-cell prolymphocytic leukemia (T-PLL). These were heavily pretreated, except for two who had been pretreated with a median of two (range, 1 to 7) prior therapies. Seventy percent had fludarabine refractory disease, and 83% were with Rai high-risk (stages III-IV) disease. Overall responses were 20% (complete remission [CR], 0%), 15% (CR, 5%), and 63% (CR, 13%) for nelarabine schedules A, B, and C, respectively (Table 1). The difference in response rate between nelarabine and fludarabine and nelarabine monotherapy was statistically significant (P = .02). On univariate analysis, no pretreatment factors (age, histology, prolymphocyte percentage, number of prior therapies, fludarabine refractoriness status, alkylator refractoriness status, Rai stage, hepatosplenomegaly, and performance status) except for treatment arm were significantly associated with response. Responses were durable, with a median time to treatment failure of 17 months in responders, and no significant difference among the three treatment arms, or between B-CLL and T-PLL. Importantly, among the six responders with fludarabine-refractory disease, time to treatment failure was durable (median, 10 months), and not significantly different from that of patients with fludarabine-sensitive disease.
Toxicity
Nonhematologic toxicities were mainly isolated to neurotoxicity (including weakness, tiredness, drowsiness, ataxia, myalgia, and confusion) that were transient and self-limiting (Table 3). Symmetric sensorimotor peripheral neuropathy complications occurred 21% of patients and were mainly observed after three or more cycles of therapy, with the majority improving spontaneously within the 12 months of therapy. One patient developed grade 4 hyperbilirubinemia after his second cycle of nelarabine; this patient had proven liver involvement by T-PLL and had previously developed grade 4 hyperbilirubinemia during fludarabine therapy. No other significant hepatotoxicity was encountered.
Plasma Pharmacology Pharmacokinetic data were available in 25 patients, although not all parameter values were available in all patients. Nelarabine maximum plasma concentration (Cmax) seemed higher after a 1-hour infusion compared with a 2-hour infusion of a similar dose (Fig 1A). For all patients (n = 11), the dose-adjusted plasma nelarabine area under the curve from baseline to infinity (AUC0-  ) value was 59 µmol/L · h, and half-life (t1/2) was 23 minutes. ara-G Cmax values occurred at or near the end of the nelarabine infusions. There was a nelarabine dose-dependent increase in ara-G Cmax (Fig 1B). There were no obvious differences after 1- and 2-hour infusions. The dose-adjusted ara-G AUC0- value was 521 µmol/L · h (range, 315 to 1177 µmol/L · h; n = 19), with a t1/2 of 3.7 hours (range, 2.4 to 7.2 hours). There were no discernable differences between patients of different lineage diseases with respect to nelarabine or ara-G plasma pharmacology.
Cellular Pharmacology of ara-GTP Leukemia cells isolated from blood samples obtained during therapy from 25 of the 35 patients were analyzed for accumulation and retention of ara-GTP on days 1 through 2. There was a wide variation in the accumulation of ara-GTP in these quiescent cells, with a median peak concentration for ara-GTP of 89 µmol/L (range, 22 to 1,438 µmol/L). Because these patients received different doses of nelarabine, dose-adjusted values of peak ara-GTP were analyzed. These values were similar to the unadjusted value, with a median of 65 µmol/L (range, 17 to 1,438 µmol/L, data not shown), suggesting that the range in concentrations is a result of inherent capability of these leukemia cells to accumulate ara-GTP rather than strictly a result of the dose of the drug. To determine whether there was diagnosis-dependent accumulation of ara-GTP, data were compared in these two diagnoses. As illustrated in Figure 2A, the concentration of ara-GTP accumulation was slightly higher in B-CLL cells (median, 130 µmol/L; range, 22 to 1438 µmol/L; n = 16) compared with accumulation in mature T lymphocytes with a median value of 46 µmol/L (range, 22 to 610 µmol/L; n = 9). However, this was not statistically different (P = .29). Hence, the variation among patients regarding accumulation of ara-GTP is not caused by T- or B-lineage of the lymphocytes.
Circulating peripheral-blood leukemia cells obtained from 13 patients were also evaluated for retention of ara-GTP after the ara-GTP peak. As shown for one patient with T-PLL, the level of ara-GTP plateaued at 12 hours, 10 hours after the end of drug infusion. After 12 hours, the triphosphate of ara-G was maintained for an additional 36 hours (Fig 2B). Such elimination kinetics would suggest incremental increases in ara-GTP after subsequent infusion. The intracellular ara-GTP increased further after second and third infusions (Fig 2C). This pharmacokinetic profile excluded the possibility of measuring accurate elimination t1/2. The median t1/2 value was more than 24 hours, with a range of 9 hours to more than 42 hours. The distribution seemed similar both in T-PLL (range, 12 to > 42 hours; n = 7) and B-CLL (range, 9 to >42 hours; n = 6) lymphocytes. These data demonstrated that, in general, ara-GTP was retained throughout the 5-day course of therapy and likely for an extended time after the final infusion. Accumulation and retention of ara-GTP were similar among courses (Figs 3A and 3B). Similar ara-GTP pharmacokinetic profiles were obtained during the third course of therapy and in two additional patient samples (data not shown).
Relationship Between Cellular Pharmacology and Clinical Responses Our first phase I study using nelarabine suggested that, in acute leukemias, there was a relationship between accumulation of ara-GTP and response to therapy. To investigate whether such a correlation also existed in patients with PLL and CLL, we compared the peak levels of ara-GTP with cytoreduction during the first course of therapy. There seems to be a direct and linear relationship between accumulation of ara-GTP and reduction in circulating leukemic lymphocytes, with an r value of 0.60 (Fig 4A). To determine whether this association translated into a relationship between ara-GTP and clinical response, the peak concentration of analog triphosphate was compared in responders and nonresponders. The median level of ara-GTP among the 15 nonresponders was 50 µmol/L (range, 22 to 178 µmol/L). The cohort of individuals among the responders (n = 10) accumulated a median 440 µmol/L of ara-GTP (range, 35 to 1,438 µmol/L; Fig 4B); which was eight-fold greater than that in the nonresponders (P = .0003).
Combining clinical experience from three phase I clinical studies, we demonstrate that nelarabine is active in indolent hematologic malignancies. Furthermore, the drug was effective both in T-PLL and B-CLL diseases. Finally, and probably most important, is the clinical observation that the drug is efficacious even in diseases that were purine nucleoside analog refractory/relapsed. Hence, future phase II studies may indicate whether nelarabine provides options for patients with indolent leukemias whose disease has been previously treated with other purine nucleoside analogs. As reported before,19-21,23 nelarabine had limited hematologic toxicity. Nonhematologic toxicities were drug-related neurotoxicity and cumulative peripheral neuropathy. Alternative administration schedules for nelarabine, such as continuous infusion, could be considered to evaluate safety and efficacy in future studies. Peripheral neuropathy is predominantly self-limiting. Infections are no greater than expected in this heavily pretreated population.36,37 Although all three schedules were effective, the most promising regimen seems to be the combination of fludarabine and nelarabine, albeit the number of patients is small in each cohort (P = .02). Significantly, this improvement in efficacy did not come with increased toxicity; hematologic and nonhematologic toxicities were similar to those in patients receiving nelarabine alone. In view of these promising results, the exploration of fludarabine with continuous-infusion nelarabine, with concomitant monitoring of intracellular ara-GTP levels, is warranted, particularly among patients with advanced CLL refractory to conventional therapies. The success of nelarabine for patients with PLL or CLL likely stems from efficient conversion of the nelarabine prodrug to ara-G, plasma pharmacology of ara-G, accumulation of effective levels of ara-GTP in circulating T-/B-lineage leukemic lymphocytes, and maintenance of this cytotoxic triphosphate. Consistent with earlier studies in monkeys16 and humans,19,26 the rapid elimination t1/2 of nelarabine in plasma (mean, 23 minutes) and the concomitant increase in the level of ara-G suggested a rapid metabolic conversion of the prodrug to ara-G in patients with indolent leukemias (Fig 1). The similarity in the peak value of ara-G after 1 or 2 hours of infusion at a given nelarabine dose (Fig 1B) also suggests efficient conversion of prodrug to drug. The peak ara-G concentration occurs at or near the end of the nelarabine infusion; with efficient conversion of nelarabine to ara-G, ara-G Cmax is affected by both infusion rate (which is higher at a given dose for 1-hour infusions) and infusion duration (which is lower at a given dose for 1-hour infusions)—that is, by nelarabine dose. The differences in peak ara-G plasma levels were a result of dose of nelarabine and not the nature of the disease. The plasma pharmacokinetic profiles of nelarabine and ara-G observed in these indolent leukemias were also comparable with those observed in acute diseases.19,26 For example, the dose-normalized peak level of nelarabine was 90 to 100 µmol/L in indolent and acute disease with an identical t1/2 of 3.7 hours in these two classes of leukemias. This is expected, because the conversion of nelarabine to ara-G is dependent on adenosine deaminase, which is present at high specific activity in large body organs and should not be influenced by the leukemia lineage or the aggressiveness of the malignancy. Data from the present investigations clearly demonstrate that the cellular pharmacokinetics of ara-GTP is favorable in leukemic lymphocytes (Fig 2A). In mature lymphocytes of T-cell origin or B-cell lineage, the Cmax was between 22 and 1,400 µmol/L. Ara-GTP accumulation in T-lymphoblasts from patients with T-ALL ranged between 50 and 400 µmol/L.19 This variation in the ara-GTP levels in the leukemia cells is likely to reflect heterogeneity in ara-G phosphorylation. The heterogeneity may be a result of the differences in the cellular levels of deoxycytidine and dGuo kinases that phosphorylate ara-G29-32 or a result of the elimination profile of ara-GTP from the immature or mature lympholineage cells.33-35 However, comparison of ara-GTP half-lives from leukemia cells demonstrated that the median t1/2 was similar in acute (> 24 hours; n = 6) and indolent leukemia subtype (> 24 hours; range 9 to > 42 hours; n = 13) which may be caused by inherent slow elimination of ara-GTP and also by phosphorylation of ara-G, further underscoring the importance of kinases in these tissues. 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. Importantly, the clinical response to this analog was directly related to the Cmax of ara-GTP, which was eight-fold greater in leukemia cells of patients who achieved remission compared with patients who experienced failure with this therapy (Fig 4B). Cellular pharmacology data in patients with wide variety of hematologic malignancies are consistent with this observation.19 Taken together, these data suggest that the capability of leukemia cells to accumulate and maintain ara-GTP is the primary determinant of clinical response to nelarabine. It will be important to prospectively evaluate the prognostic potential of triphosphate levels determined in vitro and during therapy. For determination of ara-GTP peak or plateau concentrations during therapy, blood samples should be taken at 3, 6, and 12 hours after start of infusion because time to achieve maximal level of ara-GTP varied among patient samples. In summary, this report of nelarabine in indolent leukemias demonstrates that the drug, which was effective for patients with immature T-cell diseases, is also active in mature T- and B-cell leukemias. 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. A phase II evaluation of nelarabine in B-CLL and T-PLL is warranted to fully understand the potential of this drug in these indolent diseases and for use in combination.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Roxanne C. Jewell, GlaxoSmithKline (C) Consultant or Advisory Role: Varsha Gandhi, GlaxoSmithKline (C); Susan O'Brien, Genta (C) Stock Ownership: Roxanne C. Jewell, GlaxoSmithKline Honoraria: Varsha Gandhi, GlaxoSmithKline Research Funding: Varsha Gandhi, GlaxoSmithKline; Susan O'Brien, Genentech, Berlex, Biogen Idec, EliLilly, GeminX, Novartis, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: None
Conception and design: Varsha Gandhi, William Plunkett, Michael J. Keating Provision of study materials or patients: Susan O'Brien Collection and assembly of data: Varsha Gandhi, Constantine Tam, Susan O'Brien, Roxanne C. Jewell, Susan Lerner, William Plunkett Data analysis and interpretation: Varsha Gandhi, Constantine Tam, Susan O'Brien, Roxanne C. Jewell, Carlos O. Rodriguez Jr, William Plunkett, Michael J. Keating Manuscript writing: Varsha Gandhi, Constantine Tam, Roxanne C. Jewell, William Plunkett, Michael J. Keating Final approval of manuscript: Varsha Gandhi, Constantine Tam, Susan O'Brien, Roxanne C. Jewell, Carlos O. Rodriguez Jr, Susan Lerner, William Plunkett, Michael J. Keating
We thank Min Du, Mary Ayres, and Brenita Tyler for outstanding technical assistance.
Supported in part by Grants No. CA57629 and CA81534 from the National Cancer Institute, US Department of Health and Human Services, Bethesda, MD. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
