The place of cladribine in the treatment of chronic lymphocytic leukemia: a 10-year experience in Poland

Cladribine (2-CdA) is structurally similar to another purine analog, fludarabine (FA), recently accepted in several centers as the first-line treatment in chronic lymphocytic leukemia (CLL). Unfortunately, there is less experience with the use of 2-CdA than with FA in patients with CLL in the majority of Western countries. In the last decade we performed several phase II studies and two phase III randomized trials to evaluate the activity and toxicity of 2-CdA in previously treated and untreated patients with CLL. We have also compared the results of Polish studies with the data presented by other investigators. Similarly to FA this agent has been found to be more effective in previously untreated CLL than in patients refractory to or relapsed after conventional therapy with alkylating agents. In different studies the overall response (OR) rate ranged from 70 to 85% and complete response (CR) from 10 to 47%. Higher CR and OR rates in CLL patients treated with 2-CdA and prednisone than with chlorambucil and prednisone were confirmed in our multicenter, randomized study. Subsequently, we performed a multicenter, randomized study comparing 2-CdA alone with a combination of 2-CdA and cyclophosphamide (CC) or cyclophosphamide and mitoxantrone (CMC). Our updated results seem to indicate that the CC program used as a first-line therapy in CLL gives higher CR and OR and better elimination of minimal residual disease (MRD) than 2-CdA alone. CC is also less myelotoxic than CMC. More recently, we have undertaken a phase II study to determine the efficacy and toxicity of 2-CdA combined with the anti-CD20 monoclonal antibody rituximab in CLL and other refractory or relapsed indolent lymphoproliferative disorders. The preliminary results seem to be better than in similar patients previously treated in our institution with 2-CdA alone. In conclusion, the studies performed in the last decade in Poland and other countries have shown that 2-CdA used alone or in combination with other agents is, similarly to FA, a highly active and relatively safe agent in previously treated and untreated patients with CLL.     

Treatment of hairy cell leukemia: long-term results in a developing country

Abstract

Twenty-nine consecutive patients with hairy cell leukemia (HCL) were treated in two institutions with interferon (IFN, n = 18) or cladribine (n = 11), between July 1987 and May 2011. Median age was 62 (range 29–83) years; there were 21 males and 8 females. Seven of the 18 patients in the IFN group (39%) achieved a complete remission (CR), whereas all the patients in the 2-CDA group entered a CR. Three patients in the 2-CDA group relapsed and needed an additional course of the drug, 2, 3 and 6 years after the initial one. The median overall survival (OS) of the whole group has not been reached, being above 217 months, the 217-month OS being 91%. The survival of patients treated with either IFN or 2-CDA was not statistically different (94% OS at 217 months versus 91% OS at 133 months, respectively). The data that we present here suggest that treatment of HCL with either 2-CDA or IFN is equally effective; treatment costs with IFN are substantially lower than those of the purine analog.     

A limited sampling strategy for estimation of the cladribine plasma area under the concentration versus time curve after intermittent i.v. infusion,s.c. injection,and oral administration

 Cladribine is a newly developed antimetabolite with promising activity in lymphoproliferative disorders. Recent pharmacokinetics investigations have suggested that there is a relationship between its plasma area under the concentration versus time curve (AUC) and the degree of neutropenia posttreatment as well as the therapeutic outcome in hairy-cell leukemia. To enable a simple estimation of the plasma AUC, a limited sampling strategy was developed. Stepwise linear regression was used to determine which were the most important data points for estimation of the plasma AUC after 2-h i.v. infusion, s.c. injection (5 mg/m²), and oral administration (10 mg/m²) in 27 patients. The most important data points after i.v. infusion in 12 patients were 1, 4, and 24 h, in order of importance. The AUC could be estimated as 2.9081×C _1h ⁺5.1851×C _4h ⁺20.3265×C _24h .The accuracy and precision (mean value±SD for the determined/estimated AUC was 0.99±0.053) of the model could not be increased by the addition of more data points. A somewhat lower accuracy and precision (0.96± 0.089) was seen with the 2-, 4-, and 24-h data points. These were used to test the regression technique prospectively for the estimation of the AUC after i.v. administration in another set of 10 patients. The accuracy and precision of the estimation of the AUC was similar in this group (1.01±0.109). In all, 11 patients were treated orally (10 mg/m²) and 10 patients were treated by s.c. injection (5 mg/m²). The most important data points for estimation of the AUC were 2.5, 24, and 0.5 h after oral administration (AUC=0.8630×C _0.5 h+ 4.2337×C _2.5h ⁺45.4364×C _24h ) and 9, 1, and 16 h after s.c. injection (AUC=1.8821×C _1h +16.4256×C _9h ⁺ 25.4518×C _16h ). The accuracy and precision were 1.01±0.064 after oral dosing and 0.99±0.11 after s.c. injection. The derived mathematical models are reliable for estimation of the plasma AUC of cladribine after 2-h i.v. infusion, oral administration, and s.c. injection. Received: 8 October 1995/Accepted: 1 March 1996     

Severe skin rash in two consecutive patients treated with 2‐chlorodeoxyadenosine for hairy cell leukaemia at a single institution

Summary Although hairy cell leukaemia was first described 40 years ago, it is only in the last decade that newer therapeutic agents have enabled effective treatment. The purine nucleoside analogue, 2‐chlorodeoxyadenosine (2‐CdA) is currently considered as first‐line therapy with a very high rate of complete remission. Although adverse events with 2‐CdA are increasingly recognized, severe cutaneous reactions have been reported rarely. We describe two consecutive patients treated with 2‐CdA for hairy cell leukaemia who both suffered extremely severe cutaneous reactions, one of which was life‐threatening.     

克拉屈滨对人脐静脉内皮细胞的毒性作用及机制

目的研究克拉屈滨(2-CdA)对内皮细胞活力、迁移、周期和分泌活性的影响,以评估2-CdA在临床应用中对心血管的影响。方法 CCK-8法检测不同浓度2-CdA对内皮细胞生长的影响;划痕实验检测细胞迁移;流式细胞术检测细胞周期;吖啶橙/溴化乙啶法检测细胞凋亡;Gries法测定一氧化氮(NO)含量;ELISA法检测血管内皮生长因子(VEGF)水平。结果在0.4~40μmol/L浓度范围,2-CdA对内皮细胞有明显抑制作用,IC50为4.126μmol/L。随药物浓度升高和作用时间的延长,2-CdA的抑制作用增强;2-CdA高浓度长时间作用可导致内皮细胞凋亡。5μmol/L 2-CdA作用内皮细胞后,细胞迁移能力受抑制,细胞周期明显阻滞在S期。吖啶橙/溴化乙啶细胞染色结果显示,高浓度2-CdA可诱导内皮细胞的凋亡。5μmol/L 2-CdA作用内皮细胞后导致NO和VEGF含量减少。结论 2-CdA具有内皮细胞毒性作用,引起细胞周期阻滞,并导致细胞凋亡。     

Hematological Effects of Intermittent 2-Hour Infusions of Cladribine in Multiple Sclerosis Patients: A Comparison of 2 Dosage Patterns

Cladribine is a lymphocytotoxic purine nucleoside with potential for treatment of autoimmune diseases. However, optimal administration regimens remain to be established. Twenty multiple sclerosis patients enrolled into this study were given 30 intermittent 2-hour cladribine infusions (0.07 mg/kg per infusion) each. Ten patients received cycles of 5 consecutive daily infusions at 5-week intervals (clustered dosage) on an inpatient basis; the other 10 patients received 1 infusion weekly (nonclustered dosage) on an outpatient basis. Red blood cell (RBC), platelet, and total white blood cell (WBC) counts were assessed at 5-week intervals during the treatment and at 13-week intervals during a 26-week follow-up period. Major WBC and lymphocyte subsets were assessed cytometrically at 15-week intervals during the treatment and at 13-week intervals thereafter. The clustered dosage produced a lasting decline in granulocyte count, a delayed decrease in monocyte count, and a transient decrease in RBC count. The nonclustered dosage caused a larger and persistent decline in RBC count, a smaller (P = .051. compared over the study period) decrease in monocyte count, and no change in granulocyte count. Both regimens transiently reduced natural killer and B-cell subsets (by 40%-60% and >80%, respectively) and caused lasting declines in CD4+ T-cell subsets (by >50%). No significant change was found in CD8+ T-cell subsets. These results show similar potency of these regimens with respect to major lymphocyte subsets, while suggesting that the nonclustered dosage is less toxic to myeloid precursors and more toxic to erythroid lineage precursors.     

Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG + imatinib mesylate in AML patients.Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5 mg/m² days 3–7, Cytarabine 2 gm/m² days 3–7, G-CSF 300 mcg days 2–7, and escalating doses of imatinib mesylate given on days 1–15. The level 1 Gleevec dose was 400 mg, while level 2 was 600 mg and the level 3 dose 800 mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800 mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity.Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24–333.76) and the median relapse free survival was 76 days.The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.     

Pharmacokinetics of 2-chloro-2′-deoxyadenosine administered subcutaneously or by continuous intravenous infusion

Purpose: Cladribine (2-chlorodeoxyadenosine, 2-CDA) is effective in the treatment of various lymphoproliferative disorders. In the standard protocol the compound is administered by continuous intravenous (i.v.) infusion. In order to allow outpatient therapy alternative modes of administration such as subcutaneous (s.c.) injection would be desirable. The aim of the present study was to compare the pharmacokinetics of 2-CDA after i.v. and s.c. administration. Patients and methods: Nine patients received 0.1 mg/kg 2-CDA per 24 h on one occasion by continuous i.v. infusion and on another occasion as a bolus subcutaneously. The concentrations of 2-CDA in the plasma and urine were determined by HPLC. Results: During i.v. infusion the concentration of 2-CDA in the plasma reached a plateau after 4–8 h, whereas with s.c. administration almost ten times higher peak concentrations were reached within 20 to 60 min. A two-compartment model was fitted to the data points whereby the goodness-of-fit statistics showed R ² values of >0.98. The calculated rate of elimination, k_elim, averaged 0.336 h⁻¹ with s.c. and 0.397 h⁻¹ with i.v. administration. The estimated volumes of distribution were 1.67 and 1.58 l/kg. The areas under the concentration time curves (608 ± 65 pmol · h/ml after s.c. administration vs 571 ± 50 pmol · h/ml during i.v. infusion) and the urinary excretion of 2-CDA in 24 h (4.75 ± 0.95 vs 3.55 ± 0.53 μmol/24 h) were similar in both groups, indicating identical bioavailability. Conclusions: Although the pharmacokinetic profile of 2-CDA administered s.c. differs substantially from the profile of a continuous i.v. infusion the areas under the plasma concentration time curves, the urinary excretion of unchanged drug and the estimated pharmacokinetic variables were similar with both modes of administration, indicating that the different time-courses of the plasma concentration did not influence the fraction metabolized or eliminated. Received: 3 November 1999 / Accepted: 3 March 2000     

A Comparison of Clofarabine-based (GCLAC) and Cladribine-based (CLAG) Salvage Chemotherapy for Relapsed/Refractory AML

Background

Salvage regimens for patients with relapsed/refractory acute myeloid leukemia (rrAML) lack comparative data for superiority. Thus, we conducted a retrospective analysis of clofarabine-based (GCLAC; granulocyte colony-stimulating factor [filgrastim], clofarabine, high-dose cytarabine) versus cladribine-based (CLAG; cladribine, cytarabine, granulocyte colony-stimulating factor [filgrastim]) regimens in rrAML.