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This article explores the use of cladribine (2-CdA) as a potential treatment for Rosai-Dorfman disease (RDD), a rare condition characterized by painless lymph node enlargement. The article presents case studies of adult patients with RDD who were treated with 2-CdA, showing that it can effectively reduce lymphadenopathy and improve symptoms. However, the treatment can also have severe side effects, such as bone marrow aplasia. The article suggests that 2-CdA should be reserved for patients with life-threatening or refractory RDD. [Extracted from the article]

Between July 2005and October 2006, eight patients (pts) with hairy cell leukaemia were treated with Vero- cladribine at N.N. Blokhin Cancer Research Center. All pts achieved complete remission (CR). Duration of CR ranges from 1+ to 12+ months in 7 cases. There were no serious adverse events during the treatment and follow-up periods (1-12 months). Vero- cladribine was well tolerated. Anemia (grade IV) was seen in 1 patient and thrombocytopenia (grade I) was seen in another 1 patient. No one patient has febrile neutropenia or infectious complication.

Background Hairy cell leukaemia (HCL) is an uncommon neoplasm representing approximately 2% leukaemias and < 1% lymphoid neoplasms. Although HCL remains an incurable disease, first-line treatment with intravenous (IV) or subcutaneous (SC) cladribine (2-CdA) often leads to long-term remissions. Although long-term data are available for IV administration, similar comparable data for SC administration are lacking. Material and Methods Demographic data, laboratory and clinical parameters of 20 patients with HCL, and IV and SC administrations of cladribine in primary treatment were analyzed. Results All patients were administered 2-CdA as the first-line therapy. 2-CdA was administered intravenously to 11 patients and subcutaneously to 9 patients. The hospitalization times were shorter in the SC route, and the incidence of febrile neutropenia was less; therefore, statistical significance could not be determined. There was no difference between the route of administration and the treatment response. A correlation was recorded between the level of anaemia before treatment and the time to treatment response. In addition, a correlation was recorded between the level of anaemia before treatment and minimal residual disease status after treatment. The median overall survival (OS) was 43.5 months (confidence interval 95%: 1.5-79 months), and 2- and 5-year OS was 95%. There was no increase in the incidence of second primary cancer. Conclusions The outcomes of HCL patients treated with SC 2-CdA are quite good, and, in most patients, one cycle of SC 2-CdA was adequate for long-term disease control. SC 2-CdA is an easily applicable option for outpatients, and their side effects are often easily manageable. [ABSTRACT FROM AUTHOR]

Summary: We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv‐SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv‐SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4–75) and 46 (4–140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv‐SM and 50% and 46% with ISM/SSM respectively. The presence of KIT proto‐oncogene, receptor tyrosine kinase (KIT)D816V predicted response in adv‐SM: 17 (90%) of 19 with and none of three without the mutation responded (P < 0·01). Treatment‐emergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv‐SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT‐targeted therapies and identifies the absence of KITD816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study. [ABSTRACT FROM AUTHOR]

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD), is a rare histiocytic disorder of unknown etiology. Most patients with RDD have spontaneous remission, but in some patients, the disease recurs after complete remission and may not respond to general treatment. Some patients with RDD involving the extranodal system can have serious symptoms such as vital organ dysfunction due to mass effects, neurological symptoms caused by intracranial involvement, and respiratory distress with airway involvement. We report the case of a 7-year-old girl with severe dyspnea due to refractory extranodal RDD that caused progressive upper airway obstruction. She was admitted because of nasal congestion and persistent cervical lymphadenopathy, and diagnosed as having RDD by cervical lymph node incisional biopsy. The initial prednisone treatment did not improve her symptoms. The following contrast-enhanced neck computed tomography revealed a newly developed airway mass protruding in the upper trachea. After 8 weeks of chemotherapy with vinblastine, methotrexate, and prednisone, complete remission was attained. Seven months after chemotherapy cessation, the disease recurred, and chemotherapy with vincristine, cytarabine, and prednisone was resumed. Despite the chemotherapy and emergency radiotherapy, no improvement was observed in the cervical lymph node enlargement and airway obstructive symptom due to the upper tracheal mass. 2-Chlorodeoxyadenosine (cladribine) therapy was initiated, and the patient got complete remission after 6 cycles of the cladribine treatment and maintained no evidence of disease for 2 years. We suggest that cladribine is an effective treatment option for recurrent/refractory RDD.

Summary: The nucleoside analogue, 2‐chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO−) involvement. However, we lack data on long‐term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long‐term tolerance. This study included 44 children from the French LCH registry, treated for a RO− LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3–19·7 years) and the median follow‐up after was 5·4 years (range, 0·6–15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five‐year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five‐year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long‐term therapy for treating patients with RO− LCH. Appropriate management of induced immune deficiency is mandatory. [ABSTRACT FROM AUTHOR]

Summary: Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult‐onset cases. A complete picture of the efficacy and safety of 2CdA (2‐chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a‐LCH) patients who received single‐agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3–4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m2. Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re‐treated patients, five went into CR, two in PR, and one died. Single‐agent 2CdA is effective in reactivated a‐LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine). [ABSTRACT FROM AUTHOR]

Cladribine is a nucleoside analogue widely used in the pharmaceutical industry for the treatment of several neoplasms, including hairy‐cell leukemia among others. This compound has also shown efficacy in the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In this work, a green bioprocess for cladribine biosynthesis using immobilized Arthrobacter oxydans was developed. The microorganism was stabilized by entrapment immobilization in the natural matrix alginate. Different reaction parameters were optimized obtaining a biocatalyst able to achieve cladribine bioconversion values close to 85% after 1 hr, the shortest reaction times reported so far. The developed bioprocess was successfully scaled‐up reaching a productivity of 138 mg L−1 hr−1. Also, the biocatalyst was stable for 5 months in storage and in 96 hr at operational conditions. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) tract involvement in Langerhans cell histiocytosis (LCH) is extremely rare. Langerhans cell histiocytosis with GI tract involvement (GI-LCH) is frequently associated with multi-system disease, and usually presents with severe systemic symptoms, such as protein-losing enteropathy (PLE). Although the GI tract is not included among the organs at risk, the prognosis of GI-LCH is poor, and no effective chemotherapeutic regimen has been identified. Here, we report an infant case of primary refractory GI-LCH with PLE that showed marked improvement in response to 2-chlorodeoxyadenosine (2-CdA) therapy with no severe adverse events, even under conditions of deteriorating general health. The present findings indicate that 2-CdA may be effective for refractory GI-LCH with PLE. Further studies are warranted to determine the optimal therapeutic strategies for GI-LCH with PLE. [ABSTRACT FROM AUTHOR]

Langerhans'-cell histiocytosis of unknown cause that often manifests as massive cervical lymphadenopathy in children and adults, but infiltration of other lymphatic nodes can occur. The disease can affect the skin, lungs and central nervous system. Spontaneous remissions occur, but patients with bulky or symptomatic disease require treatment. Prednisone, methotrexate and cytotoxic agents such as 2-chlorodeoxyadenosine and clofarabine are used with variable success as first line therapy. Immunomodulatory drugs (thalidomide, lenalidomide and rituximab) have shown some positive results and can be used as second line treatment. [ABSTRACT FROM AUTHOR]

Background: Langerhans cell histiocytosis (LCH) is the most common type of histiocytosis and characterized by abnormal proliferation and excess accumulation of inflammatory and langerhans cells at various tissue sites. Clinical manifestations are variable, ranging from spontaneously regressing single bone lesion to multisystem disease, life-threatening and refractory to treatment. Conventional chemotherapy has been shown to be effective in treatment of majority of patients with LCH. However, treatment of refractory disease or multiple reactivations is difficult. The aim of this study is to assess the efficacy of 2-CDA in relapsed or refractory LCH. Materials and methods: Four patients with relapsed or refractory LCH that were treated with 2-chlorodeoxyadenosin (2-CDA) enrolled in this study. All patients had received at least one prior chemotherapy regimen. The dose and schedule of 2-CDA was 6 mg/m²/day for 5 days every 3-4 weeks. Results: Median age at the time of treatment with 2-CDA was 9.7 years. Three patients had multisystem disease and one had multifocal bone lesions. All patients had multifocal bone lesions. None of them had risk organ involvement. Mean course of treatment with 2-CDA was 9.5. Radiologic evaluations revealed complete resolution of bone lesions in two (50%) patients. In one (25%) patient lesions regressed (partial response) and in another (25%) the disease remained stable. Drug related side effects were minimal. At the present time all patients are alive. Conclusion: Our study demonstrates that 2-CDA as a single agent is efficacious in treatment of multiple reactivations or refractory LCH and well-tolerated in children. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is sometimes resistant to conventional chemotherapies, and treatment with 2-chlorodeoxyadenosine (2-CdA) is gaining importance as a salvage treatment for refractory or recurrent LCH. Secondary malignancies such as acute myelogenous leukemia and myelodysplastic syndrome (MDS) due to 2-CdA have recently been reported. However, there have been no reports to date of cases of 2-CdA-related secondary MDS in which spontaneous remission was achieved. Here, we report the case of a 1-year-old boy with an occipital tumor who was diagnosed with LCH by biopsy and underwent chemotherapy. However, the disease relapsed and became refractory to chemotherapy. He received 2-CdA treatment, which was effective. However 6 months after the start of treatment, he developed MDS with chromosomal abnormality of 7q−. After 1-year observation without any intervention, his hematological findings had returned to normal, and the chromosomal abnormality had also disappeared. To our knowledge, this is the first report of 2-CdA-related MDS with spontaneous hematological remission. [ABSTRACT FROM AUTHOR]

The functional evaluation of ataxia telangiectasia mutated (ATM) and p53 was recently developed in B-cell chronic lymphocytic leukaemia (B-CLL), a disease in which the response to DNA damage is frequently altered. We identified a novel biomarker of chemosensitivity based on the induction of DNA damage by the purine nucleoside analogues (PNA) fludarabine and 2-chlorodeoxyadenosine (CdA). Using genome-wide expression profiling, it was observed that, in chemosensitive samples, PNA predominantly increased the expression of p53-dependent genes, among which PLK2 was the most highly activated at early time points. Conversely, in chemoresistant samples, p53-dependent and PLK2 responses were abolished. Using a quantitative real time polymerase chain reaction, we confirmed that PNA dose- and time-dependently increased PLK2 expression in chemosensitive but not chemoresistant B-CLL samples. Analysis of a larger cohort of B-CLL patients showed that cytotoxicity induced by PNA correlated well with PLK2 mRNA induction. Interestingly, we observed that failure to up-regulate PLK2 following PNA and chemoresistance were not strictly correlated with structural alterations in the TP53 gene. In conclusion, we propose that testing PLK2 activation after a 24-h incubation with PNA could be used to investigate the functional integrity of DNA damage-response pathways in B-CLL cells, and predict clinical sensitivity to these drugs. [ABSTRACT FROM AUTHOR]

Rosai-Dorfman disease (RDD) or "sinus histiocytosis with massive lymphadenopathy" is a rare lymphoproliferative disorder of unknown etiology. The disease usually presents with painless lymphadenopathy with occasional extranodal involvement in various organs. We report a case of a 36-year-old man with a history of non-Hodgkin lymphoma (NHL), who recently presented with inguinal lymphadenopathy. Following the diagnosis of RDD on lymph node biopsy, he developed symptoms of spinal cord compression due to a mass lesion discovered at T6-7 vertebral level. 18F-Fluorodeoxyglucose (18FDG) positron emission tomography (PET-CT) revealed extensive disease with lung, renal and bone involvement. The patient received a short course of steroid therapy for cord compression findings and 2-chlorodeoxyadenosine (2-CdA) treatment was initiated for long-term disease control. He had a dramatic sustained response to treatment with six courses of 2-CdA. These results suggest that 2-CdA can be an effective treatment of choice and positron emission tomography with 18FDG can be used for determining the extent of disease and for follow-up in RDD. [ABSTRACT FROM AUTHOR]

Before the advent of rationally designed targeted antineoplastic therapies, cladribine was identified as a lymphocyte-specific cytotoxic agent. Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström's macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin's lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions. Future Phase III clinical studies should incorporate cladribine into multiagent chemotherapy programs to more fully evaluate its potential in indolent non-Hodgkin's lymphoma. [ABSTRACT FROM AUTHOR]

Summary: Pulmonary Langerhans cell histiocytosis (LCH) is an uncommon cause of interstitial lung disease. Corticosteroids and chemotherapeutic agents are frequently used to treat symptomatic patients but their efficacy is unclear. We describe a 66-year-old with biopsy-proven pulmonary and systemic LCH, whose pulmonary abnormalities responded dramatically to treatment with 2-chlorodeoxyadenosine (2-CdA). We propose that, in selected cases, 2-CdA should be considered in the management of pulmonary LCH. [Copyright &y& Elsevier]

We previously reported (UroOncology 1:165, 2001) cross-resistance and collateral-sensitivity to 2-chlorodeoxyadenosine (CldAdo) and fludarabine (FaraA), respectively, in a human renal cell carcinoma selected for resistance to 2′-deoxytubercidin (Caki-dTub). Insofar that these drugs generally demonstrate cross resistance rather than collateral sensitivity, we further examined the bases for this phenomenon. Both CldAdo and FaraA induce apoptosis, as the triphosphates, via binding to Apaf-1. In the presence of cytochrome c, this binding leads to activation of procaspase 9 to active caspase 9 that induces apoptosis through its activation of caspase 3. CldAdo and FaraA induced caspase 3 activities in wild type and Caki-dTub cell lines in a dose-dependent manner that paralleled the cross-resistance (CldAdo, 200-fold) or collateral sensitivity (FaraA, 20-fold) with regard to cell viability. The activation of caspase 3 was inhibited by the caspase 9 inhibitor, Z-LEHD-FMK, suggesting that both drugs act via the same pathway. By differential display and direct enzyme analysis, dihydrodiol dehydrogenase (DDH) was observed to be profoundly underexpressed in the Caki-dTub compared to wild-type Caki-1 cells. Stable transfection of the Caki-dTub cells with a vector encoding the enzyme led to partial reversal of the resistance to CldAdo. Resistance to cisplatin has recently been ascribed to overexpression of DDH in a human ovarian carcinoma cell line (Deng et al. in J Biol Chem 227:15035, 2002). It is tempting to speculate a mutation in the Apaf-1 nucleotide binding site that reduces (CldAdo) or increases (FaraA) toxicity in the Caki-dTub cells; however, the recent finding by others in a human ovarian carcinoma cell line suggests that DDH expression mediates the cross-resistance and perhaps, collateral-sensitivity. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the efficacy of 2-chlorodeoxyadenosine (2-CdA), a purine nucleoside analog, in treating recurrent Langerhans cell histiocytosis (LCH) in children. This study retrospectively analysed the clinical records of 13 patients who were seen in the department for recurrent LCH. These patients were treated consecutively with 2-CdA chemotherapy between July 1997 and May 2005. Median age at diagnosis was 4 years 7 months and median pre-treatment duration of disease was 16.4 months. Four children received 0.1 mg kg-1 per day for 7 days and nine patients 5 mg m-2 per day for 5 days, repeated every 21 days. The maximum number of courses of 2-CdA per patient was limited to six. Seventy-six courses of 2-CdA were administered without difficulty. All 13 patients (100%) had a clinical response documented by radiographic investigation. Nine patients did not require additional therapy and remain in complete remission (CR). Four remaining children are currently disease-free after receiving other therapy as irradiation (two cases) or maintenance chemotherapy (vinblastine, prednisone and 6-mercaptopurine) (one case) or chemothery (vinblastine) + irradiation (one child) ( Table I). Hematologic toxicity was minimal and no infectious complications were documented. Median follow-up after initiation of 2-CdA treatment was 4 years 3 months (range 7 months – 8 years 2 months). This experience confirms the reported efficacy of 2-CdA in the treatment of LCH. However, further studies are needed to determine the role of this agent in high-risk patient who did not achieve complete remission after 2-CdA administration. [ABSTRACT FROM AUTHOR]

Purine nucleoside analogues, cladribine (2-chlorodeoxyadenosine, 2-CdA) and fludarabine (FAMP) are active agents in acute myeloid leukemias (AMLs). Synergistic interaction between FAMP or 2-CdA with cytarabine (cytosine arabinoside, Ara-C) has been demonstrated in preclinical and clinical studies. The current multicenter phase II study was initiated to evaluate the efficacy and toxicity of induction treatment consisting of 2-CdA (5 mg/m2), Ara-C (2 g/m2), mitoxantrone (MIT, 10 mg/m2) and granulocyte colony-stimulating factor (G-CSF) (CLAG-M) in refractory AML. In case of partial remission, a second CLAG-M was administered. Patients in complete remission (CR) received consolidation courses based on high-dose Ara-C and MIT with or without 2-CdA. Forty-three patients from five centers were registered: 25 primary resistant and 18 relapsed. CR was achieved in 21 (49%) patients, 20 (47%) were refractory and 2 (5%) died early. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS; 1 year) for the 42 patients as a whole and the 20 patients in CR were 43% and 73%, respectively. Disease-free survival (1 year) was 68.6%. None of the analyzed prognostic factors influenced the CR and OS probability significantly. We conclude that CLAG-M regimen has significant antileukemia activity in refractory AML, which seems to be better than the activity of many other regimens. The toxicity of the treatment is acceptable. [ABSTRACT FROM AUTHOR]

Abstract: The inborn deficiency of adenosine deaminase is characterised by accumulation of excess amounts of cytotoxic deoxyadenine nucleotides in lymphocytes. Formation of dATP requires phosphorylation of deoxyadenosine by deoxycytidine kinase (dCK), the main nucleoside salvage enzyme in lymphoid cells. Activation of dCK by a number of genotoxic agents including 2-chlorodeoxyadenosine, a deamination-resistant deoxyadenosine analogue, was found previously. Here, we show that deoxyadenosine itself is also a potent activator of dCK if its deamination was prevented by the adenosine deaminase inhibitor deoxycoformycin. In contrast, deoxycytidine was found to prevent stimulation of dCK by various drugs. The activated form of dCK was more resistant to tryptic digestion, indicating that dCK undergoes a substrate-independent conformational change upon activation. Elevated dCK activities were accompanied by decreased pyrimidine nucleotide levels whereas cytotoxic dATP pools were selectively enhanced. dCK activity was found to be downregulated by growth factor and MAP kinase signalling, providing a potential tool to slow the rate of dATP accumulation in adenosine deaminase deficiency. [Copyright &y& Elsevier]

2-Chlorodeoxyadenosine (cladribine or 2-CdA) is a purine analogue that has been used successfully in hairy cell leukaemia (HCL). Moreover, it has been increasingly used to treat chronic lymphoproliferative syndromes and paediatric acute myeloid leukaemia. Cutaneous side-effects associated with this drug have seldom been described in cases of HCL. We describe three patients with chronic lymphocytic leukaemia that presented generalized skin eruptions after treatment with 2-CdA. All patients had advanced disease, receiving 2-CdA as a second or third line chemotherapy. Skin lesions were severe and chemotherapy had to be discontinued. Histological examination of skin biopsies showed an eosinophil-rich infiltrate with flame figures, similar to what is observed in Wells’ syndrome (eosinophilic cellulitis). Corticosteroids were effective to control the eruptions. Cutaneous adverse reactions associated with 2-CdA have seldom been observed in the treatment of HCL. However, as this purine analogue has been used in more advanced cases these may be more frequent and severe. The pathophysiology of these lesions is unclear, but it is probably related to drug-induced change in T-cell imbalance in severely immunosuppressed patients. [ABSTRACT FROM AUTHOR]

A number of genotoxic and antiproliferative agents such as 2-chlorodeoxyadenosine(Cladribine; CdA) and aphidicolin(APC) have been shown to stimulate the activity of deoxycytidine kinase, the main deoxynucleoside salvage enzyme in lymphocytes. Here we show that enzyme activation could be prevented by treating cells with the membrane-permeant calcium chelator BAPTA-AM. Long-term incubations demonstrated that CdA and APC not only stimulated but also sustained deoxycytidine kinase activity in the cellular context, as compared to the control and BAPTA-AM treated enzyme activities. [ABSTRACT FROM AUTHOR]

A non-radioactive procedure to measure the deoxycytidine kinase (dCK) activity in crude cell free homogenates was developed. 2-Chlorodeoxyadenosine (CdA) was used as the substrate for dCK and was separated from its product 2-chlorodeoxyadenosine-5′-monophosphate (CdAMP) by reversed-phase HPLC. A complete separation of CdA and its metabolites was achieved in 30 min. The minimum amount of CdAMP that could be detected was 1 pmol. The assay was linear with reaction times up to at least 3 h. With respect to the protein concentration, the reaction was linear with protein concentrations up to 760 μg/ml in the assay. An amount of 8×103 cells was already sufficient to determine the specific dCK activity in SK-N-BE(2)c cells. CdA was not only converted to CdAMP but also to 2-chloroadenine and, surprisingly, also to 2-chlorodeoxyinosine, in MOLT-3 cells. The deamination of CdA was completely inhibited by deoxycoformycin, which clearly demonstrates that CdA is a substrate for adenosine deaminase. [Copyright &y& Elsevier]

Systemic mastocytosis (SM) are defined by an abnormal growth and accumulation of mast cells in bone marrow and/or other extracutaneous organs. There is currently no cure for this disease. Because of similarities and/or association of mastocytosis with myeloproliferative disorders, interferon alpha has been tested but with contradictory reported results. A first prospective multicenter phase II trial was then started in France. From 1994 to 1997, 20 adult patients with confirmed bone marrow involvement received interferon α-2b for at least 6 months, (from 1 million U per day up to 5 million U/m2/day). Thirteen patients who presented systemic and/or specific cutaneous manifestations, demonstrated objective responses: seven (35%) were partial, six (30%) minor but no complete response could be observed at the time of analysis. The bone marrow remained unchanged in 12/13. Thus, interferon should be offered to patients with severe systemic manifestations, who have not responded to symptomatic therapies, even in case of non-aggressive mastocytosis, with or without corticosteroids the first weeks. Long-term therapy should be offered to patients with initial positive response. To control more aggressive SM or mastocytosis associated with clonal hematologic non-mast cell lineage or leukaemia mast cell, other chemotherapeutic regimens should be proposed like Cladribine (2-chlorodeoxyadenosine, 2-CDA) or polychemotherapies including interferon as it is being tested in France in a new multicentric protocol, coordinated by the association AFIRMM, with interferon and oral cytarabine. [Copyright &y& Elsevier]

Purine nucleoside analogues are unique drugs that are effective in a variety of hematologic malignancies. Fludarabine and 2-chlorodeoxyadenosine (2-CdA) are active in chronic lymphocytic leukemia (CLL) both as salvage therapy and in newly diagnosed patients. These agents have revolutionized therapeutic strategies for patients with CLL that had remained unchanged for many years and included alkylating agents-based therapy with no potential for long-term remission or cure. Purine analogues have also been successfully combined with a variety of other chemotherapeutic drugs such as mitoxantrone, cyclophosphamide, corticosteroids, and monoclonal antibodies, specifically Rituximab and CAMPATH-1H. These agents are immunosuppressive and have been associated with opportunistic infections, the incidence of which can be significantly reduced by early recognition and administration of prophylactic antibiotics. In this review, the activity and toxicity of 2-CdA, fludarabine, and pentostatin in CLL as single agents and in combination with conventional chemotherapy are discussed. These drugs are increasingly used as initial therapy in CLL. Such strategies are associated with higher remission rates than have been previously achieved and in some cases, molecular remission, suggesting an important step towards cure. [Copyright &y& Elsevier]

We used three to six courses of 2-chlorodeoxyadenosine (2-CdA) (2-h infusion at 0.14 mg/kg per day × 5 days) given over a period of 3–36 months to treat four patients with aggressive systemic mast cell disease (SMCD) that was resistant to interferon-alpha (IFN-α). Treatment with 2-CdA resulted in a major response in two patients and a good partial response in one other patient (75% overall response). Treatment was well tolerated and duration of remission in responding patients ranges from 2 months to 4+ years since the completion of treatment with 2-CdA. [Copyright &y& Elsevier]

Abstract: Objectives: To evaluate the efficacy and toxicity of cladribine (2-chlorodeoxyadenosine, 2-CdA), cytarabine (Ara-C), and granulocyte-colony stimulating factor (G-CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study. Methods: The induction chemotherapy consisted of 2-CdA 5 mg/m[sup 2] , Ara-C2 g/m[sup 2] , and G-CSF. In the case of partial remission (PR), a second CLAG was administered. Patients in complete remission (CR) received two consolidation courses based on HD Ara-C, mitoxantrone or idarubicine, with or without 2-CdA. Results: Fifty-eight patients from 11 centers were registered; 50 primary resistant and eight early relapsed (CR1 < 6 months). CR was achieved in 29 (50%) patients, 19 (33%) were refractory, and 10 (17%) died early. Forty of 50 primary resistant patients received daunorubicin (DNR) and Ara-C as the first-line induction therapy (DA-7), 10 received additional 2-CdA (DAC-7). The CR rates after CLAG were 58% and 10%, respectively in each group (P = 0.015). Five of six patients with myelodysplastic syndrome (MDS)/AML achieved CR. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS, 1 yr) for the 58 patients as a whole, and the 29 patients in CR were 42% and 65%, respectively. Disease-free survival (DFS, 1 yr) was 29%. Only first-line induction treatment with DA-7 significantly influenced the probability of CR after CLAG. None of the analyzed factors significantly influenced DFS and OS. Conclusion: CLAG regimen has significant anti-leukemic activity and an acceptable toxicity in refractory AML. The addition of 2-CdA to the first-line induction treatment may worsen the results of salvage with CLAG. The high CR rate in patients with MDS preceding AML deserves further observation. [ABSTRACT FROM AUTHOR]

A 58-year-old woman with a 15-year history of chronic plaque psoriasis was diagnosed with gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. Topical treatment and ultraviolet radiation for therapy of psoriasis had been of limited efficacy. The patient received intravenous treatment with 0.12 mg/kg per day of 2-chlorodeoxyadenosine (2-CDA) over 5 days for management of MALT lymphoma, as it was resistant to eradication of Helicobacter pylori. A total of six cycles were administered from June 1999 until November 1999 (cumulative dose 244.8 mg 2-CDA). After 2 months of 2-CDA administration, psoriatic skin lesions improved significantly, and after 3 months, complete remission of skin lesions was observed. Ongoing complete remission of the MALT lymphoma could be achieved after six cycles of 2-CDA administration. After a follow-up period of 34 months, no recurrence of psoriatic lesions has occurred. The patient is at present free of psoriatic plaques and gastric MALT lymphoma. The course of disease in our patient provides evidence for sustained therapeutic efficacy of 2-CDA in chronic plaque psoriasis in the absence of severe side effects except asymptomatic lymphopenia. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the effect of three anthracyclines [doxorubicin (DOX), mitoxantrone (MIT), and idarubicin (IDA)] on the rate of apoptosis triggered by 2-chlorodeoxyadenosine (2-CdA) in peripheral blood mononuclear cells isolated from 52 untreated patients with B-cell chronic lymphocytic leukemia (B-CLL). The cells were cultured up to 48 h in the presence of drugs alone and in the following combinations: 2-CdA+DOX, 2-CdA+MIT, and 2-CdA+IDA. Apoptosis was assessed after 24 h and 48 h of incubation using annexin V/propidium iodide assay by flow cytometry. The apoptotic index (AI) was defined as a percentage of annexin V-positive B-CLL cells. Additionally, in some patients other hallmarks of apoptosis (activation of caspases, DNA fragmentation) were assessed in parallel for confirmation of apoptotic mode of induced cell death. All of the cytostatics induced apoptosis of B-CLL cells at a rate significantly higher than the index of spontaneous apoptosis occurring during 24 h and 48 h of cell culture. 2-CdA in combination with DOX significantly increased the percentage of annexin V-positive cells, particularly after 48 h of incubation, as compared with DOX used in monotherapy (median AI for 2-CdA+DOX=37.9%, median AI for DOX =13.8%, P=0.0011, and median AI for 2-CdA=22.1%, P=0.013). Combination of 2-CdA with MIT induced a similar effect, also more distinct after 48 h (median AI for 2-CdA+MIT=41.05%, median AI for MIT=16.3%, p=0.0012, and median AI for 2-CdA=22.1%, p=0.017). For both combinations median AI were similar to the sum of median AI for each drug when used alone. IDA in a concentration ten times lower (0.1 µg/ml) than used before in acute leukemia cells produced high cytotoxic effects, masking the additive effect of combination with 2-CdA. Only at a dose of 25 ng/ml of IDA, significant differences in AI after 24 h and 48 h were detected between samples treated with 2-CdA+IDA (median 27.5% and 65.0%, respectively) and those incubated with IDA alone (median 10.5% and 33.4%; P=0.0004 and 0.0274, respectively). Similarly, there were significant differences between AI of cells treated with 2-CdA+IDA and 2-CdA alone (median 9.5% at 24 h and 23.5% at 48 h; P=0.0013 and 0.0207, respectively). In conclusion; these data indicate an additive cytotoxic effect on B-CLL cells of DOX, MIT, and IDA applied in vitro with 2-CdA; all of them induced apoptosis with similar efficacy. We suggest that further preclinical and clinical studies concerning combined use of 2-CdA with anthracyclines are desirable. High sensitivity of B-CLL cells to IDA suggests the possibility of lowering its dose in patients, especially when combined with 2-CdA. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the influence of gemcitabine (2′,2′‐difluorodeoxycytidine, dFdC) used alone and in combination with 2‐chlorodeoxyadenosine (2‐CdA) on the colony growth of normal granulocyte‐macrophage progenitor cells (CFU‐GM) from 15 hematologically healthy donors as well as on CFU‐GM from 15 chronic myelogenous leukemia (CML) patients in semisolid cultures in vitro. dFdC and 2‐CdA were used either separately or in the following combinations of concentrations: (1) 0.25 nM of dFdC and 2.5 nM of 2‐CdA; (2) 0.5 nM of dFdC and 5 nM of 2‐CdA; (3) 1 nM of dFdC and 10 nM of 2‐CdA; (4) 2 nM of dFdC and 20 nM of 2‐CdA. We observed that both dFdC and 2‐CdA used separately inhibited the growth of colonies formed by normal and CML CFU‐GM cells in a dose‐dependent manner. Moreover, the combined therapy with dFdC and 2‐CdA caused statistically significant inhibition of the colony growth in both normal and CML CFU‐GM cultures. In addition, the inhibition of CML CFU‐GM colony formation was greater and statistically significant in the case of the combined therapy using higher concentrations of these drugs as compared with inhibition of the growth of normal CFU‐GM colonies. These observations were the basis for the evaluation of the interaction type between dFdC and 2‐CdA. We have shown that dFdC used in a combination with 2‐CdA acts in an additive way on normal and CML CFU‐GM cells. [ABSTRACT FROM AUTHOR]

a cDNA for the organic cation transporter (rOCT2) of the rat kidney was inserted into the retroviral plasmid pLXSN. This plasmid was used to stably transfect NIH3T3 cells. The transfected cell line exhibited an enhanced rate of tetraethylammonium (TEA) uptake and efflux compared to wild-type HNIH3T3 cells. Uptake of TEA by the transfected cells was markedly reduced upon incubation at 4°C. When the extracellular pH was lowered from 8.1 to 5.9, uptake was also reduced, suggesting inhibition of rOCT2 by extracellular protons. The apparent Km for TEA in the transfected cells was 141 μM. The classical organic cation transport inhibitors, cyanine 863 and cimetidine, produced noncompetitive inhibition with apparent Ki values of 0.81 and 198 μM, respectively. Daunomycin, vinblastine, and the deoxyadenosine analogs, 2'-deoxytubercidin and 2-chlorodeoxyadenosine, did not appear to be substrates for rOCT2. However, the anticancer drug, cisplatin, competitively inhibited TEA uptake by rOCT2 with an apparent Ki value of 925 μM, suggesting that rOCT2 may play a role in its renal secretion. In summary, transfected NIH3T3 cells provide a facile system by which this and other organic ion transporters can be studied. [ABSTRACT FROM PUBLISHER]

The purine analogue 2-chlorodeoxyadenosine (2-CDA) has been shown to possess synergistic immunosuppressive properties when given together with cyclosporin (CSA) in a rat small bowel transplant model. The present study investigated the immunosuppressive potency of 2-CDA alone and in combination after liver or heart transplantation in a fully allogeneic rat model with 5 animals in each group. Immunosuppression was provided with CSA 10 mg/kg body weight (BW)/day orally or 2-CDA 0.1 mg/kg/BW day intravenously or both compounds together in the dosages mentioned. Animals were sacrificed on day 10 following transplantation, and graft histology was assessed. In addition, cardiac graft function was evaluated by palpation immediately prior to sacrificing the animal. CSA given alone was able to mitigate but not prevent rejection. 2-CDA alone did not exhibit any detectable immunosuppressive effect. When CSA was combined with 2-CDA, no rejection was seen in 80% of the liver allografts and in 60% of heart allografts, and only mild rejection was observed in the remaining animals. All hearts of the combined treatment group, however, beat strongly. From these findings it is concluded that 2-CDA alone has no, but together with CSA a strong immunosuppressive effect in preventing solid organ allograft rejection. [ABSTRACT FROM AUTHOR]

Twenty patients suffering from subarachnoid haemorrhage due to ruptured intracranial aneurysm and operated on within 72 h after SAH were treated with an experimental immunosuppressive drug 2-chlorodeoxyadenosine (2-CDA). dose 0.05 mg/kg/day i.v. for 7 days. The 2-CDA treatment was started immediately after angiographic confirmation of ruptured aneurysm, and the standard pharmacological treatment (nimodipine and steroids) was also given. 50% of patients were severely threatened by 'delayed vasospasm' or late neurological deficit (Fisher's score 3 or 4). The neurological outcome (assessed 8-12 weeks after SAH) was good (GOS=1) in 70%, and fair (moderate disability, GOS=2) in 25%. A single case of severe disability (GOS=3), as well as two cases of less than perfect outcome (GOS=2), were related to unusual pre- or intraoperative complications. We conclude that the low doses of 2-CDA can be considered as a valuable adjunct to the standard pharmacotherapy of SAH patients operated on early. [ABSTRACT FROM AUTHOR]

Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m2 per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m2 per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m2 per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (< 1,000/microliters) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Non-hematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37 degrees-40 degrees C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cpss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m2 per day. Both the Cpss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m2 per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m2 per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies. [ABSTRACT FROM AUTHOR]

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 R2 values of >0.98. The calculated rate of elimination, kelim, 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. [ABSTRACT FROM AUTHOR]

Leukemic hairy cells are clonally proliferating B-lymphoid cells with clonal rearrangements of genes for immunoglobulin chains. We describe a patient with a new hairy-cell clone after treatment with 2-chlorodeoxyadenosine (2-CdA). In this patient, a single course of 2-CdA resulted in good partial remission of hairy-cell leukemia, but Southern blot analysis of bone marrow biopsies and polymerase chain reaction using seminested amplifications with consensus primers revealed a new rearranged band 4 months after therapy with 2-CdA. Four years after therapy, the patient is in complete clinical remission and both bands disappeared during follow-up. The new rearranged band might have been related to prior treatment of hairy-cell leukemia with 2-CdA.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Fungal infections, in addition to bacterial and opportunistic infections such as Pneumocystis carinii pneumonia, may evolve in patients with infectious complications due to iatrogenic immunosuppression. Aside from common Candida and Aspergillus species, rare fungi like Mucor must be considered in patients with neutropenia or prolonged impaired T-cell function. Here we report on a patient with a low grade lymphoma who was treated with 2-chlorodeoxyadenosine because of disease progression. After recovery from Pneumocystis carinii pneumonia he presented again with clinical signs of pneumonia. No pathogen was found on bronchoscopy and he died rapidly. In the lungs a massive necrosis was seen in which nonseptated hyphae identified as Mucor species were demonstrated. [ABSTRACT FROM AUTHOR]