pirarubicin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Pirarubicin (tetrahydropyranyl-adriamycin: THP) is a derivative of doxorubicin with reportedly less cardiotoxicity in adults. However no studies of cardiotoxicity in children treated with THP have been reported. This study was performed to assess the THP-induced cardiotoxicity for children with acute lymphoblastic leukemia (ALL).. This study comprised 61 asymptomatic patients aged from 7.6 to 25.7 years old. Median follow-up time after completion of anthracycline treatment was 8.1 years (range: 1.7-12.5). The cumulative dose of THP ranged from 120 to 740 mg/m(2) with a median of 180 mg/m(2) . Patients underwent electrocardiogram (ECG), echocardiography, the 6-min walk test (6MWT), and measurements of serum brain natriuretic peptide (BNP) before and after exercise.. All subjects showed normal left ventricular function assessed by echocardiography. Ventricular premature contraction in Holter ECG and reduced exercise tolerance in the 6MWT were detected in 2/46 (3.3%) and 5/41(12.2%), respectively. Abnormal BNP levels were detected in 6/60 (10%) both before and after exercise. The cumulative dose of THP was significantly correlated with BNP levels after exercise (r = 0.27, P = 0.03), but not with any other cardiac measurements. Further analysis revealed that subjects with a high cumulative dose ≧300 mg/m(2) had significantly higher BNP levels after exercise compared with subjects with a low cumulative dose <300 mg/m(2) (P = 0.04).. No significant cardiac dysfunction was detected in long-term survivors who received THP treatment. The use of post-exercise BNP level to indicate high cardiotoxicity risk should be verified by further study.

Topics: Adolescent; Adult; Anthracyclines; Antineoplastic Agents; Child; Doxorubicin; Electrocardiography; Heart Diseases; Heart Function Tests; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors; Young Adult

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Valproic Acid

Spinal cord compression is a rare complication of acute lymphoblastic leukemia (ALL). We report a 13-year-old boy with B-precursor ALL, presenting with restriction of breathing and back pain. Cerebrospinal fluid examination showed extremely high protein levels. Radiologic examination indicated that leukemia extended from the thoracic to sacral epidural spaces over 21 vertebral lengths in a band-shaped form, threatening to induce compressive spinal cord neuropathy. Prompt initiation of systemic chemotherapy relieved the obstruction of cerebrospinal fluid flow without local irradiation or surgical intervention. To our knowledge, this patient has shown the most extensive epidural involvement among ALL patients previously reported.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Epidural Neoplasms; Humans; Lumbar Vertebrae; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Sacrococcygeal Region; Spinal Cord Compression; Thoracic Vertebrae; Vincristine

To evaluate the therapeutic effects of chemotherapeutic regimen containing pirarubicin (THP) on the treatment of high-risk or refractory and relapsed acute leukemia (AL) in adults.. Forty patients with high-risk or refractory and relapsed AL, 26 males and 14 females, aged 33 (14-63) received treatment regimens with THP: TA regimen [THP + cytosine-arabinoside (Ara-C)] for acute myeloid leukemia (AML) and TAOP regimen [THP + Ara-C + vincristine (VCR) + prednisone (Pred)] for acute lymphocytic leukemia (ALL) or biphenotype-AL. Forty matched patients received mitoxantron (MIT) + Ara-C for AML or MIT + Ara-C + VCR + Pred for ALL and biphenotype AL as controls. The therapeutic effects were observed.. The complete remission (CR) rate was 47.5% vs 45% (P > 0.05), partial response (PR) rate was 25% vs 20% (P > 0.05), and overall response (OR) rate was 72.5% vs 65% (P > 0.05) in the treatment group and control group. The continuous CR time was 528 days in the treatment group, significantly longer than in the control group (463 days, P < 0.05). Marrow suppression was more serious in the treatment group. The patients in the treatment group had higher incidence of infections (P < 0.05). The time with sustained recovery of platelet number was 13.9 days in the treatment group, significantly longer than in the control group (P < 0.05).. Regimens with THP are more effective on treatment of high-risk or refractory and relapsed AL in adults, however, with more serious marrow suppression and higher incidence of infection.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Vincristine

To evaluate the therapeutic effects of chemotherapeutic regimen with pirarubicin in the management of adult high-risk acute leukemia.. Twenty-nine high-risk acute leukemia patients were selected as the treatment group and another 29 patients with similar pretreatment conditions as the control group. In the treatment group, 18 patients had acute non-lymphocytic leukemia (ANLL), and 8 had acute lymphocytic leukemia (ALL) and 3 had mixed leukemia, all received treatment regimens with pirarubicin+cytarabine, vincristine+pirarubicin+prednisone, Vincristine+pirarubicin+L-asparaginase (L)+prednisone or pirarubicin+cytarabine+vincristine+prednisone. Routine therapeutic regimens were adopted in the management of the control.. In ANLL patients, the overall remission rate was significantly higher in the treatment group than in the control group (77.78% vs 44.44%, P=0.031). Patients in the treatment group had greater marrow suppression and higher incidence of infections than the control group (P=0.012).. Regimens with pirarubicin is more effective than the routine regimens in the management of patients with high-risk ANLL and produce greater but tolerable marrow suppression.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Antibiotics, Antineoplastic; Child, Preschool; Death, Sudden, Cardiac; Doxorubicin; Electrocardiography; Fatal Outcome; Female; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

It is vital to develop effective therapy for children with acute lymphoblastic leukemia (ALL), in whom no remission occurs or who suffer relapse with current protocols. Cellular drug resistance is thought to be an important cause of induction failure and relapse. We performed in vitro tests of bone marrow samples in 196 children with newly diagnosed ALL with a 4-day culture and a methyl-thiazol-tetrazolium assay. We tested 16 drugs and calculated the 70% lethal dose (LD70) for 14 drugs and the leukemic cell survival (LCS) rate for dexamethasone and prednisolone. For each single drug, patients were classified into two groups, sensitive or resistant, by median concentration of LD70 or LCS. When patients were classified into three groups by sensitivity to four drugs of DPAV (dexamethasone, prednisolone, L-asparaginase, and vincristine), 3-year event-free survival (EFS; 95% confidence intervals) of the super sensitive group (SS; sensitive to all 4 drugs) was 0.833 (0.690 to 0.976), that of the intermediate sensitive group (IS; sensitive to 2 or 3 drugs) was 0.735 (0.609 to 0.863), and that of the relatively resistant group (RR; sensitive to no drugs or to 1 drug) was 0.541 (0.411 to 0.670; P = .0008). We then investigated the relationship between the above four-drug sensitivity and the time of relapse. The SS and IS patients tended to maintain continuous complete remission, and RR patients tended to undergo induction failure and early and late relapse (P = .004). Initial white blood cell count, immunologic classification, and age were also predictive factors, but the patient numbers showed no statistical correlation between these factors and the four-drug sensitivity groups (SS, IS, and RR). When we took three groups SS/IS/RR and investigated the EFS for various clinical groups, DPAV sensitivity strongly influenced EFS in the standard-risk ALL (P = .016). In vitro drug sensitivity testing provides additional prognostic information about childhood ALL, and early detection of drug resistance at the time chemotherapy commences may provide a successful strategy for individualizing treatment, as the results indicate de novo resistance to front-line drugs and suggest alternative, second-line drugs.

Topics: Aclarubicin; Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bleomycin; Bone Marrow; Cell Survival; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Follow-Up Studies; Humans; Infant; Infant, Newborn; Life Tables; Melphalan; Methotrexate; Mitomycin; Mitoxantrone; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Recurrence; Remission Induction; Tumor Cells, Cultured; Vincristine

Confocal microspectrofluorometry allows the analysis of fluorescent molecules such as anthracylines in isolated living cells. An optical microscope fitted with a phase-contrast 100 X water-immersion objective enables simultaneous observation of the sample, focusing of the laser beam on the selected cell fraction (nucleus) and collection of the fluorescence emitted from the sample. The resulting intranuclear spectra are interpreted according to a quantitative model of the fluorescence spectra of both free and DNA-bound anthracycline. The intranuclear drug concentration can thus be determined. This technique has been applied to blast cells collected in patients with acute leukemia. Leukemic cells are aspirated from bone marrow, separated by Ficoll sedimentation and resuspended in RPMI-1640 containing 10% fetal calf serum and 200 nM tetrahydropyranyl-doxorubicin (THP-DOX). After one hour, 20 cells are analyzed and the mean nuclear drug content is determined (C1). Cells are then resuspended in the same medium but without anthracycline for 3 hours and the mean intranuclear drug concentration is then also determined (C3). From C1 and C3 the retention rate (RR) is calculated. Firstly, the accuracy of the method was checked. In 4 AML patients, two different samples aspirated on the same day were divided into two portions. Thus, two measurements were made on each one (4 values per patient). Coefficients of variation were satisfactory (4, 6, 12, and 12%). Secondly, blast cells collected in patients with AML and ALL at diagnosis or in relapse were studied. P-glycoprotein (P-gp) and CD34 expression was also studied using respectively immunohistochemistry land flow cytometry. Results obtained from the first 21 patients showed that there was no correlation between RR and either P-gp or CD34 expression. This could result from the efflux of THP-DOX by other mechanisms and/or low sensitivity of the staining technique.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antigens, CD34; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Bone Marrow; Cell Nucleus; Child; Doxorubicin; Drug Resistance, Multiple; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid; Microscopy, Confocal; Microspectrophotometry; Middle Aged; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Microspectrofluorometry allows the analysis of fluorescent molecules such as anthracyclines in the nucleus of isolated living cells. Using this technique, we confirmed that the amount of doxorubicin or THP-doxorubicin incorporated into the nucleus was related to the resistant or sensitive character of K562 cells. It was then extended to the study of fresh leukemic cells and kinetic studies were performed allowing the calculation of the retention rate (RR) of anthracycline (THP-doxorubicin) into the cell nucleus. A reproducibility study confirmed the accuracy of the method. Blast cells collected in patients with acute myeloid (n = 22) or lymphoid (n = 8) leukemia, at diagnosis (n = 26), or in relapse (n = 4) have been studied. RR varied from 8 to 98% independently of the type of leukemia or the clinical status. RR did not correlate either with P-glycoprotein or with CD34 expression although this latter result should be confirmed on a higher number of subjects. Among 18 patients presenting with AML at diagnosis, 14 have been treated with intensive chemotherapy including anthracyclines; the only one who had resistant disease had the lowest RR value. In conclusion, the results obtained here show that microspectrofluorometry allows the performance of kinetic studies on fresh leukemic cells in order to quantify chemo-resistance phenomena related to drug transport.

Topics: Biological Transport; Cell Compartmentation; Cell Nucleus; Doxorubicin; Drug Resistance; Humans; In Vitro Techniques; Leukemia, Myeloid, Acute; Microscopy, Confocal; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Spectrometry, Fluorescence; Tumor Cells, Cultured