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Fludarabine Phosphate (NSC 312878) Infusions for the Treatment of Acute Leukemia: Phase I and Neuropathological Study1

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Fludarabine Phosphate (NSC 312878) Infusions for the Treatment of Acute Leukemia: Phase I and Neuropathological Study1 [CANCER RESEARCH 46, 5953-5958, November 1986] Fludarabine Phosphate (NSC 312878) Infusions for the Treatment of Acute Leukemia: Phase I and Neuropathological Study1 David R. Spriggs,2 Edward Stopa, Robert J. Mayer, William Schoene, and Donald W. Kufe3 Dana Farber Cancer Institute [D. R. S., R. J. M.. D. W. K.J and Department ofPathology, Brigham and Women 's Hospital [E. S., W. SJ, Boston, Massachusetts 0211S ABSTRACT a relationship between dose and lethargy. The schedule of drug administration in these studies was not a 5-day infusion. A Fludarabine phosphate (NSC 312878), an adenosine deaminase resist ant analogue of 9-/9-D-arabinofuranosyladenine, has entered clinical trials. single bolus was used in one study while the other used a single bolus followed by a 48-h infusion. Eleven patients with acute leukemia in relapse received 14 courses of fludarabine phosphate as a 5-day continuous infusion administered at Based on the myelosuppressive effects of fludarabine phos doses of 40 to 100 mg/m2/day. Toxicity was characterized by uniform phate in Phase I testing, we instituted a Phase I and II trial to myelosuppression, as well as occasional nausea, vomiting, and hepato- identify the toxicity and efficacy of fludarabine phosphate in toxicity. Three episodes of metabolic acidosis and lactic acidemia were the treatment of acute leukemia. The drug was administered as noted. In addition, three patients suffered neurotoxicity. Two of these a 5-day continuous infusion at a starting dose equivalent to the three patients had a severe neurotoxicity syndrome characterized by maximum tolerated dose reached in patients with solid tumors. blindness, encephalopathy, and coma. Neither patient recovered neuro This report describes 11 patients with acute leukemia treated logical function. Neuropathological findings at autopsy were character with continuous infusion fludarabine phosphate. ized by a diffuse, necrotizing leukoencephalopathy which was most severe in the occipital lobes. The medullary pyramids and posterior columns MATERIALS AND METHODS were also severely affected. This sporadic fatal neurotoxicity was ob served only at doses greater than 40 mg/m2/day. The maximum tolerated Selection of Patients. All patients entered on this trial had acute dose for a 5-day infusion of fludarabine phosphate is thus 40 mg/m2/day. leukemia in relapse as documented by bone marrow aspiration and biopsy. Ten patients had acute myelogenous leukemia and one had acute lymphocytic leukemia. All patients had already received at least INTRODUCTION one established drug regimen for acute leukemia. The characteristics of ara-C4 has become a keystone in the treatment of acute the patients are listed in Table 1. Ten of 11 patients had been treated with high dose ara-C prior to entry. All patients were followed until leukemia (1). The related purine nucleoside, ara-A, has had less death and no patient received subsequent antineoplastic therapy because clinical utility because of its rapid deamination by ADA (2). of infection, poor performance status, or patient preference. Prior to Inhibitors of ADA, such as DCF, have been used clinically to entry, patients had an Eastern Cooperative Oncology Group perform prolong the effective half-life of ara-A (3, 4). However, DCF ance status of 2 or better (Eastern Cooperative Oncology Group 2 = also increases intracellular dATP pools which compete with confined to bed less than 50% of waking hours) serum creatinine <1.5 ara-A for incorporation into DNA (5). This antagonism, as well mg/dl and serum bilirubin <1.5 mg/dl. Informed consent was obtained as the undesirable clinical side effects of DCF, has stimulated from all patients. the development of ADA-resistant ara-A analogues (6). F-ara- Treatment Plan. Fludarabine phosphate was provided by the National A was synthesized as one of these analogues (7). This compound Cancer Institute. The sterile lyophilized powder containing sodium hydroxide to adjust the pH to 6.5-8.5 was reconstituted with sterile is resistant to deamination by ADA and has antitumor activity water. The drug was administered i.v. in 500 ml of 5% dextrose and in vitro and in vivo (8). Because it is relatively insoluble, the water over a 24-h period. monophosphate derivative, fludarabine phosphate (NSC The drug was administered as a continuous infusion for 5 consecutive 312878), has been formulated for clinical use. days. Patients with decreased numbers of leukemic cells on day 14 bone Fludarabine phosphate has activity in a number of animal marrow aspirates or biopsies were eligible for a second course of tumor systems including LI210 leukemia, CD8F mammary treatment beginning on day 15. The starting dose of fludarabine phos adenocarcinoma, P388 leukemia, and human LX-1 lung tumor phate was 40 mg/m2/day and at least three courses were administered xenograft (9). The preclinical toxicology of fludarabine phos at each dose level. Doses of 40, 60, and 80 mg/m2/day were tested. Two patients each received a single course of 100 mg/m2/day. phate has demonstrated myelosuppression of all hematopoietic lineages, as well as vomiting, diarrhea, liver enzyme abnormal All treatments were administered on the inpatient service at the Dana ities, and occasional azotemia. The inital Phase I trials of Farber Cancer Institute. Patients received standard supportive care including antibiotics, antiemetics. and blood products. fludarabine phosphate demonstrated that myelosuppression is the dose-limiting toxicity (10, 11). Mild lethargy was reported Study Parameters. During therapy, patients had daily complete blood counts and twice weekly measurements of liver function and renal following bolus administration, while there was no other re function. Electrolytes, blood gases, and other clinical studies were ported neurotoxicity. These studies, however, did not establish performed as indicated. During the 4 weeks after therapy, complete blood counts were obtained at least twice weekly and measures of liver Received 3/7/86; revised 6/24/86; accepted 7/31/86. and renal function were monitored weekly. All patients were considered The costs of publication of this article were defrayed in part by the payment évaluablefortoxicity and 10 of 11 patients were évaluableforresponse. of page charges. This article must therefore be hereby marked advertisement in A complete remission in this study was defined as the achievement of accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This investigation was supported by Grant CH-199 awarded by the American an Ml bone marrow as well as the recovery of normal peripheral blood counts (WBC >3000/mm3, platelets >IOO,000/mm3, and hemoglobin Cancer Society. 'Supported by USPHS Grant 1K08 CA00994-01 awarded by the National >10 g/dl.) A remission of less than 30 days in duration was not Cancer Institute, Department of Health and Human Services. 'Supported by an American Cancer Society Faculty Research Award. To considered to be complete. Patients who did not achieve complete whom requests for reprints should be addressed, at the Dana Farber Cancer remission were analyzed for the mechanism of failure ( 12). Institute, 44 Binney Street, Boston. MA 02115. 4The abbreviations used are: ara-C, 9-/J-D-arabinofuranosylcytosine; F-ara-A, RESULTS 9-|8-D-arabinofuranosyl-2-iluoroadenine; ara-A, 9-/3-r>arabinofuranosyladenine; DCF, 2'-deoxycoformycin; ADA, adenosine deaminase; CSF, cercbrospinal fluid; The first objective of this study was to determine the maxi CNS, central nervous system; PAS, periodic acid-Schiff. mum tolerated dose of fludarabine phosphate in the treatment 5953 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1986 American Association for Cancer Research. FLUDARABINE PHOSPHATE INFUSIONS FOR ACUTE LEUKEMIA of acute leukemia. AH 14 courses of therapy were évaluablefor toxicity. The potential for late toxicity (defined as toxicity first 30 appearing more than 28 days after the initiation of treatment) was évaluablein8 of 11 patients. The clinical toxicity of fludarabine phosphate is summarized 25 in Table 2. Severe myelosuppression was uniformly seen, af fecting WBC, platelets, and RBC. Intensive support was re quired for all courses including platelet transfusions, RBC transfusions, and broad spectrum antibiotics for fever and neu- 20 tropenia. The duration of leukopenia, defined as WBC <1000/ mM/L mm3, was more than 2 weeks in 10 of 11 patients. One patient with acute lymphocytic leukemia in relapse received a dose of 15 40 mg/m2/day but his peripheral lymphoblast count never fell below 1000/dl. Both patients receiving a dose of 100 mg/m2/ day for 5 days had leukopenia for more than 30 days (32 and 10 45 days). Three patients received a second dose of fludarabine phosphate 15-17 days after the initiation of treatment because of persistent leukemic cells in the day 14 bone marrow aspirate. In these patients, the leukopenic phase persisted for 14-30 days after the second treatment. Nausea and vomiting were seen in 6 of 14 courses but were generally mild and readily controlled with antiemetics at all dose levels. Hepatotoxicity, as manifested by 2-3-fold eleva tions of the serum transaminases, was observed in 6 of 14 579 11 courses. This toxicity was reversible within 7 days of treatment DAY OF TREATMENT and not clearly related to dose. One patient had a significant Fig. 1. Fludarabine phosphate-related metabolic acidosis. An infusion of flu but reversible elevation of serum creatinine (1.5-3.3 mg/dl) darabine phosphate was administered over 5 days. Measurement of the plasma while receiving fludarabine phosphate concurrently with neph- bicarbonate (•)and anióngap (columns) demonstrated a progressive acidosis. A serum lactate (arrow) drawn on the seventh day of treatment was elevated (23 rotoxic antibiotics. Another patient had mild, reversible mg/dl). F-ARA-AMP, 5-fluoro-9-/3-D-arabinofuranosyladenine 5'-phosphate. changes in serum creatinine occurring 2 weeks after fludarabine phosphate treatment. Two patients developed erythematous several days after the completion of the fludarabine phosphate maculopapular rashes while receiving fludarabine phosphate infusion.
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