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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute leukemia (AL) is a relatively uncommon, but dreaded, complication occurring with increased frequency in individuals with Down syndrome (DS). This selective update includes aspects of AL in DS in which a change or advancement in our understanding of this disease has occurred. Despite previous reports describing a worse outcome for these individuals, more recent studies have suggested an improved response to current treatment strategies (including high-dose AraC) equaling, or even surpassing, the survival of non-DS individuals with AL. An increased toxicity to methotrexate in DS patients has also been recognized. While the leukemia of DS infants has been described as megakaryoblastic, the spectrum of in vitro differentiation is much broader including (in addition to megakaryocytic colonies) various myeloid, macrophage, and even erythroid colonies. Although the cause(s) of DS-AL remains unknown, potential candidate genes include those encoded on chromosome 21 that play a role in other defined leukemias in non-DS individuals. The AML1/PEBP2alpha gene maps to the DS critical region and is characteristically associated with two leukemia-associated chromosomal translocations: 1) the 8;21 translocation involving an AML1/ETO fusion transcript commonly seen in acute myelogenous leukemia (AML) and; 2) a 3;21 translocation identified in certain chemotherapy-related myelodysplasias/leukemias and occasionally in the blast crisis of chronic myelogenous leukemia cells. Similarly, the ETS-related gene, ERG, involved in the AML 16;21 maps to the q22 region of chromosome 21. Lastly, a familial platelet disorder with a propensity to develop myeloid leukemia has been linked to 21q22.1-22.2 and conceivably might involve AML1, ERG or yet another gene.
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PMID:Down syndrome and leukemia, an update. 854 49

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.
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PMID:Improved outcome in adult B-cell acute lymphoblastic leukemia. 855 71

We report a case of AML with diabetes insipidus (DI). A 68-year-old female was admitted to our hospital because of fever and leukocytosis. The WBC was 197,000/microliter with 98% blasts positive for myeloperoxidase, CD33, CD34 and HLA-DR. While, on admission, urine volume was more than 6 liters daily. Blood vasopressin level was 0.3 microgram/ml. The patient was diagnosed as having AML with DI. By chemotherapy consisting of BHAC, DNR, 6-MP and PSL and intrathecal administration of AraC, MTX and PSL, and nasal drip of DDAVP, complete remission was attained and the urine volume was reduced to normal. Finally DDAVP became unnecessary. Although the exact cause of DI cannot be ascertained, rapid increase of leukemic blasts and leukostasis in small vessels might be associated with hypothalamus-pituitary system damage. Reportedly, DI is a rare complication of leukemia and administration of DDAVP could be halted in only two patients with leukemia and DI.
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PMID:[Acute myelogenous leukemia with diabetes insipidus without desmopression administration by anti-leukemic chemotherapy]. 858 72

Chlorinated tap water often contains 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), which is a potent directly acting bacterial mutagen. We have investigated the induction of DNA damage by MX in a promyelocytic human leukaemia cell line (HL-60 cells). Exposure of HL-60 cells to 100-300 microM MX resulted in increased levels of DNA single-strand breaks and/or alkali-labile sites (SSBs) as detected by alkaline filter elution. When adding inhibitors of DNA break repair (AraC plus hydroxyurea), increased levels of DNA SSBs were observed at very low concentrations (1-3 microM) of MX, as observed by both alkaline filter elution and the single-cell gel electrophoresis assay. Increased DNA SSBs could also be observed if DNA repair inhibitors were added immediately after exposure to 10 microM MX, indicating that low concentrations of MX cause a relatively stable modification of DNA that may be recognized and incised by DNA repair enzyme activities. Further studies with DNA break repair inhibitors indicated that HL-60 cells exposed to 10 microM MX for 1 h repaired 50% of their initial DNA damage during a 2-h period and the repair appeared to be complete at 22 h. Analysis of MX-treated DNA by sequencing methods indicated that MX preferentially reacts with guanines in DNA.
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PMID:DNA damage induced by 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX) in HL-60 cells and purified DNA in vitro. 915 Jul 66

Biphenotypic acute leukaemia (BAL) patients represented 8% of the 287 de novo consecutive adult acute leukaemias (23 BAL, 230 acute myeloid leukaemia (AML) and 34 acute lymphoblastic leukaemia (ALL)) referred to our department during the last 4-year period. Of these 23 BAL patients, 14 patients showed myeloid morphology and nine cases lymphoid morphology according to FAB criteria. There were no differences between lymphoid and myeloid BAL according to clinical and biological presentation and treatment outcome. We confirm the poor prognosis of BAL when compared to AML or ALL seen during the same period of time, in terms of complete remission (47%, 62% and 82% respectively, BAL v AML, NS and BAL v ALL, P = 0.006) and 4-year overall survival (8.1%, 25.8% and 23.8% respectively, BAL v AML, P = 0.05 and BAL v ALL, P = 0.003). Comparing adult BAL patients with AML patients, we found an increase in poor prognostic factors: CD34+ phenotype (82% v 60% respectively, P = 0.03), unfavourable karyotype (60% v 20%, P < 0.0001) and Pgp over-expression by RT-PCR (0.705 v 0.107, P < 0.0001) and flow cytometry (0.824 v 0.391, P = 0.0001). MRP and LRP were not found to be poor prognostic factors. Comparing BAL patients with ALL patients, we found also an increase in poor prognostic factors: age (51 v 39, P = 0.003) and CD34+ phenotype (82% v 50%, P = 0.02). We conclude that BAL patients need a more aggressive treatment procedure, including high-dose AraC or the use of Pgp modulators for first-line therapy.
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PMID:Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression. 945 Aug 4

Sixty-six consecutive adult patients with acute lymphoblastic leukaemia (ALL) were treated with intensified chemotherapy which included a 'pre-induction' course of cytarabine (AraC) and etoposide (VP16) when the white blood cell count (WBC) was > or = 30 x 10(9)/l (18 patients), and maintenance chemotherapy with regular intensifications for a total treatment duration of 3 years. Patients with a mediastinal mass (17) received consolidation courses with intermediate-dose AraC and VP16 followed by mediastinal irradiation. 11 patients underwent allogeneic bone marrow transplantation in first complete remission (CR). 58 patients (87.9%, CI 77.5-94.6) attained CR; with a median follow-up of 7 years, 35 of them (60.3%, CI 46.6-73.0) remain in CR. Toxicity was mild, although three patients died during remission induction, including two who were over 70 years of age. 23 patients (39.7%, CI 27.1-53.4) relapsed, seven of them primarily in the central nervous system (CNS), necessitating intensification of CNS-directed therapy. Only one of 13 patients with WBC 30-100 x 10(9)/l, but eight of nine with WBC > 100 x 10(9)/l, relapsed. The survival of older patients in CR did not differ from younger patients. The outcome of ALL in adult patients could thus be improved by slight intensification of treatment whilst keeping the toxicity within acceptable limits. 'Pre-induction' with AraC and VP16 might improve the prognosis, especially in patients with WBC < 100 x 10(9)/l. Patients with WBC > 100 x 10(9)/l, however, almost always relapse, and the intensified chemotherapy might not be tolerated well by patients over 70 years of age.
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PMID:Improved outcome of adult acute lymphoblastic leukaemia by moderately intensified chemotherapy which includes a 'pre-induction' course for rapid tumour reduction: preliminary results on 66 patients. 948 13

Although cytosine arabinoside (AraC) represents the most effective single agent in the treatment of adults with acute myeloid leukemia (AML) when given at doses exceeding 200 to 500 mg per application, its optimal dosage is still a matter of controversial discussion. While pharmacokinetic investigations suggest that the AraC-activating enzyme deoxycytidine kinase is saturated at drug concentrations achieved by short-term infusion of 0.5 to 1.0 g/m2 AraC and that higher doses are therefore not more effective, recent evidence indicates that additional mechanisms of AraC cytotoxicity may exist which could be enhanced by further dose escalation. In order to test this thesis in the clinical setting, a prospective randomized comparison of high-dose (HD-AraC) vs intermediate-dose (ID-AraC) AraC was carried out in patients with refractory or relapsed AML on the basis of the sequential high-dose AraC and mitoxantrone regimen (S-HAM). AraC was given as a 3-h infusion q 12 h on days 1, 2, 8 and 9. Patients younger than 60 years were randomized to AraC doses of 3.0 g/m2 vs 1.0 g/m2 while older patients received either 1.0 g/m2 or 0.5 g/m2 per single dose. Mitoxantrone was given to all patients on days 3, 4, 10 and 11 at a daily dose of 10 mg/m2. Randomization was stratified for primary refractoriness against induction therapy and length of first remission in relapsed patients. From 186 evaluable patients, 88 (47%) and 10 cases (5%) achieved a complete (CR) or partial (PR) remission, 39 patients (21%) had persisting leukemia (non-response (NR)), and 49 cases (26%) died within 6 weeks after the start of therapy (early death (ED)). In patients younger than 60 years the higher dose level resulted in a significant reduction of NR (12% vs 31%; ordinal chi2 test: P = 0.01) but also a higher rate of ED (32% vs 17%) thus leading to a marginally higher CR rate only (52% vs 45%). Within the subgroup of patients with refractory AML the tendency towards a higher CR rate after HD-AraC was more pronounced (46% vs 26%; P = 0.045). In patients older than 60 years, corresponding though less evident differences were observed with a higher rate of NR in the lower dose group (26% vs 16%) and ED occurring more frequently after higher doses (36% vs 26%). These data indicate that HD-AraC reveals a significantly higher antileukemic efficacy than ID-AraC as expressed by a significant reduction of failure from NR. This advantage, however, does not fully translate into an increase in remission rate due to a higher incidence of ED after HD-AraC predominantly from uncontrolled infections. In order to take full advantage of the higher antileukemic activity of HD-AraC an improvement of supportive care and infection control is warranted.
Leukemia 1998 Jul
PMID:Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison. 966 89

The prognosis of infant ALL, characterized by a high incidence of the immature CD10 negative B-lineage ALL (proB ALL) is poor. This study aimed to determine the resistance profile of infant ALL cells. In vitro drug resistance was determined by the MTT assay of 395 children with ALL at initial diagnosis: there were 21 infants <1.5 years of which nine <1 year, 284 children aged 1.5-10 years (intermediate age group) and 90 children >10 years. Immunophenotyping resulted in 310 cALL/preB ALL, 69 T-ALL, 15 proB ALL and one unknown cases. The following drugs were tested: daunorubicin, doxorubicin, mitoxantrone, idarubicin (Ida), prednisolone (Pred), dexamethasone (DXM), vincristine (VCR), Asparaginase (Asp), 6-MP, 6-TG, AraC, VM26 and 4-HOO-ifosfamide (Ifos). Infants <1.5 years were significantly more resistant to Pred (>500-fold), Asp (11-fold) and VM26 (2.7-fold) but significantly more sensitive to Ara-C (2.3-fold) compared to the intermediate age group. When analyzing infants <1 year of age similar results were found. ProB ALL cells (seven infants <1.5 years; eight children >1.5 years) were significantly more resistant to glucocorticoids, Asp, thiopurines, anthracyclines and Ifos compared to cALL/preB ALL but more sensitive to Ara-C. Cells from children >10 years were significantly more resistant to Pred, DXM, Asp, Ida and 6-MP. T-ALL cells showed a strong resistance to Pred, Asp and VCR and a mild but significant resistance to all other drugs except thiopurines and VM26. We conclude that the poor prognosis of infant ALL is associated with a resistance to glucocorticoids and Asp. However, ALL cells from infants show a relatively high sensitivity to Ara-C which suggests that infants with ALL might benefit from treatment schedules that incorporate more Ara-C than the current treatment protocols.
Leukemia 1998 Sep
PMID:Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia--implications for treatment of infants. 973 81

Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamination with half-lives ranging from 1 h (i.v.) to 4 h (s.c.) -- and cannot be applied orally due to its hydrophilic properties. These limitations might be overcome by YNK01 -- a lipophilic prodrug of AraC -- that is resistant to deoxycytidine deaminase and can be applied orally. In the present study the therapeutic activity, side-effects and pharmacokinetics of YNK01 were evaluated in a phase I/II study including patients with relapsed or refractory acute myeloid leukemia (AML) (n=23) or low-grade non-Hodgkin's lymphoma (NHL) (n=20). YNK01 was given by 14 day cycles with escalating doses starting with a daily dose of 50 mg/m2 (equivalent to 20 mg/m2 AraC on a molar basis). The maximum tolerated dose was reached at the 600 mg/m2 dose level with WHO grade 3-4 diarrhoea as the main toxicity. In the 23 patients with AML two complete remissions, four partial remissions and three patients with stable disease were observed. In the 23 patients with AML two complete remissions, four partial remissions and three patients with NHL two cases reached partial remission and six other patients mainained stable disease. Pharmacokinetic evaluations were performed during 34 treatment cycles in 28 patients. The data suggest that YNK01 was absorbed in the distal part of the small intestine and taken up into hepatocytes. After hepatic psi and subsequent beta-oxydation of YNK01 the released AraC (and its deamination product AraU) appeared in the systemic circulation. Time of maximum concentration (h), half-life (h) and area under the curve (ng x h/ml, at the 1200 mg dose level) were as follows (VC variation coefficient) YNK01: 1.0 (0.58), 10.1 (0.43), 12622 (0.65); AraC: 23.2 (0.57), 22.6 (0.36), 3496 (0.76); AraU: 19.2 (0.58) 22.3 (0.33) 15441 (0.66). Of the total dose of YNK01 15.8% was absorbed and metabolized to AraC and AraU, defining the metabolic bioavailability of this prodrug. A linear relationship was observed between YNK01 dose and YNK01 AUC and AraC AUC over the whole dose range tested. AraC was released from hepatocytes over a prolonged period of time resulting in long lasting plasma levels similar to a continuous i.v. infusion. After administration of YNK01 at a dosage of 100-150 mg/m2 plasma levels of AraC were comparable to those achieved after low-dose AraC treatment (20 mg/m2) while at doses of YNK01 of 450-600 mg/m2 concentrations of standard-dose AraC (100 mg/m2) were obtained. We conclude that YNK01 shows considerable activity against relapsed and refractory AML and NHL and that its pharmacokinetic properties offers advantages in comparison to (standard) i.v. or s.c. AraC in clinical practice.
Leukemia 1998 Oct
PMID:Oral cytarabine ocfosfate in acute myeloid leukemia and non-Hodgkin's lymphoma--phase I/II studies and pharmacokinetics. 976 8

Acute myeloid leukemia (AML) appears related to some environmental factors and higher age. The morphological subtypes reflect genotypes as detected by specific chromosome translocations and related fusion genes. Genotypes determine the disease biology and prognosis. Chemotherapy remains as the backbone of treatment and has brought the long-term disease-free survival to 30-40%. Factors contributing to the improved results are prolonged maintenance, double induction strategy and high dose AraC in postremission and induction phase. Allogeneic bone marrow transplantation adds to the improvements by the graft versus leukemia effect. Autologous stem cell transplantations may allow further escalation of postremission chemotherapy and might thus further improve the cure rate in AML.
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PMID:[Acute myeloid leukemia (AML)]. 1019 14


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