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Japanese Journal of Clinical Oncology Pages 146-153

Phase I Study of Cladribine (2-Chlorodeoxyadenosine) in Lymphoid Malignancies
Introduction
Patients And Methods
   Patients
   Drug Formulation
   Study Design
   Response
   Pharmacokinetic Study
   Statistical Analysis
Results
   Patient Accrual and Monitoring Committee
   Hematologic Toxicity
   Non-hematologic Toxicity
   Response
   Pharmacokinetics
Discussion
Acknowledgements
References

Phase I Study of Cladribine (2-Chlorodeoxyadenosine) in Lymphoid Malignancies

Phase I Study of Cladribine (2-Chlorodeoxyadenosine) in Lymphoid Malignancies Kensei Tobinai1, Michinori Ogura2, Tomomitsu Hotta3, Yukio Kobayashi1, Masaru Narabayashi1, Ritsuro Suzuki2, Tomohiro Kinoshita3, Mitsuo Kozuru4, Naokuni Uike4 and Yasuo Ohashi5 and Members of the Cladribine Study Group

1Department of Medical Oncology, National Cancer Center Hospital, Tokyo, 2Department of Hematology and Chemotherapy, Aichi Cancer Center Hospital, Nagoya, 3Department of Internal Medicine, Nagoya University, Nagoya, 4Department of Hematology, National Kyushu Cancer Center Hospital, Fukuoka, 5School of Health Sciences and Nursing, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Cladribine (2-chlorodeoxyadenosine; ) is a purine analogue with clinical activity against hairy cell leukemia, chronic lymphocytic leukemia and indolent lymphoma. To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximum of three cycles. We enrolled 10 previously-treated patients with various lymphoid malignancies. No dose-limiting toxicity (grade 4 hematologic and/or grade 3 or more non-hematologic) was observed in the three patients who received 0.06 mg/kg/day (Level 1). Of the seven patients who received 0.09 mg/kg/day (Level 2), one patient developed grade 4 hypoxemia and grade 4 thrombocytopenia, and another developed grade 4 neutropenia. Of the seven patients treated at Level 2, one with cutaneous T-cell lymphoma attained complete remission, and one with mantle cell lymphoma, one with chronic lymphocytic leukemia and one with adult T-cell leukemia-lymphoma attained partial remission. A pharmacokinetic analysis of the seven patients without leukemic cells showed that their area under the concentration versus time curves of plasma cladribine increased dose-dependently from 2661.3 +- 300.4 nM*h at Level 1 (n = 3) to 3411.3 +- 341.0 nM*h at Level 2 (n = 4) (P = 0.034). We conclude that the recommended phase II dose of cladribine (0.09 mg/kg/day as a seven-day continuous i.v. infusion) in Caucasian patients can be safely administered to Japanese patients. The encouraging results prompted us to plan subsequent phase II studies of cladribine against adult T-cell leukemia-lymphoma, hairy cell leukemia and indolent lymphoma.

Key words:cladribine - 2-chlorodeoxyadenosine - 2-CdA - phase I study - lymphoid malignancy

INTRODUCTION

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a chlorinated purine analogue that is resistant to degradation by adenosine deaminase. Phosphorylated derivatives of 2-CdA accumulate in lymphocytes with high deoxycytidine kinase activity, resulting in DNA strand breaks and cell death. Since the cytotoxic properties of 2-CdA are independent of cell division, 2-CdA is expected to be an effective agent in the treatment of indolent lymphoid malignancy with low-growth fraction. The agent was synthesized and has been investigated extensively by researchers at the Scripps Clinic and Research Foundation in the United States (1-3). Several clinical trials conducted in the United States and European countries have shown the clinical activity of 2-CdA against B-cell malignancies such as hairy cell leukemia (HCL) (4-7), B-chronic lymphocytic leukemia (B-CLL) (8-10), B-prolymphocytic leukemia (B-PLL) (11) and indolent B-lymphoma (12-14).

It is known that deoxycytidine kinase is rich in T-lymphocytes, and an in vitro study showed the sensitivity of T-lymphoblastoid cell lines to 2-CdA (15). In addition, 2-CdA has been reported to be effective against cutaneous T-cell lymphoma (CTCL) (16-18). Therefore, 2-CdA could be effective in the treatment of adult T-cell leukemia-lymphoma (ATL), which is a T-cell malignancy with an extremely poor prognosis. With the aim of establishing an effective new treatment against ATL and other resistant lymphoid malignancies, we initiated a clinical trial of 2-CdA in Japan. The primary purpose of this phase I study was to determine the feasibility of the recommended phase II dose of 2-CdA (0.09 mg/kg/day by seven-day continuous i.v. infusion) for Japanese patients; this dose has been established in Caucasian patients. Another purpose was to evaluate the efficacy of 2-CdA against relapsed or refractory lymphoid malignancies.

PATIENTS AND METHODS

Patients

Previously treated patients with lymphoid malignancies were eligible if they met the following criteria: 1, histologic and/or cytologic confirmation of lymphoid malignancies such as non-Hodgkin's lymphoma (NHL), ATL, CTCL, Hodgkin's disease (HD), CLL, PLL and HCL; 2, patients with refractory lymphoid malignancy against standard chemotherapy, those relapsed after attaining complete remission (CR), or those who showed disease progression after attaining partial remission (PR); 3, no chemotherapy or irradiation within two weeks prior to the study; 4, life expectancy of at least eight weeks; 5, >= 15 years and <75 years of age; 6, performance status 2 or better on the Eastern Cooperative Oncology Group Scale; 7, adequate bone marrow function (neutrophil count >= 1500/[mu]l, platelet count >= 100 000/[mu]l, hemoglobin >= 8.0 g/dl), adequate hepatic function (bilirubin <2.0 times the upper limit of normal, transaminases <2.5 times the upper limits of normal), adequate renal function (creatinine <1.5 times the upper limit of normal), adequate pulmonary function (PaO2 >= 65 mmHg) and normal electrocardiogram; 8, no severe complications; and 9, written informed consent given. The study was approved by the Institutional Review Board of each institution.

In total, ten patients with relapsed or refractory lymphoid malignancies were enrolled in the study between May and October 1995. Their clinical characteristics are shown in Table 1.

One patient (Case 4) was judged to be ineligible for this study after receiving 2-CdA, because she had received radiation alone (no chemotherapy). All ten patients treated were evaluable for toxicity. Therapeutic efficacy was evaluated in nine eligible patients and in all ten patients treated. The median age was 64 years, and the male:female ratio was 6:4. According to the Working Formulation (19) and the Revised European-American Lymphoma Classification (REAL Classification) (20), one patient had follicular small cleaved-cell lymphoma, three had follicular mixed cell lymphoma, two had mantle cell lymphoma (MCL), one had CLL of B-cell type (B-CLL), one had ATL, and two had CTCL. The number of prior chemotherapeutic regimens was zero in one patient, 1 in six, 2 in two and 6 in one case.

Drug Formulation

2-CdA was supplied by Janssen-Kyowa Co. Ltd., Tokyo, Japan as a 0.1% (1 mg/ml) solution of endotoxin-free 2-CdA in sterile 0.9% sodium chloride. The desired dosage of 2-CdA was added to preservative-free normal saline to make a total volume of 500 to 1000 ml, and infused through central or peripheral venous access.

Table 1. Characteristics of ten patients in the phase I study of cladribine (2-CdA)
Case no.

 Age/sex


 PS


 Disease (immunophenotype)

 Prior therapy (response)
[no. of prior chemotherapeutic regimens]		 Disease status
1

 65/M

 0

 FM (B)

 C-MOPP (PR); [1]

 progressed after PR
2

 58/F

 0

 FM (B)

 SM5887+COP (NE); CHOP (CR); [2] relapsed after CR
3

 73/M

 0

 FM (B)

 VDS+CPM+PSL (PR); VEPA (PR); LSG4 (CR);
VDS+CPM+PCZ+PSL (PR); Radiation (CR);
VDS+CPM+MTX+PSL (PR); VP-16 (NC); [6]		 refractory after relapse
*4

 71/F

 0

 CTCL (T)

 Radiation (CR); [0]

 relapsed after CR
5

 73/M

 2

 ATL (T)

 Sobuzoxan (NC); [1]

 primary refractory
6

 63/F

 0

 MCL (B)

 C-MOPP (CR); [1]

 relapsed after CR
7

 45/M

 0

 FSC (B)

 LSG9 (PR); [1]

 progressed after PR
8

 63/M

 0

 MCL (B)

 mLSG4 (CR); [1]

 relapsed after CR
9

 68/F

 0

 CLL (B)

 VP-16 (NC); [1]

 primary refractory
10

 62/M

 0

 CTCL (T)

 IFN-[gamma] (NC); CHOP (NC); [2] primary refractory
*ineligible case because of no preceding chemotherapy. PS, performance status; no., number; F, female; M, male; FM, follicular mixed cell type; FSC, follicular small cleaved cell type; CTCL, cutaneous T-cell lymphoma; ATL, adult T-cell leukemia-lymphoma; MCL, mantle cell lymphoma; CLL, chronic lymphocytic leukemia; C-MOPP, cyclophosphamide (CPM) + vincristine (VCR) + procarbazine (PCZ) + prednisolone (PSL); COP, CPM + VCR + PSL; CHOP, CPM + doxorubicin (DOX) + VCR + PSL; VEPA, VCR + CPM + PSL + DOX; mLSG4, second-generation combination chemotherapy consisting of VCR, CPM, DOX, bleomycin (BLM), PSL, methotrexate (MTX), vindesine (VDS), etoposide (VP-16), PCZ; LSG9, third-generation combination chemotherapy consisting of the same 9 agents as LSG4; VLB, vinblastine; ACNU, nimustine; IFN-[gamma], interferon-[gamma]; CR, complete remission; PR, partial remission; NC, no change; NE, not evaluable

Table 2. Dose-escalation schema of the phase I study of cladribine (2-CdA)
Level

 Cladribine
(mg/kg/day)
1 0.06
2 0.09
3 0.12
4 0.15

Study Design

We administered 2-CdA with a schedule of seven-day continuous i.v. infusion every 28 days up to a maximum of three cycles. The dose-escalation schema of 2-CdA is shown in Table 2. Based on the results of the previously-reported clinical trials in Western countries (4,7,9,10,12-14,16,18,21,22) the starting dose of 2-CdA was 0.06 mg/kg/day (Level 1), and dose escalations of 0.03 mg/kg/day increments were planned up to 0.15 mg/kg/day (Level 4). Intrapatient dose escalation was not allowed.

The treatment was repeated every 28 days, unless patients developed progressive disease or critical toxicities. In this study the critical toxicities were defined as grade 4 hematologic toxicity and/or non-hematologic toxicity of grade 3 or more, according to the toxicity grading criteria of the Japan Clinical Oncology Group (JCOG) (23), which is an expanded version of the National Cancer Institute (NCI) Common Toxicity Criteria.

Granulocyte colony-stimulating factor (G-CSF) was planned for daily administration when neutrophil counts decreased to <1000/[mu]l. Three patients were scheduled for entry at each dose level. If each of the above-mentioned critical toxicities was observed in one of the three patients, an additional three patients were scheduled for treatment at the same dose level. The maximum tolerated dose (MTD) was defined as the dose level at which critical toxicities were observed in two or more of three to six patients.

Response

Tumor response was assessed according to the standard response criteria against each neoplastic disease; i.e., the World Health Organization criteria (24) for NHL, HD and CTCL, the response criteria for ATL by the Lymphoma Study Group of the JCOG (JCOG-LSG), the response criteria for CLL and PLL by the NCI-sponsored Working Group (25), and the standard response criteria against HCL (26). For NHL, HD and CTCL, CR was defined as the disappearance of all evidence of disease, clinically and with imaging studies, for at least four weeks. PR was defined as >50% decrease in the product of the perpendicular diameters of the indicator lesion(s) with no new lesion of malignancy for at least four weeks. All other categories of tumor response were defined as no changes (NC).

Pharmacokinetic Study

Blood was sampled in heparinized tubes just before initiating the infusion of 2-CdA (0 hour), and at 23, 47, 71, and 143 hours during continuous i.v. infusion. At the end of the seven-day continuous i.v. infusion and 2, 4, 6, 9, 24 and 48 hours later, venous blood samples were taken in heparinized tubes and centrifuged, and the plasma was stored at -20oC until analysis. The concentration of 2-CdA in plasma was determined by liquid chromatography/mass spectrometry (LC/MS) with 0.1 ng/ml as the low quantitation limit. The analytical procedure is shown in Fig. 1. The area under the concentration versus time curve (AUC) was calculated according to the trapezoid rule from time zero to the last measurable concentration, and extrapolated to time infinity. The t1/2 of 2-CdA in plasma was calculated using log-linear regression of the points considered to be in the terminal phase.

Table 3. Toxicity profiles and responses of ten patients who received cladribine (2-CdA)
Case no.

 No. of
administered		 Grades of
hematologic toxicities		 Non-hematologic

 Response
  courses WBC Neu Plt Hb    
Level 1 (0.06 mg/kg/day)
1 3 2 2 0 0 none NC
2 2 3 3 0 0 nausea/vomiting (1) NC
3

 2

 2

 2

 0

 2

 dermatitis (1), herpes zoster (1), fever (2) NC
Level 2 (0.09 mg/kg/day)
*4

 3

 3

 3

 4

 3

 hypoxemia (4), fever (2), vascular pain (2), infection (1) CR
5 3 0 2 0 0 none PR
6 3 2 2 0 2 none PR
7 1 2 2 0 0 nausea/vomiting (1) PD
8 2 2 3 0 0 none NC
9 1 0 4 2 2 dermatitis (1), tachycardia (1) PR
10 2 0 0 0 0 none NC
*ineligible case; no., number; WBC, leukocyte; Neu, neutrophil; Plt, platelet; Hb, hemoglobin; CR, complete remission; PR, partial remission; NC, no change; PD, progressive disease.

Statistical Analysis

Comparisons of pharmacokinetic parameters between the dose levels were analyzed by the Wilcoxon rank-sum test, using SAS, Release 6.08.


Figure 1. Analytical procedure for determination of 2-CdA in human plasma by liquid chromatography/mass spectrometry (LC/MS).

RESULTS

Patient Accrual and Monitoring Committee

Between May 15 and June 28, 1995, three patients were enrolled at Level 1 (0.06 mg/kg/day). As shown in Table 3 (Cases 1 to 3), no patient developed critical toxicities. According to the dose- escalation schema of the protocol, three patients were enrolled at Level 2 in August, 1995. When we reviewed the clinical data of these six cases, we found that Case 4 (CTCL) was ineligible because she had not previously received chemotherapy (only radiation).

Immediately after the first course of 2-CdA was finished in all six patients, a monitoring committee was convened on September 18, 1995. At that point, no critical toxicities had occurred among the six patients. The three members (T.N., H.M. and M.S.) of the monitoring committee reviewed the clinical data. They recommended that an additional four patients should be treated at Level 2, and that the dose of 2-CdA should not be escalated further, based on the data of the present study and recent publications (13,21,22) from the United States regarding 2-CdA. In particular, taking the warning about the neurotoxicity of purine analogues by Cheson and colleagues at the NCI (22) into consideration, we stopped any further dose escalation to avoid the occurrence of severe or irreversible neurotoxicity. According to the recommendations by the monitoring committee, an additional four patients were enrolled at Level 2.

Hematologic Toxicity

The toxicity profiles and antitumor responses of all ten patients are shown in Table 3. Of the three patients who were treated at Level 1 (0.06 mg/kg/day), one patient developed grade 3 leukopenia and grade 3 neutropenia, and the remaining two developed grade 2 leukopenia and grade 2 neutropenia.

Of the seven patients treated at Level 2 (0.09 mg/kg/day), one patient with CTCL (Case 4) developed grade 4 thrombocytopenia (24 000/[mu]l) on day 44 of the third course. One patient with B-CLL (Case 9) developed grade 4 neutropenia on day 36 of the first course. Other hematologic toxicities encountered at Level 2 were of grade 3 or less. In total, two of the seven patients treated at Level 2 developed grade 4 hematologic toxicities.

Non-hematologic Toxicity

One patient with CTCL (Case 4), who was treated at Level 2, developed grade 4 hypoxemia (PaO2 48.1 mmHg). She was diagnosed as suffering from interstitial pneumonitis based on clinical symptoms such as hypoxemia and non-productive cough and on chest X-ray findings. When a diagnosis of interstitial pneumonitis was made on day 7 of the third course, the administration of 2-CdA was immediately discontinued. She recovered from the interstitial pneumonitis following treatment with high dose glucocorticoid, immunoglobulin products and sulfamethoxazole/trimethoprim.

Other non-hematologic toxicities were of grade 2 or less, such as grade 2 fever in two patients, grade 2 vascular pain in one, and grade 1 dermatitis in two. The infectious complications encountered in all ten patients treated were grade 1 herpes zoster and grade 1 infection only. In five patients, non-hematologic toxicities were not observed. No neurotoxicity was encountered in any patient.

Response

In the three patients treated at Level 1, two showed >50% reduction in superficial lymph nodes. However, no apparent reduction of abdominal lymph nodes was documented by computer tomography. The antitumor response to 2-CdA in these three patients was assessed as NC.

In the seven patients treated at Level 2, one patient with CTCL (Case 4) attained CR by three courses of 2-CdA. One of the two patients with mantle cell lymphoma attained PR by three courses. One patient with B-CLL attained PR by a single course.

Table 4. Pharmacokinetic data of nine patients who received cladribine (2-CdA)
Case no.

 T1/2
(hour)		 Cmax
(nM)		 Css
(nM)		 AUC
(nM*h)
Level 1 (0.06 mg/kg/day)
1 22.1 20.4 17.1 2878.7
2 15.4 17.1 14.0 2318.5
3 30.1 18.1 16.6 2786.7
mean +- SD (n = 3) 22.5 +- 7.4 18.5 +- 1.7* 15.9 +- 1.7[dagger] 2661.3 +- 300.4[Dagger]
Level 2 (0.09 mg/kg/day)
5 32.2 14.8 13.7 2300.8
6 32.0 22.1 17.9 3001.3
7 22.1 26.0 22.1 3704.8
8 27.2 22.8 21.9 3679.0
9 21.2 20.3 16.8 2822.7
10 47.3 19.7 19.4 3260.2
mean +- SD (n = 6) 30.3 +- 9.5 21.0 +- 3.7 18.6 +- 3.2 3128.1 +- 538.0
mean +- SD (n = 4)[sect] 32.1 +- 10.9 22.7 +- 2.6* 20.3 +- 2.0[dagger] 3411.3 +- 341.0[Dagger]
*P = 0.077; [dagger]P = 0.034; [Dagger]P = 0.034; [sect]pharmacokinetic data of the four patients excluding those with leukemic cells in peripheral blood (Cases 5 and 9). T1/2, elimination half life; Cmax, maximum concentration of drug in plasma during infusion; Css, steady state concentration of drug in plasma during infusion; AUC, area under the concentration versus time curve; SD, standard deviation.

One patient with ATL of acute type (Case 5) achieved PR after three courses of 2-CdA. When he was entered into this phase I study, his leukocyte count was 196 900/[mu]l with 90% ATL cells. Approximately five months after the termination of the 2-CdA treatment, the ATL cells had completely disappeared from the peripheral blood. PR was maintained without subsequent therapy for approximately 10 weeks until the recurrence of lymphadenopathy.

In total, no response was obtained in the three patients who were treated at Level 1. In the seven patients treated at Level 2, four showed responses including one CR and three PR. Excluding Case 4, three of the six eligible patients who were treated at Level 2 achieved PR.

Pharmacokinetics

The pharmacokinetic data of nine patients who received 2-CdA are shown in Table 4. The data of Case 4 was not evaluable because of insufficient blood sampling.


Figure 2. Plasma concentration of cladribine (2-CdA) in the three patients treated at Level 1 (0.06 mg/kg/day by seven-day continuous i.v. infusion). Mean concentrations (nM) and standard deviations (SDs) are shown.The mean plasma concentrations of 2-CdA and their standard deviations (SD) at Level 1 and Level 2 are shown in Figs. 2 and 3 respectively. The maximum concentration of 2-CdA in plasma (Cmax) was 18.5 +- 1.7 nM (mean +- SD) in the three patients at Level 1, and 21.0 +- 3.7 nM in the six patients at Level 2 (P = 0.302). The steady concentration of 2-CdA in plasma (Css) was 15.9 +- 1.7 nM at Level 1 and 18.6 +- 3.2 nM at Level 2 (P = 0.197). The AUC of plasma 2-CdA was 2661.3 +- 300.4 nM*h at Level 1 and 3128.1 +- 538.0 nM*h at Level 2 (P = 0.197).

DISCUSSION

The primary purpose of this phase I study of 2-CdA was to clarify the toxicity profiles of 2-CdA with a schedule of seven-day continuous i.v. infusion. The major toxicity of 2-CdA observed in this study was myelosuppression, as the investigators in the United States reported (4-13,16-18,21,27) The hematologic toxicities observed at Level 1 (0.06 mg/kg/day) were of grade 3 or less, and two of the seven patients at Level 2 (0.09 mg/kg/day) developed grade 4 hematologic toxicities. No severe infectious or hemorrhagic complications were observed.

Regarding non-hematologic toxicities, the only critical toxicity encountered in this study was grade 4 hypoxemia in Case 4, which was successfully managed by supportive care. Infectious pathogens were not detected in this patient. She was clinically diagnosed as suffering from interstitial pneumonitis. Her serum IgE markedly increased from 340 [mu]g/ml before 2-CdA administration to 10 500 [mu]g/ml after the first course was given. Pulmonary infiltrates on chest X-ray rapidly disappeared following glucocorticoid therapy. Although the possibility of opportunistic infection is not excluded, allergic reaction to 2-CdA may have occurred in this patient. Other non-hematologic toxicities were of grade 2 or less. From these results, we concluded that the recommended phase II dose of 2-CdA (0.09 mg/kg/day as a seven-day continuous i.v. infusion) that was established in Caucasian patients can be safely administered to Japanese patients. In subsequent phase II studies against HCL, ATL and indolent lymphoma, we are administering 2-CdA with this dose schedule (0.09 mg/kg/day as a seven-day continuous i.v. infusion).


Figure 3. Plasma concentration of cladribine (2-CdA) in the six patients treated at Level 2 (0.09 mg/kg/day by seven-day continuous i.v. infusion). Mean concentrations (nM) and standard deviations (SDs) are shown.

One of the objectives of the present study was to establish the MTD of 2-CdA, as we described in the study design. However, the monitoring committee, which was convened after three patients were treated at Level 2 (0.09 mg/kg/day as a seven-day continuous i.v. infusion), did not recommend further dose escalations over Level 2. We accepted this recommendation because of the following reasons. First, Cheson and colleagues at the NCI authored a review article regarding the neurotoxicity of purine analogues including 2-CdA, based on the literature and case records as well as the Adverse Drug Reaction reports to the NCI (22). They reported that at higher than recommended doses, life-threatening and fatal neurotoxicity were encountered with all three purine analogues. Second, the phase I study reported by the investigators at the Scripps Clinic revealed that 2-CdA penetrated the blood-brain barrier, and the spinal fluid concentrations of 2-CdA showed an approximately seven-fold increase (from 2.2 nM at 0.10 mg/kg/day to approximately 18 nM at 0.15 mg/kg/day) (21). In their phase I study, one patient treated with 0.15 mg/kg/day developed a sensorimotor polyneuropathy that prevented ambulation. Another patient treated with 0.20 mg/kg/day developed a Brown-Sequard syndrome with progressive coma and paraplegia. Third, in our present phase I study, two of the seven patients treated at Level 2 developed critical toxicities. It was thought that Level 2 (0.09 mg/kg/day) was very close to the MTD defined in this study. Fourth, four of the seven patients treated at Level 2 (recommended phase II dose of 2-CdA in Caucasian patients) showed objective responses.

In the literature from Western countries, the recommended phase II dose of 2-CdA with a schedule of seven-day continuous i.v. infusion was reported to be 0.1 mg/kg/day (4,7,9,10,12-14,16,18 ,21,22). However, as Beutler described in the review article, the actual dose of 2-CdA that had been administered was only 87% of the amount stated, after standardization by use of the extinction coefficient of chloroadenine (3). Therefore, in the present study, we judged the recommended phase II dose that had been established in Caucasian patients to be 0.09 mg/kg/day with a schedule of seven-day continuous i.v. infusion.

Recently, Larson and colleagues at the University of Chicago reported the results of a dose escalation trial of 2-CdA using five daily 1 hour i.v. infusions in patients with advanced hematologic malignancies (28). In their phase I study, hematologic toxicity was not a criterion for determining the MTD. Dose-limiting non-hematologic toxicity was not observed even at the highest dose level of 21.5 mg/m2/day (approximately 0.55 mg/kg/day). The mean Cmax of 2-CdA at 18 mg/m2/day was 210 ng/ml (735 nM), which was approximately ten-fold higher than those in our study. Even at these higher Cmax levels, neurotoxicity was not observed using this schedule (1 hour i.v. infusions for five days). In contrast, Vahdat and colleagues at the Memorial Sloan-Kettering Cancer Center reported that sensorimotor peripheral neuropathy was dose-limiting non-hematologic toxicity in a dose escalation study in patients with acute myeloid leukemia, excluding hematologic toxicity as a criterion for determining the MTD (29). In the Memorial Sloan-Kettering Cancer Center study, the MTD was 17 mg/m2/day (approximately 0.44 mg/kg/day) using a schedule of five-day continuous i.v. infusion. These results suggest that the toxicity profiles of 2-CdA may be different according to the schedule of drug administration.

The AUC of plasma 2-CdA in Case 5 (ATL) and that in Case 9 (B-CLL) were smaller than those in the remaining patients treated at Level 2. The Cmax and Css values of Case 5 and Case 9 also showed a tendency toward lower values. When these patients were entered in this study, they had increased number of leukemic cells in the peripheral blood; 196 900/[mu]l with 90% ATL cells in Case 5 and 47 200/[mu]l with 85% B-CLL cells in Case 9. Liliemark et al. in Sweden reported that the cellular concentration of 2-CdA was 320 times higher than the plasma concentration of 2-CdA (30). When we analyzed the pharmacokinetic data at Level 2 excluding these two highly leukemic patients, the mean AUC of 2-CdA showed a dose-dependent increase from 2661.3 +- 300.4 nM*h at Level 1 to 3411.3 +- 341.0 nM*h at Level 2 (P = 0.034) (Table 4). The plasma concentrations of 2-CdA and their SDs in the remaining four patients are shown in Fig. 4. As shown in Table 4, a tendency for the AUC, Cmax and Css values to increase according to the dose of 2-CdA was recognized. We analyzed whether the pharmacokinetic parameters such as AUC and Cmax were correlated with the toxicity or response observed in this study; however, no correlation was found (data not shown).


Figure 4. Plasma concentration of cladribine (2-CdA) in the four patients treated at Level 2 (0.09 mg/kg/day by seven-day continuous i.v. infusion), excluding the two highly leukemic patients (Case 5 and Case 9). Mean concentrations (nM) and standard deviations (SDs) are shown.

Liliemark et al. also reported the pharmacokinetic data of 2-CdA in Caucasian patients with lymphoid malignancy, using 2- and 24-hour i.v. infusions of 0.14 mg/kg/day (31). They reported that the Css and AUC of the 24-hour infusion were 22.5 +- 11.2 nM and 552 +- 258 nM*h per day respectively. The dose in their study was 1.4-fold higher than that at Level 2 in our study, their assay method for plasma concentration was different from ours, and approximately half of the patients in their study had significant tumor cell counts in the peripheral blood. Although it is difficult to compare precisely the pharmacokinetic data in the present study with theirs, we consider that the pharmacokinetic profiles of 2-CdA during continuous i.v. infusion in Japanese patients are not very different from those in Caucasian patients.

In the present phase I study, the overall response rate was four of ten (40%) for all patients treated, and four of seven (57%) treated at Level 2. The responses of CTCL and B-CLL to 2-CdA were already reported (8-10,16-18). It is very encouraging that one of the two patients with MCL and one with ATL responded to 2-CdA, because the prognosis of both diseases is considered extremely poor with current combination chemotherapies (32-35). So far, three consecutive clinical trials using combination chemotherapies against ATL have been conducted by the JCOG-LSG. These trials (157 patients in total) revealed that the median survival of ATL patients with acute and lymphoma types was only eight months (33-35). With the aim of establishing an effective new treatment against ATL and intractable lymphoid malignancies, we are now conducting three kinds of multicenter phase II studies of 2-CdA against ATL, indolent lymphoma and HCL.

Acknowledgements

This study was supported in part by Janssen-Kyowa Co. Ltd., Tokyo, Japan. We thank the many doctors participating in this multicenter trial for their excellent cooperation. Drs. T. Nakamura (Fukui Medical College), H. Mizoguchi (Tokyo Women's Medical College) and M. Shimoyama (National Nagoya Hospital) are acknowledged for their critical review of the clinical data as the members of the monitoring committee, and Dr. Y. Sasaki (National Cancer Center Hospital East) is acknowledged for reviewing the manuscript. We also thank Y. Ishikawa, H. Ohno, T. Takahara, Y. Muramoto, T. Ikeda and T. Kagawa (Janssen-Kyowa Co.) for their help with data collection and analysis.

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Received November 25, 1996; accepted January 16, 1997
For reprints and all correspondence: Kensei Tobinai, Department of Medical Oncology, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan
Abbreviations: 2-CdA, cladribine (2-chlorodeoxyadenosine); HCL, hairy cell leukemia; CLL, chronic lymphocytic leukemia; PLL, prolymphocytic leukemia; B-CLL, B-chronic lymphocytic leukemia; B-PLL, B-prolymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; ATL, adult T-cell leukemia-lymphoma; NHL, non-Hodgkin's lymphoma; HD, Hodgkin's disease; MCL, mantle cell lymphoma; G-CSF, granulocyte colony-stimulating factor; MTD, maximum tolerated dose; NC, no changes; LC/MS, liquid chromatography/mass spectrometry; AUC, area under the concentration versus time curve; Cmax, maximum concentration of 2-CdA in plasma.

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