Cladribine

Cladribine is an adenosine deaminase inhibitor.Adenosine deaminase is an enzyme that involved in purine metabolism.
Cladribine is a well-known purine nucleoside analog with particular activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL). In U266, RPMI8226 and MM1.S cells, Cladribine inhibited cell proliferation in a dose-dependant way with IC50 value of 2.43, 0.75 and 0.18 μmol/L, respectively. Apoptosis assays showed that Cladribine induced apoptosis of U266, RPMI8226 and MM1.S cells in a dose-dependant way [1]. In MM1.S cells, Cladribine (0.2uM) induces activation of caspase-3, -8, and -9 and PARP cleavage in a time-dependent way and reduces the phospho-STAT3 levels in a dose-dependent way. Also, Cladribine induces accumulation of DNA strand breaks and then activates the tumor suppressor p53 in lymphocytes [1].
In the treatment of indolent lymphoid malignancies, lower doses of Cladribine (5 mg/m2/week) are highly active and possibly better tolerated than standard doses [2].
References:
[1]. Ma J, Wang S, Zhao M, et al. Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma. BMC Cancer, 2011, 11: 255.
[2]. Robak T, Korycka A, Robak E. Older and new formulations of cladribine. Pharmacology and clinical efficacy in hematological malignancies. Recent Pat Anticancer Drug Discov, 2006, 1(1): 23-38.

Clinical and Radiologic Responses to Cladribine for the Treatment of Erdheim-Chester Disease.[Pubmed:28253394]

JAMA Oncol. 2017 Sep 1;3(9):1253-1256.

Importance: While Cladribine is best known for the treatment of hairy cell leukemia and other lymphoid cancers, it also has activity against myeloid neoplasms, such as Erdheim-Chester disease (ECD). Objective: To assess the efficacy of Cladribine (2-chloro-2'-deoxyadenosine) in the treatment of ECD. Design, Setting, and Participants: This study was a single-institution retrospective medical record review from January 1, 1998, to April 6, 2016, at a tertiary academic medical center. In all eligible cases, the diagnosis of ECD was made using clinical criteria in conjunction with histopathologic findings. Exposure: Cladribine therapy in first-line treatment or later. Main Outcomes and Measures: Two response criteria were used, clinical and radiological. For clinical response, the following criteria were used: complete response (complete resolution of symptoms attributed to ECD), partial response (partial resolution of symptoms attributed to ECD), stable disease (no change in symptoms attributed to ECD), and progressive disease (worsening of symptoms attributed to ECD). For radiological response, the following categories were used: complete response (complete resolution of proven or suspected lesion due to ECD), partial response (partial resolution of proven or suspected lesion due to ECD), stable disease (no significant change in proven or suspected lesion due to ECD for >/=3 months), and progressive disease (progression or worsening of proven or suspected lesion due to ECD). Results: A total of 63 adult patients with confirmed ECD were identified. Their median age at diagnosis of ECD was 54 years (age range, 18-80 years), and 67% (42 of 63) were male. Cladribine was the most commonly used chemotherapeutic agent and was administered in 21 of 63 patients (33%). Their median age at the time of Cladribine therapy was 62 years (age range, 40-78 years). Cladribine was used as the first-line treatment in 9 patients and as later-line treatment in the remaining 12 patients. The median number of cycles of Cladribine administered was 2.5 (range, 1-6). The overall clinical response rate was 52% (9 of 17) (6% [1 of 17] complete response and 46% [8 of 17] partial response), with 18% (3 of 17) stable disease and 30% (5 of 17) progressive disease. Among patients who responded to Cladribine therapy, the median duration of clinical response was 9 months (range, 6-129 months), with ongoing response in 2 patients. The overall radiological response rate was 54% (8 of 15) (all partial response), with 26% (4 of 15) stable disease and 20% (2 of 15) progressive disease. Treatment-related adverse effects included 2 infectious complications (pneumonia and central line infection, both requiring hospitalization) and 2 hematologic adverse effects (grade 4 neutropenia and thrombocytopenia, and grade 3 neutropenia, both requiring therapy discontinuation). Conclusions and Relevance: Cladribine has moderate clinical efficacy in the treatment of ECD and can be considered a treatment option in cases without the BRAF V600E mutation. It is generally well tolerated and may result in a durable response.

Efficacy and Toxicity of Induction Therapy with Cladribine, Idarubicin, and Cytarabine (IAC) for Acute Myeloid Leukemia.[Pubmed:28179321]

Anticancer Res. 2017 Feb;37(2):713-717.

We report our single-center experience with cytarabine and idarubicin for induction therapy for acute myeloid leukemia (AML) with an additional 5 days of Cladribine (IAC therapy). From July 2012 to September 2014, 38 patients completed a full course of IAC induction. Median patient age was 61 years, 61% of patients were >/=60 years old, and 71% were male. The complete remission (CR) rate was 63% following a single induction course, three patients (8%) required a second induction course to achieve CR, for an overall response rate of 71%. The median duration of severe neutropenia was 30.5 days. Thirty-two percent of patients developed mucositis, 76% experienced diarrhea, and 61% developed a rash. Incidence of CR following IAC induction therapy for AML was comparable to historical data, but with frequent diarrhea, rash, and fungal infections. This study found IAC efficacy and toxicity was similar irrespective of age.

Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.[Pubmed:28255849]

Clin Pharmacokinet. 2017 Oct;56(10):1245-1253.

PURPOSE: The aims of this study were to characterize the concentration-time course of Cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. METHODS: This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. RESULTS: The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) beta-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNbeta-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance. CONCLUSIONS: Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR. Trial registration number for study 25643: NCT00213135.

Successful treatment of histiocytic sarcoma with cladribine and high-dose cytosine arabinoside in a child.[Pubmed:28247189]

Int J Hematol. 2017 Aug;106(2):299-303.

Histiocytic sarcoma, a rare hematopoietic neoplasm with evidence of histiocytic differentiation, is often refractory to conventional chemotherapy and radiotherapy, and its prognosis is generally dismal. The optimal management of this malignancy has not been established. We report a case of 8-year-old girl with histiocytic sarcoma involving the left femur. The tumor rapidly responded to a combination of Cladribine and high-dose cytosine arabinoside, an aggressive salvage regimen for refractory Langerhans cell histiocytosis, and became impalpable during the first cycle. The patient has remained in complete remission more than 7 years from diagnosis.

Older and new formulations of cladribine. Pharmacology and clinical efficacy in hematological malignancies.[Pubmed:18221024]

Recent Pat Anticancer Drug Discov. 2006 Jan;1(1):23-38.

The purine nucleoside analog (PNA)--Cladribine (2-CdA, 2-chlorodeoxyadenosine) is a cytotoxic agent of high efficacy in lymphoid and myeloid malignancies. This drug was approved by the FDA for treatment of hairy cell leukemia and in some European countries for treatment of refractory/relapsed chronic lymphocytic leukemia. 2-CdA is usually administered as continuous or intermittent intravenous infusion. Recently however, new formulations of this agent has been developed for subcutaneous and oral administration. In contrast to other PNA, 2-CdA is equally cytotoxic to both proliferating and quiescent cells and several pathways may be responsible for the mechanism of its action. In addition, recent data indicate that 2-CdA combined with other cytotoxic agents and monoclonal antibodies show synergistic proapoptotic and cytotoxic activity on lymphoid and myeloid neoplastic cells. This review article summarizes recent achievements in the understanding of 2-CdA mechanism of action, pharmacokinetics of different pharmaceutical formulations and its approved and possible future applications in the treatment of hematological malignancies. The most important recent patents concerning oral formulations of 2-CdA have been presented.

Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies.[Pubmed:7507037]

Drugs. 1993 Nov;46(5):872-94.

Cladribine (2-chloro-2'-deoxyadenosine) is an adenosine deaminase-resistant analogue of deoxyadenosine. In the treatment of hairy cell leukaemia, Cladribine has demonstrated excellent efficacy (complete response in 33 to 92% of patients) in noncomparative studies. Cladribine appears to compare favourably with other systemic agents in this indication as it achieves a high degree of efficacy after a single 7-day course, with an acceptable tolerability profile. However, long term data and direct comparative studies with interferon-alpha and pentostatin (deoxycoformycin) are required to confirm the finite advantages offered by Cladribine. Preliminary results obtained in other indications including chronic lymphocytic leukaemia, non-Hodgkin's lymphoma, cutaneous T cell lymphoma, Waldenstrom's macroglobinaemia and acute myeloid leukaemia in children have been sufficiently encouraging to warrant further study. Early pharmacokinetic data suggest that Cladribine may be administered by oral and subcutaneous routes, both of which permit convenient outpatient therapy. Myelosuppression, the dose-limiting toxicity of Cladribine, and culture-negative fever are the most common adverse effects associated with therapy. However, Cladribine appears to be only rarely associated with many of the other adverse effects that characterise antineoplastic therapy. In the weeks post-treatment, there is a small but definite risk of serious infection; infections with a fatal outcome have been reported in a number of studies with Cladribine. In conclusion, preliminary data concerning Cladribine have been extremely encouraging. Should early response rates in patients with hairy cell leukaemia be sustained, the efficacy of the drug, together with a short treatment regimen, a favourable tolerability profile, and the possibility of oral therapy, suggest that Cladribine is likely to supersede other agents available for this indication.

Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes.[Pubmed:2579098]

J Clin Invest. 1985 Feb;75(2):377-83.

Deoxyadenosine has been implicated as the toxic metabolite causing profound lymphopenia in immunodeficient children with a genetic deficiency of adenosine deaminase (ADA), and in adults treated with the potent ADA inhibitor deoxycoformycin. However, the biochemical basis for deoxyadenosine toxicity toward lymphocytes remains controversial. The present experiments have examined in detail the sequential metabolic changes induced in nondividing human peripheral blood lymphocytes by incubation with deoxyadenosine plus deoxycoformycin, or with 2-chlorodeoxyadenosine (CdA), an ADA resistant deoxyadenosine congener with anti-leukemic and immunosuppressive properties. The lymphotoxic effect of deoxyadenosine and CdA required their phosphorylation, and was inhibited by deoxycytidine. As early as 4 h after exposure to the deoxynucleosides, strand breaks in lymphocyte DNA began to accumulate, and RNA synthesis decreased. These changes were followed by a significant fall in intracellular NAD levels at 8 h, a drop in ATP pools at 24 h, and cell death by 48 h. Incubation of the lymphocytes with 5 mM nicotinamide, a NAD precursor and an inhibitor of poly(ADP-ribose) synthetase, prevented NAD depletion. The nicotinamide treatment also rendered the lymphocytes highly resistant to deoxyadenosine and CdA toxicity, without altering dATP formation or the accumulation of DNA strand breaks. The poly(ADP-ribose) synthetase inhibitor 3-aminobenzamide exerted a similar although less potent effect. These results suggest that NAD depletion, probably triggered by poly(ADP-ribose) formation, is the principle cause of death in normal resting human lymphocytes exposed to deoxyadenosine plus deoxycoformycin, or to CdA.