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"An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia." (MeSH 2013)

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Latest Research Publications

Web Resources: Cladribine (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Matutes E, Martínez-Trillos A, Campo E
Hairy cell leukaemia-variant: Disease features and treatment.
Best Pract Res Clin Haematol. 2015; 28(4):253-63 [PubMed] Related Publications
Hairy cell leukaemia-variant (HCL-V) is a rare B-cell malignancy that affects elderly males and manifests with splenomegaly, lymphocytosis and cytopenias without monocytopenia. The neoplastic cells have morphological features of prolymphocytes and hairy cells. The immunophenotype is that of a clonal B-cell CD11c and CD103 positive but, unlike classical HCL, CD25, CD123 and CD200 negative. The spleen histology is similar to classical HCL and the pattern of bone marrow infiltration is interstitial and/or intrasinusoidal. Mutations of the immunoglobulin heavy chain (IGVH) are seen in two thirds of cases with a preferential VH4-34 family usage. There is no distinct chromosomal abnormality but del17p13 and mutations of the TP53 gene are frequent. Mutations in the MAP2K1 gene have been documented in half of the cases. The course is chronic with median survivals of 7-9 years. Patients are refractory to purine analogues and the most effective therapy is the combination of 2-chlorodeoxyadenosine and Rituximab.

Ravandi F
Chemoimmunotherapy for hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):230-5 [PubMed] Related Publications
Success in the treatment of patients with hairy cell leukemia (HCL) over the last several decades is largely due to the high efficacy of the nucleoside analogs, cladribine and pentostatin. However, the relapse-free survival curves have not shown a plateau and many patients treated with these agents will eventually relapse. Although better understanding of the pathogenic mechanisms in HCL have led to effective and novel options for the treatment of relapse, long term durability of the responses obtained with these agents still remains unclear. Combination of nucleoside analogs with monoclonal antibodies such as rituximab has been shown to be safe and effective and has the potential to supersede the nucleoside analogs as the frontline strategy. Such chemo-immunotherapy approaches are under further investigation and will have to be assessed with socioeconomic considerations in mind. Other novel monoclonal antibodies, approved for the treatment of other lymphoid neoplasms, may also be considered for future studies of chemo-immunotherapy.

Else M, Dearden CE, Catovsky D
Long-term follow-up after purine analogue therapy in hairy cell leukaemia.
Best Pract Res Clin Haematol. 2015; 28(4):217-29 [PubMed] Related Publications
Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.

Shen Y, Chen J, Liu Y, Wu D
Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison.
Chemotherapy. 2014; 60(5-6):368-74 [PubMed] Related Publications
OBJECTIVES: The aims of this study were to evaluate a novel induction regimen composed of idarubicin (IDA), cytarabine (Ara-C) and cladribine (IAC regimen) for acute myeloid leukemia (AML) patients, and to identify the prognostic factors affecting treatment outcomes.
METHODS: The clinical data of 27 untreated AML patients who received the IAC regimen as primary induction therapy in our hospital between April and November 2014 were analyzed retrospectively. The treatment outcomes of the IAC regimen were compared with two IA (IDA + Ara-C) regimens (IDA 10 mg/m² and IDA 12 mg/m²) in a pair-matched analysis.
RESULTS: The complete remission (CR) rate in the IAC arm was higher compared to the IA(L) arm (p = 0.002) as was the overall efficacy rate (p = 0.017). There was no significant difference in outcomes between the IAC and IA(H) (Ara-C with high-dose IDA) arms. The IAC arm contained significantly higher CR rates than the IA(L) (Ara-C with low-dose IDA) arm in both the intermediate group (p = 0.050) and the unfavorable group (p = 0.013). Toxicity did not differ between the IAC group and the other two arms. High WBC at diagnosis (p = 0.022) and an unfavorable karyotype (p = 0.026) were related to a poorer response. The IAC regimen (p = 0.013) had greater superiority over the IAL regimen on efficacy than over the IA(H) regimen (p = 0.041).
CONCLUSIONS: The IAC regimen achieved a more significant advantage over the IA(L) regimen without increasing the risk of adverse events. The efficacy of induction therapy is associated with WBC at diagnosis, karyotype and induction regimen.

Satishkumar S, Vuram PK, Relangi SS, et al.
Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.
Molecules. 2015; 20(10):18437-63 [PubMed] Related Publications
Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

Akin C
Cladribine for mastocytosis: benefits and risks.
Blood. 2015; 126(8):931-2 [PubMed] Related Publications
In this issue of Blood, Barete et al report the safety and efficacy of cladribine in 68 adult patients with mastocytosis.

Sakai T, Masaki Y, Otsuki N, et al.
Prospective clinical study of R-CMD therapy for indolent B cell lymphoma and mantle cell lymphoma from the Hokuriku Hematology Oncology Study Group.
Med Oncol. 2015; 32(9):232 [PubMed] Free Access to Full Article Related Publications
Standardized treatments for indolent B cell lymphoma primarily consisting of follicular lymphoma (FL) and for mantle cell lymphoma (MCL) have yet to be established. Here the Hokuriku Hematology Oncology Study Group conducted a multicenter prospective study to investigate the efficacy and safety of a combination regimen of rituximab, cladribine, mitoxantrone, and dexamethasone (R-CMD) in indolent B cell lymphoma and MCL. A total of 33 CD20-positive patients who received care between January 2008 and August 2011 were investigated. These patients' illnesses were FL (n = 21), nodal marginal zone B cell lymphoma (NMZB, n = 3), MCL (n = 3), splenic marginal zone B cell lymphoma (n = 2), hairy cell leukemia (n = 1), Waldenstrom macroglobulinemia (WM, n = 1), and lymphoplasmacytic lymphoma (LPL, n = 2). Patients received four 21-day cycles of rituximab 375 mg/m(2) (day 1), cladribine 0.10 mg/kg (days 1-3), mitoxantrone 8 mg/m(2) (day 1), and dexamethasone 8 mg/body (days 1-3), with four additional rituximab doses at 4-week intervals. Of the 33 patients, 26 achieved complete response/unconfirmed complete response, and six achieved a partial response (4 with FL, 1 with NMZB, 1 with WM). One had progressive disease (FL), and four relapsed after remission (1 with FL, 2 with MCL, 1 with LPL). R-CMD therapy was relatively convenient and effective in indolent B cell lymphoma and MCL. Nonetheless, to suppress the number and function of both B cells and T cells, comprehensive infection prevention and follow-up are necessary in the future.

Marisavljević D, Marković O, Živković R
Specificity of treatment is mandatory in very old patients with hairy cell leukemia.
Vojnosanit Pregl. 2015; 72(5):466-8 [PubMed] Related Publications
INTRODUCTION: There are only a few available data about hairy cell leukemia (HCL) in very old patients. We presented three very different cases of HCL in very old patients diagnosed in a single center and discussed some epidemiological and therapeutical issues in such patients.
CASE REPORT: The first patient, 89-year-old, had symptomatic cytopenia and achieved sustained complete remission after cladribine treatment. The second patient, 89-year-old, had asymptomatic disease with stable full blood counts during a 3-year follow-up period in which watch-and-wait policy was adopted. The third patient, 82 years old, had two malignancies (HCL and presumably metas- tatic colorectal carcinoma) and his only treatment were occasional red blood cell transfusions and symptomatic therapy.
CONCLUSION: The presented illustrative examples confirm individualization of treatment is mandatory in very old patients with HCL.

Barete S, Lortholary O, Damaj G, et al.
Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis.
Blood. 2015; 126(8):1009-16; quiz 1050 [PubMed] Related Publications
Mastocytosis (M) is a clonal myeloid-disabling disorder for which no curative therapy is currently available. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic purine analog cytoreductive treatment, for which efficacy is mostly reported in advanced M. Here we report, with a long-term follow-up period (>10 years) efficacy and safety in 68 adult patients with M (36 [53%] had indolent M and 32 [47%] had advanced M) treated by 2-CdA (0.14 mg/kg in infusion or subcutaneously, days 1-5; repeated at 4-12 weeks until 1 to 9 courses). Median 2-CdA courses number was 3.7 (1-9). The overall response rate was 72% (complete remission [R]/major/partial R: 0%/47%/25%) and according to indolent/advanced M was 92% (major/partial R: 56%/36%) and 50% (major/partial R: 37.5%/12.5%), respectively. Clinical improvement was observed for 10 of 11 mediator release and 6 of 7 mast cell infiltration-related symptoms including urticaria pigmentosa and organomegaly (P < .02). Serum tryptase levels decreased (P = .01). Median durations of response were 3.71 (0.1-8) and 2.47 (0.5-8.6) years for indolent and aggressive M, respectively. The most frequent grade 3/4 toxicities were lymphopenia (82%), neutropenia (47%), and opportunistic infections (13%). 2-CdA appears to provide a significant efficacy with some toxicity in various M subtypes, mostly in indolent M, refractory to multiple symptomatic therapies.

Creutzig U, Dworzak M, Zimmermann M, et al.
Randomised Introduction of 2-CDA as Intensification during Consolidation for Children with High-risk AML--results from Study AML-BFM 2004.
Klin Padiatr. 2015; 227(3):116-22 [PubMed] Related Publications
BACKGROUND: The outcome in children and adolescents with high-risk (HR) acute myeloid leukemia (AML) is still unsatisfactory. Therefore, in study AML-BFM 2004 we aimed to improve outcome of HR-patients by adding moderately dosed 2-Chloro-2-Deoxyadenosine (2-CDA) to the respective consolidation treatment backbone without increasing toxicity. The aim was to improve prognosis especially in FAB M4/M5/MLL patients, who represent the largest subgroup of HR patients.
PATIENTS AND METHODS: In total, 343 children and adolescents with HR-AML were randomized to receive or not 2-CDA (6 mg/m²/d, days 1, 3) in combination with cytarabine/idarubicine (AI=500 mg/m² cytarabine 5 days continuous infusion plus 7 mg/m²/d idarubicin, days 3 and 5).
RESULTS: RESULTS for patients of the AI/2-CDA arm (n=168) vs. the AI-arm (n=175) were similar: 5-year overall survival 68±4 vs. 72±4%, plogrank=0.38, event-free survival 53±4 vs. 49±4%, plogrank=0.77; cumulative incidence of relapse at 5 years: 35±4 vs. 37±4%, p(Gray)=0.89. RESULTS in patients with MLL rearrangement or FAB M4/M5 were also similar in the treatment groups. In addition, toxicities did not differ between the two arms.
CONCLUSION: We conclude that additional, moderate dose 2-CDA does not improve prognosis in HR-patients when given during consolidation treatment. Its effect might be too low in this multidrug regimen, where the strongest effects are achieved during induction, or the chosen dose of 2-CDA might have been too low.

Valdez BC, Li Y, Murray D, et al.
Comparison of the cytotoxicity of cladribine and clofarabine when combined with fludarabine and busulfan in AML cells: Enhancement of cytotoxicity with epigenetic modulators.
Exp Hematol. 2015; 43(6):448-61.e2 [PubMed] Free Access to Full Article Related Publications
Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia. We sought to determine whether the more affordable drug cladribine (Clad) can provide a viable alternative to Clo, with or without panobinostat (Pano) and 5-aza-2'-deoxycytidine (DAC). Both Clad+Flu+Bu and Clo+Flu+Bu combinations showed synergistic cytotoxicity in KBM3/Bu250(6), HL60, and OCI-AML3 cell lines. Cell exposure to these drug combinations resulted in 60%-80% inhibition of proliferation; activation of the ATM pathway; increase in histone modifications; decrease in HDAC3, HDAC4, HDAC5 and SirT7 proteins; decrease in mitochondrial membrane potential; activation of apoptosis and stress signaling pathways; and downregulation of the AKT pathway. These drug combinations activated DNA-damage response and apoptosis in primary cell samples from AML patients. At lower concentrations of Clad/Clo, Flu, and Bu, inclusion of Pano and DAC enhanced cell killing, increased histone modifications and DNA demethylation, and increased the levels of P16/INK4a, P15/INK4b and P21/Waf1/Cip1 proteins. The observed DNA demethylating activity of Clad and Clo may complement DAC activity; increase demethylation of the gene promoters for SFRP1, DKK3, and WIF1; and cause degradation of β-catenin in cells exposed to Clad/Clo+Flu+Bu+DAC+Pano. The overlapping activities of Clad/Clo+Flu+Bu, Pano, and DAC in DNA-damage formation and repair, histone modifications, DNA demethylation, and apoptosis may underlie their synergism. Our results provide a basis for supplanting Clo with Clad and for including epigenetic modifiers in the pre-hematopoietic stem cell transplantation conditioning regimen for myeloid leukemia patients.

Lock AD, McNamara CJ, Rustin MH
Sustained improvement in urticaria pigmentosa and pruritus in a case of indolent systemic mastocytosis treated with cladribine.
Clin Exp Dermatol. 2015; 40(2):142-5 [PubMed] Related Publications
Systemic mastocytosis (SM) is a myeloproliferative disorder, characterized by a clonal proliferation of abnormal mast cells accumulating in internal organs and sometimes in the skin, leading to cutaneous and systemic symptoms. Mutations within the gene KIT, which encodes the receptor tyrosine kinase (KIT) on mast cells, is found in most patients with SM. We report a case of a 62-year-old woman presenting with a pruritic rash on her limbs and trunk. Several years later she developed gastrointestinal symptoms, associated with raised serum tryptase. Skin and bone marrow biopsies confirmed a diagnosis of SM, initially presenting with urticaria pigmentosa. Responses to multiple therapies, including potent topical steroids, oral antihistamines, phototherapy and the tyrosine kinase inhibitor, nilotinib, were inadequate. Treatment with cladribine (2-chlorodeoxyadenosine) produced a marked and sustained reduction in her symptoms and serum tryptase level.

Hacioglu S, Bilen Y, Eser A, et al.
Multicenter retrospective analysis regarding the clinical manifestations and treatment results in patients with hairy cell leukemia: twenty-four year Turkish experience in cladribine therapy.
Hematol Oncol. 2015; 33(4):192-8 [PubMed] Related Publications
In this multicenter retrospective analysis, we aimed to present clinical, laboratory and treatment results of 94 patients with Hairy cell leukemia diagnosed in 13 centers between 1990 and 2014. Sixty-six of the patients were males and 28 were females, with a median age of 55. Splenomegaly was present in 93.5% of cases at diagnosis. The laboratory findings that came into prominence were pancytopenia with grade 3 bone marrow fibrosis. Most of the patients with an indication for treatment were treated with cladribine as first-line treatment. Total and complete response of cladribine was 97.3% and 80.7%. The relapse rate after cladribine was 16.6%, and treatment related mortality was 2.5%. Most preferred therapy (95%) was again cladribine at second-line, and third line with CR rate of 68.4% and 66.6%, respectively. The 28-month median OS was 91.7% in all patients and 25-month median OS 96% for patients who were given cladribine as first-line therapy. In conclusion, the first multicenter retrospective Turkish study where patients with HCL were followed up for a long period has revealed demographic characteristics of patients with HCL, and confirmed that cladribine treatment might be safe and effective in a relatively large series of the Turkish study population.

Freyer CW, Gupta N, Wetzler M, Wang ES
Revisiting the role of cladribine in acute myeloid leukemia: an improvement on past accomplishments or more old news?
Am J Hematol. 2015; 90(1):62-72 [PubMed] Related Publications
Originally studied in lymphoid diseases, cladribine (CdA) is an adenosine deaminase resistant analog of adenosine that was later discovered to induce myeloid cell apoptosis. The activity of CdA in myeloid malignancies was first reported in relapsed/refractory (RR) pediatric acute myeloid leukemia (AML) with complete response (CR) rates of up to 47%. Consequently, several studies have confirmed the efficacy of single agent CdA or CdA combination regimens in AML. Established CR rates for combination regimens in RR adults are approximately 50%, while CR rates for newly diagnosed (ND) adults are approximately 70% and show similar toxicity profiles to previously used regimens. Despite these promising data, many centers have yet to adopt CdA combination regimens for these difficult to treat populations. We review the pharmacology, pharmacokinetics, clinical data, and safety of CdA monotherapy and combination regimens for the management of pediatric and adult ND and RR-AML.

Inwards DJ, Fishkin PA, LaPlant BR, et al.
Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma.
Ann Oncol. 2014; 25(10):2020-4 [PubMed] Related Publications
BACKGROUND: We conducted this trial to determine the maximum tolerated dose (MTD) of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma.
PATIENTS AND METHODS: A standard phase I cohort of three study design was utilized. The fixed doses of rituximab and cladribine were 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. There were five planned temsirolimus i.v. dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1, 8 and 15; and 25 mg days 1, 8, 15, and 22.
RESULTS: Seventeen patients were treated: three each at levels 1-4 and five at dose level 5. The median age was 75 years (52-86 years). Mantle Cell International Prognostic Index (MIPI) scores were low in 6% (1), intermediate in 59% (10), and high in 35% (6) of patients. Five patients were treated at level 5 without dose limiting toxicity. Hematologic toxicity was frequent: grade 3 anemia in 12%, grade 3 thrombocytopenia in 41%, grade 4 thrombocytopenia in 24%, grade 3 neutropenia in 6%, and grade 4 neutropenia in 18% of patients. The overall response rate (ORR) was 94% with 53% complete response and 41% partial response. The median progression-free survival was 18.7 months.
CONCLUSIONS: Temsirolimus 25 mg i.v. weekly may be safely added to rituximab and cladribine at 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma.

Klanova M, Lorkova L, Vit O, et al.
Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents.
Mol Cancer. 2014; 13:159 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive.
METHODS: Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies.
RESULTS: Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts.
CONCLUSIONS: Acquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.

Mulligan SP, Karlsson K, Strömberg M, et al.
Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia.
Leuk Lymphoma. 2014; 55(12):2769-77 [PubMed] Related Publications
We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

Grever MR
Hairy cell: young living longer but not cured.
Blood. 2014; 123(2):150-1 [PubMed] Related Publications
In this issue of Blood, Rosenberg et al provide a detailed retrospective description of the long-term outcome of young patients with a diagnosis of hairy cell leukemia treated with cladribine.

Mazur L, Opydo-Chanek M, Stojak M, et al.
In vitro response of human pathological hematopoietic cells to cladribine.
Folia Biol (Krakow). 2013; 61(3-4):143-8 [PubMed] Related Publications
The influence of cladribine (2-chloro-2'-deoxyadenosine, CdA) on in vitro response of human acute lymphoblastic leukemia MOLT-4 cells, human histiocytic lymphoma U-937 cells, and human promyelocytic leukemia HL-60 cells, was determined using the MTT spectrophotometric and Beckman Coulter methods. Cell viability, cell volume and count were compared 24h and 48h after cladribine application at four concentrations--50 nM, 100 nM, 250 nM, and 500 nM. Different patterns of temporary changes in the viability, volume and count of pathological hematopoietic cells exposed to the action of CdA were found. The effects of CdA on MOLT-4, U-937, and HL-60 cells were dependent on the agent tested and its concentration, the time intervals after agent application, and the cell line used. The various in vitro cytotoxic activities of CdA against the three human pathological hematopoietic cell lines were shown.

Kreitman RJ, Wilson W, Calvo KR, et al.
Cladribine with immediate rituximab for the treatment of patients with variant hairy cell leukemia.
Clin Cancer Res. 2013; 19(24):6873-81 [PubMed] Free Access to Full Article Related Publications
PURPOSE: In contrast with the classic form, variant hairy cell leukemia (HCLv) responds poorly to single-agent purine analogs, expresses unmutated BRAF, has shorter overall survival, and lacks effective standard therapy. No treatment has achieved a high complete remission (CR) rate even in small series, and of 39 reported cases from six studies, overall response rate after cladribine was 44% with 8% CRs. Rituximab has been found to increase the sensitivity of malignant cells to cladribine, suggesting that combination with cladribine might improve response in HCLv. To test this hypothesis, patients with HCLv were treated with simultaneous cladribine and rituximab.
EXPERIMENTAL DESIGN: Patients with HCLv with 0 to 1 prior courses of cladribine received cladribine 0.15 mg/kg for days 1 to 5, with eight weekly doses of rituximab 375 mg/m(2) beginning day 1. Restaging was performed, and minimal residual disease (MRD) in blood and marrow was quantified using PCR, immunohistochemistry, and flow cytometry.
RESULTS: By 6 months, 9 (90%) of 10 patients achieved CR, compared with 3 (8%) of 39 reported cases treated with cladribine alone (P < 0.0001). Of the 9 CRs, 8 remain free of MRD at 12 to 48 (median 27) months of follow-up. No dose-limiting toxicities were observed when beginning cladribine and rituximab on the same day, although most patients required short-term steroids to prevent and treat rituximab infusion reactions. Cytopenias in CRs resolved in 7 to 211 (median 34) days without major infections.
CONCLUSION: Although cladribine alone lacks effectiveness for early or relapsed HCLv, cladribine with immediate rituximab achieves CRs without MRD and is feasible to administer.

Keklik M, Sivgin S, Kontas O, et al.
Langerhans cell sarcoma of the nasopharynx: a rare case.
Scott Med J. 2013; 58(4):e17-20 [PubMed] Related Publications
Langerhans cell sarcoma, a tumour with markedly malignant cytological features that originates from Langerhans cells, is a very rare disease. We report the first case of 39-year-old male with Langerhans cell sarcoma arising in the nasopharynx. We chose the 2-chlorodeoxyadenosine (2-CDA) regimen as first-line chemotherapy, and clinical improvement of Langerhans cell sarcoma was obtained. After the fourth cycle of 2-CDA therapy, however, disease progression was observed, and we administered ESHAP regimen (etoposide, carboplatin, cytarabine, methylprednisolone) as a second-line therapy. After we administered two cycles of ESHAP, however, the patient developed aggressive progression and he died. The importance of immunohistochemical findings is obvious in Langerhans cell sarcoma diagnosis. Considering that Langerhans cell sarcoma behaves in a very malignant fashion, a more aggressive treatment approach is necessary for patients with Langerhans cell sarcoma.

Rosenberg JD, Burian C, Waalen J, Saven A
Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single-institution series.
Blood. 2014; 123(2):177-83 [PubMed] Related Publications
Hairy cell leukemia (HCL) is a rare, indolent B-cell disorder in which single courses of cladribine induce high rates of complete responses. We report on 88 young HCL patients (≤40 years of age at diagnosis) treated with cladribine from the Scripps Clinic HCL Database, of whom 83 were evaluable for response. Seventy-three patients (88%) achieved an initial complete response and 10 (12%) a partial response, with a median response duration of 57 months. Forty-eight patients (58%) relapsed, with a median time to first relapse for all responders of 54 months. Eight patients developed 11 second primary malignancies with an excess frequency of 1.60 (95% confidence interval, 0.80-2.89). Thirteen (15%) patients died with a mortality ratio compared with age-matched normals of 1.85 (95% confidence interval, 1.07-3.18). Median overall survival for all patients following the first cladribine course was 231 months, and 251 months from diagnosis. Single courses of cladribine induce high rates of complete and durable responses in the majority of young HCL patients and are therefore recommended for HCL patients regardless of age.

López Rubio M, Da Silva C, Loscertales J, et al.
Hairy cell leukemia treated initially with purine analogs: a retrospective study of 107 patients from the Spanish Cooperative Group on Chronic Lymphocytic Leukemia (GELLC).
Leuk Lymphoma. 2014; 55(5):1007-12 [PubMed] Related Publications
Abstract Purine analogs are highly effective in hairy cell leukemia (HCL) with response rates of 85%, but with many late relapses. We have retrospectively reviewed the clinical data from 107 patients treated with pentostatin (n = 27) or cladribine (n = 80), to investigate the long-term efficacy and to identify factors associated with the treatment-free interval (TFI). Complete remission and minimal residual disease (MRD) rates were similar in both groups. Median TFI was shorter (95 vs. 144 months) in the pentostatin group, although the difference was not significant (p = 0.476). MRD+ patients had shorter TFI than MRD- patients (97 months vs. not reached, p < 0.049). A hemoglobin level < 10 g/dL predicted for a shorter TFI only in the pentostatin group. Quality of response and number of hairy cells in the bone marrow are independent risk factors of treatment failure. The relationship between MRD+ and shorter TFI makes it of special interest to explore consolidation therapy with monoclonal antibodies to achieve durable responses.

Cervetti G, Galimberti S, Pelosini M, et al.
Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up.
Ann Oncol. 2013; 24(9):2434-8 [PubMed] Related Publications
BACKGROUND: Splenic marginal zone lymphoma with or without villous lymphocytes (SLVL/SMZL) is an indolent lymphoma that typically affects elderly patients and that has a median survival >10 years. It presents with marked splenomegaly. Treatment is required in symptomatic cases. Splenectomy remains one of the first-line options in patients fit for surgery. The best pharmacological strategy has not yet been identified for poor surgical risk cases. Among different possible chemotherapeutic approaches, purine analogs, alone or in association with Rituximab, seem to be a valid therapeutic choice.
PATIENTS AND METHODS: Fifty SMZL patients were treated with Cladribine ± anti-CD20 monoclonal antibody.
RESULTS: Forty-seven of 50 patients were evaluable for response. ORR was 87%: 24 of 47 patients (51%) achieved a complete hematological response (CR), 17 of 47 (36%) a partial response (PR) and 6 (13%) resulted unresponsive. Interestingly, 15 of 24 cases (62%) in CR achieved also a molecular remission. After a median follow-up of 48 months, 7 of 41 responsive cases relapsed and the 5-year PFS was 80%.
CONCLUSIONS: These data confirm the efficacy of this schedule emphasizing the impact of minimal residual disease even in the outcome of SMZL patients.

Suzuki D, Kobayashi R, Sano H, et al.
Spontaneous remission of 2-chlorodeoxyadenosine (2-CdA)-related secondary myelodysplastic syndrome in a patient with refractory Langerhans cell histiocytosis.
Int J Hematol. 2013; 97(6):782-5 [PubMed] Related Publications
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.

Singh V, Prajeeth CK, Gudi V, et al.
2-Chlorodeoxyadenosine (cladribine) induces apoptosis in human monocyte-derived dendritic cells.
Clin Exp Immunol. 2013; 173(2):288-97 [PubMed] Free Access to Full Article Related Publications
2-Chlorodeoxyadenosine (cladribine, CdA) is an immunosuppressive drug that is licensed to treat hairy cell leukaemia, and has been shown recently to have beneficial effects in patients with multiple sclerosis (MS). The therapeutic effects of CdA have been suggested to be mediated partly through its potent toxicity towards lymphocytes. However, the effects of CdA on other immune cells are poorly understood. In the present study, we investigated the effects of CdA on the induction of apoptosis in human monocytes, monocyte-derived immature (ImDC) and mature (mDC) dendritic cells. Treatment of monocytes with CdA strongly induced apoptosis after 24 h, while apoptosis induction in DC was evident after 72 h. Furthermore, CdA treatment strongly induced caspase-3 and caspase-9 in monocytes, whereas activation of caspases was undetected in DC. The mitochondrial membrane potential in DC was reduced significantly after CdA treatment. DNA hypodiploid assessment showed fragmented nuclei in DC after CdA treatment together with activation of p53 protein. These results revealed that CdA induces caspase-independent apoptosis in DC and suggest cell type specific effects of CdA. This mechanism may contribute to the effect of CdA in autoimmune diseases.

Blonski JZ, Robak T, Chojnowski K, et al.
Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil--follow-up of PALG-CLL randomized trials.
Eur J Haematol. 2013; 91(1):1-9 [PubMed] Related Publications
OBJECTIVES: The relationship between treatments of chronic lymphocytic leukemia (CLL) with cladribine (2-CdA) or chlorambucil and immune thrombocytopenia (IT) has not been yet determined.
METHODS: The records of 777 patients in two randomized Polish Adult Leukemia Group (PALG)-CLL programs treated with these agents were retrospectively analyzed.
RESULTS: Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence were seen between patients on chlorambucil or 2-CdA-based regiments (P = 0.33). IT developed at a median time of 0.499 yr (0.06-4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yr, 95% CI: 0.06-4.22) in relation to patients treated with 2-CdA-based regiments (0.52 yr, 95%CI: 0.34-0.69, P = 0.049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yr vs. 3.2 yr P = 0.23) but the severity of bleeding was more pronounced in the 2-CdA group. The responses to IT therapy were 35%, 54% and 75% for steroids, chemotherapy and splenectomy, respectively.
CONCLUSIONS: In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2-CdA-based regiments compared to chlorambucil regimen, the clinical course of hemorrhagic diathesis was more severe in 2-CdA group. Also, the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative relationship. The appearance of IT did not influence the median time of OS.

Wolska A, Cebula-Obrzut B, Smolewski P, Robak T
Effects of Toll-like receptor 7 and Toll-like receptor 9 signaling stimulators and inhibitors on chronic lymphocytic leukemia cells ex vivo and their interactions with cladribine.
Leuk Lymphoma. 2013; 54(6):1268-78 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant B lymphocytes in the peripheral blood that are regarded as poorly antigenic to the host immune system. Nonetheless, they are thought to be able to undergo stimulation and become antigen-presenting cells possibly through Toll-like receptors (TLRs). Several studies have examined the effect of TLR7 and TLR9 stimulation on the biology of CLL cells, revealing contradictory results in terms of cell proliferation and apoptosis. On the other hand, suppression of TLRs has not been studied in CLL so far, and the rationale for this may be increasing evidence of the supportive role of TLR signaling in CLL. In our study we assessed the effect of a synthetic oligodeoxynucleotide with immunoregulatory sequences (IRS 954) on peripheral blood cells from patients with untreated CLL, in terms of expression of costimulatory molecules, production of cytokines and cell viability ex vivo. Agonists of TLR7 (imiquimod, IMI) and TLR9 (oligodeoxynucleotide ODN 2006) acted as positive internal controls. ODN 2006 most markedly induced CD86 expression compared to IMI and IRS 954. Both oligodeoxynucleotides - IRS 954 and ODN 2006 - caused 1.5- and 5-fold increases of CD40 on CLL cells, respectively. Immunostimulatory ODN 2006 induced CD95 expression 1.5-fold. Changes in costimulatory molecule expression were accompanied by a moderate response from CD4 + and CD8 + T lymphocytes. TLR7 and TLR9 agonists led to significantly higher production of interleukin 6 (IL-6) and IL-10. IRS 954 and ODN 2006 markedly increased the concentration of tumor necrosis factor α (TNFα). IL-17A was significantly decreased by 50% after IMI. IRS 954 and IMI induced significant necrosis at all concentrations, and the effect was augmented by the addition of cladribine (2CdA). ODN 2006 presented a dual effect on cell viability, which was related to disease stage and baseline IL-17A concentration. The addition of 2CdA had little effect in a group where ODN 2006 supported cell survival, and further enhanced cytotoxicity of ODN 2006 in the second group. Inhibitory oligodeoxynucleotides seem to exert promising antileukemic effects regardless of sample background, and thus may become a new modality in CLL. The response of leukemic cells to ODN 2006 varies between samples and cannot yet be predicted.

Kohnke PL, Mactier S, Almazi JG, et al.
Fludarabine and cladribine induce changes in surface proteins on human B-lymphoid cell lines involved with apoptosis, cell survival, and antitumor immunity.
J Proteome Res. 2012; 11(9):4436-48 [PubMed] Related Publications
Fludarabine and cladribine are purine analogues used to treat hematological malignancies. Alone or in combination with therapeutic antibodies, they are effective in treating patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma. However, the mechanisms of action of these drugs are not well understood. Plasma membrane proteins perform a variety of essential functions that can be affected by malignancy and perturbed by chemotherapy. Analysis of surface proteins may contribute to an understanding of the mechanisms of action of purine analogues and identify biomarkers for targeted therapy. The surface of human cells is rich in N-linked glycoproteins, enabling use of a hydrazide-coupling technique to enrich for glycoproteins, with iTRAQ labeling for quantitative comparison. A number of plasma membrane proteins on human leukemia and lymphoma cells were affected by treatment with a purine analogue, including decreases in CD22 (an adhesion and signaling molecule) and increases in CD205 (a "damaged cell marker") and CD80 and CD50 (T-cell interaction molecules). Purine analogues may affect B-cell receptor (BCR) signaling and costimulatory molecules, leading to multiple signals for apoptosis and cell clearance. Fludarabine and cladribine induce differential effects, with some cell survival proteins (ECE-1 and CD100) more abundant after fludarabine treatment. Cell surface proteins induced by fludarabine and cladribine may be targets for therapeutic antibodies.

Girardi K, Paviglianiti A, Cirillo M, et al.
Tuberculous meningoencephalitis in a patient with hairy cell leukemia in complete remission.
J Clin Exp Hematop. 2012; 52(1):31-4 [PubMed] Related Publications
Tuberculous meningoencephalitis is a rare disease associated with high morbidity and mortality. We report a patient with hairy cell leukemia in complete remission who, after a single cycle of chemotherapy with cladribine, presented fever and neurological deficits. Laboratory diagnosis of tuberculous meningoencephalitis was made by polymerase chain reaction testing for Mycobacterium tuberculosis in cerebrospinal fluid. Despite the prompt institution of antitubercular-therapy, patient's general condition did not improve and he died. Mycobacterial infection should be considered in patients with intra-cranial lesions, affected by hematological malignancies and persistent immunosuppression.

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