Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic lymphocytic leukemia (CLL) is considered an incurable disease and therefore the management is palliative and more disease-related symptoms directed. Recently, the high activity of nucleoside analogs as fludarabine (FAMP), 2-chlorodeoxyadenosine (2-CDA) and 2-deoxycoformycin (DCF) in low-grade NHLs has caused a new reawakening interest in CLL concerning new treatment strategies, the biology and prognostic factors of this disease. Predominantly FAMP has widely been studied in CLL with impressive remission rates of 30-70%, including some complete remission (CR) in refractory or relapsed CLL. In previously untreated patients, the remission rate is about 80% with a CR rate of up to 60%. These results open new treatment strategies, even with a curative intention such as high-dose chemotherapy combined with autologous stem cell support or allogeneic stem cell transplantation. The clinical experience with 2-CDA in CLL is limited, but the preliminary results suggest a similar efficacy as FAMP, whereas DCF seems to be less effective. The major treatment-related morbidity is due to myelo- and immunosuppression by long-lasting T cell depletion, which may facilitate a greater susceptibility of infections including those with opportunistic organisms as herpes simplex or herpes zoster, cytomegalovirus, Pneumocystis carinii, mycobacteria, listeriosis, candida and aspergillus in pretreated patients. However, in previously untreated patients no increased incidence of infections has been reported compared with other schedules. Whether FAMP treated patients have any advantage for overall or progression-free survival has to be answered by ongoing randomized trials. Presently, the position of FAMP and 2-CDA as two extremely active single agents in CLL is that of second-line therapy. Their appropriate indication in the first-line strategy of CLL has, however, still to be defined by clinical studies in progress.
Leukemia 1997 Apr
PMID:Present status of purine analogs in the therapy of chronic lymphocytic leukemias. 917 35

There is no doubt about 2-CDA being a very potent lymphotoxic agent that displays high efficacy in the treatment of CLL. It interferes with the intranuclear machinery of DNA regulation, and causes death to proliferative active, as well as resting lymphocytes. Interruption of crucial pathways that are evident for cell survival translates into high clinical response rates in CLL. CR and PR rates comparable to those reported on fludarabine are achieved in relapsed or refractory CLL. Even though trials on previously untreated CLL are still ongoing, a consistent trend towards durable, high CR rates becomes apparent. The toxicity is comparable to that of fludarabine and consists of infections, as well as thrombocytopenia. Clinical as well as in vitro studies suggest a crossresistance between the two purine analogues, indicating that sequential treatment is not useful. Given these data, although preliminary in case of de novo CLL, 2-CDA has to be recognized as one of the most effective cytostatic drugs currently available for CLL treatment. Large prospective trials (in comparison with fludarabine) will assess the role of 2-CDA as standard treatment. Such trials should also have the aim to substantiate the potential of 2-CDA as induction treatment followed by high-dose consolidation.
Leukemia 1997 Apr
PMID:Is there a place for 2-CDA in the treatment of B-CLL? 917 36

2-chlorodeoxyadenosine (2-CDA) is very effective in the treatment of patients with hairy-cell leukaemia, with an overall response rate of 80-95%. The standard treatment is a continuous intravenous infusion for 7 days. The bioavailability of 2-CDA after subcutaneous injection is 100%, but the concentration-time profile is completely different compared to continuous intravenous administration. In the present study we compared the intravenous standard treatment (group 1, n = 22; 0.1 mg/kg/d for 7 days, civ.) with subcutaneous administration of 2-CDA (group 2, n = 62; 0.14 mg/kg/d for 5 days, s.c.) in patients with hairy-cell leukaemia. In group 1, 96% (21/22) of patients responded to 2-CDA (complete remission 73%, partial remission 23%) and in the second group 97% were responsive (complete response 76%, 47/62; partial remission 21%, 13/62). The percentage for moderate and severe infections in the trial with intravenous and subcutaneous treatment was 14% and 26% respectively (p = 0.37). We conclude that subcutaneous administration of 2-CDA in patients with hairy-cell leukaemia is feasible and economical and results in comparable responses and toxicity compared to the intravenous standard treatment.
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PMID:[2-CDA in treatment of hairy cell leukemia: a comparison between intravenous and subcutaneous administration. Swiss Study Group of Applied Cancer Research]. 982 88

Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS). Lymphocytes seem to play a crucial role in the pathogenesis of the disorder. They are rich in, among others, beta-2Microglobulin (beta 2M)--a low molecular weight protein located extracellularly and associated with class 1 antigens of the major histocompatibility complex. beta-2M is considered as a marker for disease activity in immune disorders. Its precise role in pathology remains still unknown, but there is evidence that it may be involved in lymphocyte activation. Cladribine (2-chloro-2-deoxyadenosine, 2-CDA) is a potent lymphocytotoxic agent under investigation in the treatment in MS patients, earlier used in hairy-cell-leukemia therapy. Previous studies in MS populations showed beta 2-microglobulin to be moderately increased. Suspecting that beta 2M levels might indicate inflammatory events in CNS we determined CSF-beta 2M and serum beta 2M concentration in patients with relapsing-remitting MS (n = 15) before and after cladribine treatment as well as in a control group diagnosed as tension type headache (n = 10). There was a significant decrease in the CSF and sera beta 2M level in MS patients after cladribine treatment, associated with a slight but significant clinical improvement measured by Kurtzke's Expanded Disability Status Scale. We conclude that beta 2M is a sensitive marker of the CDA influence on the immune system in MS patients; however, increase in CSF and sera beta 2M is not specific as there was no statistically significant difference between MS and control patients.
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PMID:[The effect of cladribine treatment on beta-2 microglobin in the cerebrospinal fluid and serum of patients with multiple sclerosis]. 1096 21

Hairy cell leukaemia, previously known as leukaemic reticuloendotheliosis, is an indolent lymphoproliferative disorder of unknown etiology. It typically affects males, causes marked splenomegaly and moderate enlargement of the liver, whilst lymphadenopathy is inconspicuous. Pancytopenia is characteristic with unusually profound monocytopenia, variable reduction in platelets, and the presence in the peripheral blood and marrow of abnormal small lymphocytes having irregular cytoplasmic margins. Ultrastructure, combined with cytochemistry and flow cytometry, have refined diagnosis. A variant exists between this classical entity and B prolymphocytic leukaemia, where blastic transformation or massive lymph node enlargement are found, and this is of ominous significance. In all these patients with this entity conventional chemotherapy is ineffective and shortens survival. Our previous experience with splenectomy results in excellent clinical control for long periods of time, but without disease eradication. There followed a vogue for the use of interferon but this is limited by high cost and dose-dependent side-effects. Contemporary management centres on the purine analogues, where durable responses are possible with fludarabine and deoxycoformycin, but best with 2'chlorodeoxyadenosine (2-CDA). To document the efficacy of the latter agent, we analysed the outcome in seventeen consecutive patients treated over the last five years. Four were ineligible for analysis, although two had 2-CDA. The other thirteen, managed on a standard seven-day course of 0.1 mg/kg 2-CDA given as a continuous intravenous infusion, all responded promptly. Apart from transient leucopenia complications have been minimal, and oral co-trimoxazole prophylaxis for pneumocystis carinii was maintained during the first one year. In all thirteen there was a rapid return to normal of peripheral blood count and marrow on aspiration and trephine biopsy. Even in the longest follow-up clinical and haematologic remission has been maintained and no patients have required retreatment. One individual has relapsed in the marrow at two years. Despite the relative expense of the agent the excellent treatment outcome and patient acceptability, coupled with its safety, leads to the recommendation that in South Africa - as elsewhere in the world - this be regarded as the first line of treatment.
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PMID:Malignancy: 2'-Chlorodeoxyadenosine Effectively Induces Complete Remission in Hairy Cell Leukaemia. 1139 82

To identify treatment factors that may affect the survival of children with inv(16)(p13.1q22), we compared the outcomes of 19 patients with this genetic feature treated at our institution during two treatment eras. Nine patients were treated during era 1 (1980 to 1987), and 10 were treated during era 2 (1988 to 1996). All entered complete remission (CR) with induction therapy. Eight of the nine children treated in era 1 died, seven of relapsed leukemia. In contrast, three of 10 patients treated during era 2 have died, all of non-disease-related causes. Event-free survival (EFS) estimates were significantly higher for patients treated during era 2 than for those treated during era 1 (P = 0.03); the 6-year estimates were 70 +/- 15% (s.e.) and 11 +/- 7%, respectively. Era 2 treatment protocols differed from those of era 1 in their use of higher doses of cytarabine and etoposide during induction and consolidation chemotherapy and in their use of 2-chlorodeoxyadenosine (2-CDA). These results suggest that dose intensification of cytarabine benefits children with AML and inv(16), as is the case in adults. They also suggest that dose intensification of etoposide and addition of 2-CDA may also offer an advantage. This study underscores the dependence of the prognostic impact of cytogenetic features on the efficacy of treatment.
Leukemia 2001 Sep
PMID:Impact of treatment on the outcome of acute myeloid leukemia with inversion 16: a single institution's experience. 1151 92

To test the hypothesis that analyses of drug targets for polymorphism will help to establish gene-based information for the treatment of cancer patients, we investigated the functional single-nucleotide polymorphisms in the human cytidine deaminase (HDCA) gene. The cDNAs from 52 leukaemia/lymphoma samples and 169 control blood samples were direct-sequenced and analysed for the polymorphisms. Three different polymorphisms (A79C, G208A and T435C) were identified in the coding region of the HDCA gene and displayed allelic frequencies of 20.1%, 4.3% and 70.1%, respectively. No association with susceptibility to disease was observed. A novel polymorphism, G208A produced an alanine to threonine substitution (A70T) within the conserved catalytic domain. By introduction of the polymorphic HCDA genes into the yeast CDA-null mutants, the HCDA-70T showed 40% and 32% activity of prototype for cytidine and ara-C substrates, respectively (P < 0.01). The ara-C IC50 value of the yeast transformants carrying HCDA-70T was 757 +/- 33 micromol and was significantly lower (P < 0.01) than that of prototype (941 +/- 58 micromol). This study demonstrated a population characterized with 208A genotype for, which potentially leads one more sensitive to ara-C treatment than prototype. Accumulation of polymorphisms in the genes responsible for drug metabolism and determination of polymorphism-induced biological variations could provide the additional therapeutic strategies in risk-stratified protocols for the treatment of childhood malignancies.
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PMID:A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. 1254 10

A case of hairy cell leukaemia (HCL), a rare leukaemia, is reported here. The patient was presented with high grade continuous fever with left upper abdominal discomfort for 6 days. He was moderately anaemic, had no peripheral lymphadenopathy with mild hepatosplenomegaly. He was anaemic (Hb-7.8 gm/dl), total leukocyte count was 20 x 109/L. Peripheral blood film showed lymphocytosis (92%) with neutropenia (8%) and absolute neutophil count (ANC) was 1 x 109/L. On review, 88% of the peripheral cells had peripheral hairy projections resembling hairy cell (HC). Bone marrow examination was consistent with HCL (morrow hairy cell = 52%) including marker studies. Tartrate resistant acid phosphatase test (TRAP) was also positive. He had opportunistic mycobecterial infection giving a positive bronchial lavage for acid fast bacilli. After controlling the infection he was advised a single dose chemotherapy of 2-chlorodeoxyadenosine (2-CDA). After that he was in partial remission and after 25 months clinical and pathological relapses occurred and a second dose of 2-CDA was given and the patient went into complete remission.
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PMID:Hairy cell leukaemia with advanced treatment - a case report. 1289 49

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 alpha-2b for at least 6 months, (from 1 million U per day up to 5 million U/m(2)/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.
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PMID:Interest of interferon alpha in systemic mastocytosis. The French experience and review of the literature. 1521 17

Archived tumor tissue is a useful resource for retrospective studies addressing relationships between genetic polymorphisms and treatment outcomes. However, genotypes determined in tumor and somatic tissues may differ due to cytogenetic and molecular changes associated with malignant transformation and progression. Discordance between germ line and tumor genotypes may be particularly relevant in leukemia because cytogenetic abnormalities are frequent. We compared genotypes determined in DNA extracted from paired pretreatment bone marrow and buccal samples from 80 adult patients with acute myeloid leukemia (AML). Paired AML and buccal DNA samples were genotyped for polymorphisms (21 single nucleotide polymorphisms and 2 gene deletions) on genes encoding proteins involved in drug metabolism (CYP3A4, CYP2C8, CDA, and GSTP1), oxidative stress mechanisms (CAT, MnSOD, GSTT1, GSTM1, GSTA1, and GPX1), drug transport (MDR1, MRP1, and BCRP), and DNA repair (MGMT, XPD, and XRCC1). Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, except GSTM1 and GSTT1, for which deletion genotypes were determined using multiplex PCR. Concordance of genotypes was tested by kappa statistics. kappa statistics for paired AML and buccal DNA samples ranged between 0.94 and 1.00, indicating excellent agreement. The GSTT1 and GSTM1 genotypes were in perfect concordance for the paired samples. Agreement was also excellent for genes at AML chromosome deletion and translocation breakpoints, including MDR1 at 7q21.1 and MRP1 at 16p13.1. Based on these data, genotypes derived from archived AML bone marrow samples were not likely to differ from those from genomic DNA, and archived bone marrow samples may be useful for the conduct of retrospective pharmacogenetic studies.
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PMID:Concordance of pharmacogenetic polymorphisms in tumor and germ line DNA in adult patients with acute myeloid leukemia. 1750 36


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