National Cancer Institute®
Last Modified: September 1, 2002
UI - 12060673
AU - Tinhofer I; Anether G; Senfter M; Pfaller K; Bernhard D; Hara M; Greil R
TI - Stressful death of T-ALL tumor cells after treatment with the anti-tumor agent Tetrocarcin-A.
SO - FASEB J 2002 Aug;16(10):1295-7
AD - Laboratory of Molecular Cytology, Department of Internal Medicine, University of Innsbruck, A-6020 Innsbruck, Austria. Inge.Tinhofer@uibk.ac.at
The T-ALL cell lines CCRF-CEM and Jurkat were studied for their sensitivity toward apoptosis induced by tetrocarcin-A (TC-A), an antibacterial and antitumor agent isolated from the actinomycete Micromonospora. This substance promoted cell death via a mitochondrial signaling pathway, that is, by activation of Bid and Bax, loss of the mitochondrial transmembrane potential, release of cytochrome c, and activation of effector caspases, even under conditions of Bcl-2 overexpression. Furthermore, sensitivity to TC-A was not dependent on expression of wild-type caspase-8. In contrast, this apoptotic pathway was inhibited markedly by pretreatment of cells with cycloheximide, an inhibitor of de novo protein synthesis. cDNA microarray chip analysis revealed that TC-A induced a significant up-regulation of members of the heat shock protein family known to be involved in the endoplasmic reticulum (ER)-stress-induced apoptotic program. The activation of caspase-12, the central inducer caspase involved in ER-stress by TC-A treatment, is in concordance with this result. These results show that, in T-ALL cells, TC-A induces an apoptotic machinery via mitochondrial and ER signaling, which is not inhibited by aberrant expression/function of important regulators of death receptor- and drug-induced apoptosis.
UI - 11831563
AU - Eiser C; Tillmann V
TI - Learning difficulties in children treated for acute lymphoblastic leukaemia (ALL).
SO - Pediatr Rehabil 2001 Jul-Sep;4(3):105-18
AD - Department of Psychology, Western Bank, Sheffield UK. firstname.lastname@example.org
Concern about the adverse affects of brain irradiation used in treatment for childhood leukaemia on children's learning have been put forward since the 1960s. Early work based on assessment of IQ suggested considerable problems associated with CNS irradiation of 2400cGy, and that children who were younger on diagnosis (below 5 years) were particularly at risk. Consequently, new protocols were introduced in which the amount of irradiation was reduced, or children were treated by chemotherapy alone. There is some evidence that reduction from 2400 to 1800cGy irradiation is beneficial, especially for younger children, as is treatment by chemotherapy alone. Methodological problems in conducting this work and limitations in relying on IQ tests are discussed. Where there are no indications of differences in survival, there would seem to be implications for reducing as far as possible the use of CNS directed therapy among young children treated for leukaemia.
UI - 12149298
AU - Seiter K; Liu D; Loughran T; Siddiqui A; Baskind P; Ahmed T
TI - Phase I study of temozolomide in relapsed/refractory acute leukemia.
SO - J Clin Oncol 2002 Aug 1;20(15):3249-53
AD - Department of Medicine, Zalmen A. Arlin Cancer Institute, Munger Pavilion Room 250, New York Medical College, Valhalla, NY 10595, USA. email@example.com
PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia. PATIENTS AND METHODS: Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m(2)/d for 7 days or 200 mg/m(2)/d for 9 days. RESULTS: Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment. CONCLUSION: Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.
UI - 11238093
AU - Cornelissen JJ; Carston M; Kollman C; King R; Dekker AW; Lowenberg B;
TI - Anasetti C Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome.
SO - Blood 2001 Mar 15;97(6):1572-7
AD - University Hospital Rotterdam/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. firstname.lastname@example.org
Between 1988 and 1999, 127 patients with poor-risk acute lymphoblastic leukemia (ALL) received a matched unrelated donor transplant using marrow procured by National Marrow Donor Program (NMDP) collection centers and sent out to 46 transplant centers worldwide. Poor risk was defined by the presence of the translocations t(9;22) (n = 97), or t(4;11) (n = 25), or t(1;19) (n = 5). Sixty-four patients underwent transplantation in first remission (CR1), 16 in CR2 or CR3, and 47 patients had relapsed ALL or primary induction failure (PIF). Overall survival at 2 years from transplant was 40% for patients in CR1, 17% in CR2/3, and 5% in PIF or relapse. Treatment-related mortality (TRM) and relapse mortality, estimated as competing risk factors, were 54% and 6%, respectively, in CR1, 75% and 8% in CR2/3, and 64% and 31% in PIF or relapse. Currently 23 CR1 patients are alive and free of disease with a median follow-up of 24 months (range, 3-97). Multivariable analysis showed that CR1, shorter interval from diagnosis to transplantation, DRB1 match, negative cytomegalovirus (CMV) serology (patient and donor), and presence of the Philadelphia chromosome, t(9;22), were independently associated with better disease-free survival (DFS). Transplantation in CR and presence of t(9;22) were associated with lower risk of relapse. Shorter interval from diagnosis to transplantation, DRB1-match, negative CMV, higher marrow cell dose, and Karnofsky score of 90 or higher were associated with less TRM. These results indicate that, despite a relatively high TRM, the low relapse rate resulted in a 37% +/- 13% DFS for CR1 patients, comparing favorably to results obtained with chemotherapy alone and matching results following HLA-identical sibling transplantation.
UI - 11853786
AU - Griffin JD
TI - Resistance to targeted therapy in leukaemia.
SO - Lancet 2002 Feb 9;359(9305):458-9
AD - Leukemia Program, Dana-Farber Cancer Institute, Boston, MA 02115, USA. email@example.com
UI - 12060122
AU - Faderl S; Thall PF; Kantarjian HM; Estrov Z
TI - Time to platelet recovery predicts outcome of patients with de novo acute lymphoblastic leukaemia who have achieved a complete remission.
SO - Br J Haematol 2002 Jun;117(4):869-74
AD - Department of Leukaemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Survival in acute leukaemia depends on the achievement of complete remission (CR). However, CR is not a clear-cut phenomenon and certain variables of its definition could more accurately characterize the quality of the remission. Because platelet recovery > 100 x 10(9)/l is an essential component of CR in acute leukaemia, we hypothesized that time to platelet recovery (TPR) might be predictive of overall survival (OS) or disease-free survival (DFS) in acute lymphoblastic leukaemia (ALL). We analysed TPR in 249 patients with ALL who entered CR after one course of induction chemotherapy and correlated TPR with DFS and OS. TPR was significantly associated with both DFS and OS if it occurred within a maximum of about 60 d from start of therapy. Furthermore, during that time period, the relative risk of death increased with increasing TPR. Although presence of the Philadelphia chromosome was the single most important adverse feature at diagnosis, the effect of TPR on survival continued to be significant within this patient subgroup. This effect was so pronounced that Philadelphia chromosome-positive patients with a TPR of 12 d had a better outcome than Philadelphia chromosome-negative patients with a TPR of 48 d. Thus, a short TPR seems to be able to override adverse characteristics in the outcome of ALL patients treated with chemotherapy. We conclude that a quicker TPR predicts longer DFS and OS in patients with ALL. As platelet counts are obtained almost daily in patients undergoing chemotherapy, TPR can readily be utilized to assess the prognosis of these patients.
UI - 12060133
AU - Kircher B; Stevanovic S; Urbanek M; Mitterschiffthaler A; Rammensee HG;
TI - Grunewald K; Gastl G; Nachbaur D Induction of HA-1-specific cytotoxic T-cell clones parallels the therapeutic effect of donor lymphocyte infusion.
SO - Br J Haematol 2002 Jun;117(4):935-9
AD - Laboratory for Tumour- and Immunobiology, Bone Marrow Transplant Unit, Division of Haematology and Oncology, Department of Internal Medicine, Innsbruck University Hospital, Anichstrasse 35, 6020 Innsbruck, Austria. firstname.lastname@example.org
Donor lymphocyte infusions (DLI) can induce a graft-versus-leukaemia (GvL) reaction in patients with relapsed disease. However, the mechanisms involved in remission induction are not completely known. A patient with chemotherapy-refractory relapse 1 year after human leucocyte antigen (HLA)-identical, unrelated stem cell transplantation (SCT) for bcr/abl-positive common acute lymphoblastic leukaemia (ALL) received a DLI from the original donor, and achieved complete cytogenetic and molecular remission concomitantly with extensive graft-versus-host disease (GvHD). Seven CD8+, donor-derived, alloreactive T-cell clones were generated by stimulating post-DLI remission cells with the patient's pretransplant mature dendritic cells. The minor histocompatibility antigen (mHag) recognized by these T-cell clones was identified as HA-1, a mHag associated with acute GvHD after SCT. Our finding provides evidence of HA-1-associated GvL effects after DLI that paralleled the eradication of full-blown, chemotherapy-refractory ALL relapse after allogeneic SCT.
UI - 12100139
AU - Ooi J; Iseki T; Takahashi S; Tomonari A; Nagayama H; Ishii K; Ito K;
TI - Sato H; Takahashi T; Shindo M; Sekine R; Ohno N; Uchimaru K; Nagamura F; Shirafuji N; Tojo A; Tani K; Asano S A clinical comparison of unrelated cord blood transplantation and unrelated bone marrow transplantation for adult patients with acute leukaemia in complete remission.
SO - Br J Haematol 2002 Jul;118(1):140-3
AD - Department of Haematology and Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. email@example.com
We performed a clinical comparison of unrelated cord blood transplantation (UCBT) and unrelated bone marrow transplantation in adult acute leukaemia patients in complete remission (CR) who received the same conditioning regimen, graft-versus-host disease (GvHD) prophylaxis and supportive treatment. The incidence of acute GvHD was almost the same between the two groups, but the haematopoietic recovery was delayed and the incidence of chronic GvHD was higher in the UCBT group. The probability of 2 year disease-free survival was similar between the two groups. These results suggest that adult acute leukaemia patients in CR without a suitable donor should be considered as candidates for UCBT.
UI - 11594516
AU - Hatta Y; Takeuchi J; Ohshima T; Horikoshi A; Iizuka Y; Kawamura M;
TI - Kanemaru M; Horie T Analysis of 20-year follow-up study of LVP regimen for adult acute lymphoblastic leukemia.
SO - Int J Hematol 2001 Aug;74(2):157-64
AD - First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan. firstname.lastname@example.org
In an attempt to develop a new intensive chemotherapy for adults with untreated acute lymphoblastic leukemia (ALL), 3 sequential programs were designed for 62 patients (age range, 15 to 74 years; median age, 32 years) consisting of the LVP-79 (1979-1984, 27 patients), LVP-85 (1984-1986, 14 patients), and LVP-87 (1987-1989, 21 patients) regimens. The influence of clinical and biologic characteristics on the patient outcome was also examined. L-asparaginase (L-asp), vincristine, and prednisolone, defined collectively as LVP, were administered for induction chemotherapy in all protocols. After achieving complete remission (CR), patients underwent 2 years of multi-agent consolidation, intensification, and maintenance therapy consisting of various combinations. No significant differences were noted between the 3 groups regarding CR rate or survival. In total, 47 of 62 patients (75.8%) achieved CR. The median overall survival (OS) and median CR durations were 550 days and 341 days, respectively. Overall, the estimated survival rate at 20 years was 18.1%. The disease-free survival rate at 20 years was 26.2%. According to univariate analysis, the most favorable pretreatment characteristic for achieving CR was age. A younger age (<40 years of age), platelet count >30 x 10(9)/L, having L1 morphology (French-American-British [FAB]classification subtype), female sex, and the absence of chromosomal abnormalities also helped improve survival rate. According to multivariate analysis, presence of Ph chromosome was found to be a major influencing factor for OS. Although higher doses of L-asp were administered than those used in previous studies, the adverse effect of L-asp was rarely identified. Therefore, it should be considered one of the key drugs for treatment of adult ALL. Further strategies still need to be developed to obtain better survival in adult ALL.
UI - 11594517
AU - Hara J; Park YD; Yoshioka A; Yumura-Yagi K; Koudera U; Hosoi G; Sako M;
TI - Kosaka Y; Sano K; Misu H; Mabuchi O; Aoyagi N; Yamamoto M; Tawa A; Miyata H; Tanaka H; Kikkawa M; Shimodera M; Kawa-Ha K; Osaka Childhood Leukemia Study Group Intensification of chemotherapy using block therapies as consolidation and reinduction therapies for acute lymphoblastic leukemia during childhood.
SO - Int J Hematol 2001 Aug;74(2):165-72
AD - Department of Developmental Medicine, Osaka University, Graduate School of Medicine, Suita, Japan. email@example.com with newly diagnosed acute lymphoblastic leukemia (ALL), except for those patients with t(9;22), were treated according to protocol-94 of the Osaka Childhood Leukemia Study Group. In this trial, the intensity of chemotherapy was enforced in the consolidation and reinduction phases by introducing AML-type block therapies consisting of concentrated administration of 4 to 6 drugs during 5 or 6 days. For patients in the higher risk groups, rotational combination chemotherapy was introduced following the early phase. A total of 124 children with B-cell precursor ALL (B-pre ALL) were classified into 3 groups, the ultrahigh-risk group (UHRG) (15 patients), the high-risk group (HRG) (61 patients), or the standard-risk group (SRG) (48 patients), based on age. leukocyte count, immunophenotype, central nervous system leukemia, response to treatment, and selected chromosomal abnormalities. The complete remission rate was 93%, and the 6-year event-free survival (EFS) rate was 79%+/-4%. EFS rates for the UHRG, HRG, and SRG groups were 67%+/-12%, 80%+/-6%, and 81%+/-6%, respectively. Nineteen patients with T-cell ALL were treated with the protocol for the UHRG. Thirteen patients (68%) attained complete remission, and the 6-year EFS rate was 55%+/-12%. Thus, intensification of chemotherapy improved the EFS rate and AML-type block therapies appeared to be effective as the consolidation and reinduction therapies for B-pre ALL.
UI - 12149204
AU - Dervieux T; Brenner TL; Hon YY; Zhou Y; Hancock ML; Sandlund JT; Rivera
TI - GK; Ribeiro RC; Boyett JM; Pui CH; Relling MV; Evans WE De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo.
SO - Blood 2002 Aug 15;100(4):1240-7
AD - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital and University of Tennessee, Memphis, 38105, USA.
Methotrexate (MTX) and mercaptopurine (MP) are widely used antileukemic agents that inhibit de novo purine synthesis (DNPS) as a mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to receive low-dose MTX (LDMTX: 6 oral doses of 30 mg/m(2)) or high-dose MTX (HDMTX: intravenous 1 g/m(2)) followed by intravenous MP; or intravenous MP alone (1 g/m(2)), as initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia cells was 3-fold higher in patients with T-lineage ALL compared with those with B-lineage ALL (769 +/- 189 vs 250 +/- 38 fmol/nmol/h; P =.001). DNPS was not consistently inhibited following MP alone but was markedly inhibited following MTX plus MP (median decrease 3% vs 94%; P <.001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared with MP alone (-50% +/- 4%, -56% +/- 3%, and - 20% +/- 4%, respectively; P <.0001). Full DNPS inhibition was associated with greater antileukemic effects compared with partial or no inhibition (-63% +/- 4% vs -37% +/- 4%; P <.0001) in patients with nonhyperdiploid B-lineage and T-lineage ALL. HDMTX plus MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX plus MP (2148 +/- 298 vs 1075 +/- 114 pmol/10(9) cells; P <.01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P <.001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more frequent after HDMTX.
UI - 11877270
AU - Avramis VI; Sencer S; Periclou AP; Sather H; Bostrom BC; Cohen LJ;
TI - Ettinger AG; Ettinger LJ; Franklin J; Gaynon PS; Hilden JM; Lange B; Majlessipour F; Mathew P; Needle M; Neglia J; Reaman G; Holcenberg JS; Stork L A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study.
SO - Blood 2002 Mar 15;99(6):1986-94
AD - Children's Hospital, Los Angeles, CA, USA. firstname.lastname@example.org
For this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population.
UI - 12088885
AU - Ramesh J; Kapelushnik J; Mordehai J; Moser A; Huleihel M; Erukhimovitch
TI - V; Levi C; Mordechai S Novel methodology for the follow-up of acute lymphoblastic leukemia using FTIR microspectroscopy.
SO - J Biochem Biophys Methods 2002 May 31;51(3):251-61
AD - Department of Physics, Ben Gurion University, 84105, Beersheba, Israel.
In this report, we present a novel spectroscopic method of follow-up during chemotherapy treatment for B- and T-cell childhood leukemia patients. We isolated peripheral lymphocytes from blood drawn from patients before and after the chemotherapy and collected Microscopic FTIR (FTIR-MC) spectra of the isolated lymphocytes. Our results showed that nucleic acids content decreased in both types of patients. Changes in phospholipids and proteins level could be observed. The overall effects of drugs administered to the patients can be understood at the molecular level using FTIR-MC and these results are expected to stimulate wider applications of spectroscopy in leukemia research.
UI - 12138898
AU - Yumura-Yagi K; Hara J; Horibe K; Tawa A; Komada Y; Oda M; Nishimura S;
TI - Yoshida M; Kudo T; Ueda K; Japan Association of Childhood Leukemia Study Outcome after relapse in childhood acute lymphoblastic leukemia.
SO - Int J Hematol 2002 Jul;76(1):61-8
AD - Department of Pediatrics, Osaka Medical Center and Research Institute for Child and Maternal Health, Izumi, Japan. email@example.com
Among 157 children with acute lymphoblastic leukemia (ALL) who experienced relapse at 54 institutes participating in the Japan Association of Childhood Leukemia Study, we analyzed the outcomes after relapse in 103 and 30 eligible cases with bone marrow (BM) and central nervous system (CNS) relapse, respectively. Reinduction rates in BM and CNS relapse cases were 72.3% and 83.3%, respectively. High reinduction rates were observed in B-precursor (B-pre) phenotype ALL in both relapse groups and in late (more than 24 months from onset) BM-relapse patients. After BM relapse, the overall 5-year survival rate was superior in the allogeneic stem cell transplantation (SCT) group compared to the non-SCT group (41.9%+/-8.2% versus 13.6%+/-6.5%, P < .0001). In contrast, the 4-year overall survival rate was not significantly different between the SCT (allogeneic plus autologous) and non-SCT groups after CNS relapse (26.8%+/-14.2% versus 61.9%+/-12.3%, P = .252). The late BM-relapse patients showed a significantly higher survival rate than did early-relapse patients, and survival rates were similar between the allogeneic and autologous group when the patients underwent SCT during a second complete remission. Moreover, B-pre ALL patients classified in the standard-risk group according to National Cancer Institute/Rome's criteria at onset had a good prognosis after allogeneic SCT. Improving the cure rate in relapsed ALL patients requires more intensive reinduction therapy and efforts to succeed with SCT in early BM-relapse patients as well as the establishment of a treatment strategy including indications of SCT for CNS-relapse patients.
UI - 12138903
AU - Abe Y; Yashiki S; Choi I; Hara K; Matsushima T; Nishimura J; Inaba S;
TI - Nawata H; Muta K Eradication of virus-infected T-cells in a case of adult T-cell leukemia/lymphoma by nonmyeloablative peripheral blood stem cell transplantation with conditioning consisting of low-dose total body irradiation and pentostatin.
SO - Int J Hematol 2002 Jul;76(1):91-3
AD - Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. firstname.lastname@example.org
We describe the case of a 55-year-old man with adult T-cell leukemia/lymphoma (ATL) in first remission who underwent nonmyeloablative allogeneic peripheral blood stem cell transplantation with conditioning consisting of 4 courses of pentostatin and low-dose total body irradiation. Complete chimerism in peripheral blood was achieved on day 42 without severe myelosuppression. Concomitantly, the proviral DNA load for human T-cell leukemia virus I (HTLV-I) in peripheral blood mononuclear cells decreased below detectable limits and was still undetectable on day 270. This fact indicates that eradication of ATL cells is feasible by induction of an alloimmune response without high-dose chemoradiotherapy.
UI - 12176883
AU - Powles R; Sirohi B; Treleaven J; Kulkarni S; Tait D; Singhal S; Mehta J
TI - The role of posttransplantation maintenance chemotherapy in improving the outcome of autotransplantation in adult acute lymphoblastic leukemia.
SO - Blood 2002 Sep 1;100(5):1641-7
AD - Leukaemia Unit, The Royal Marsden Hospital, Surrey, United Kingdom.
Extending the principle of conventional acute lymphoblastic leukemia (ALL) therapy to transplantation, 77 adult patients receiving autografts in first remission after melphalan with or without total body irradiation were scheduled to receive 6-mercaptopurine (6MP), methotrexate (MTX), and vincristine-prednisone (VP) for 2 years after transplantation to reduce relapse. Seventy-one percent of patients received 6MP, 57% received MTX, and 38% received VP. Thirty patients had a relapse at 1.5 to 80 months (median, 12.5 months), 15 in the first year and 7 beyond 3 years. The cumulative incidence of relapse at 10 years was 42% (95% CI, 31%-55%). The 10-year probabilities of disease-free survival (DFS) and overall (OS) survival were 50% (95% CI, 38%-62%) and 53% (95% CI, 41%-65%), respectively. Age older than 30 years, more than 4 weeks to attain remission, and high-risk karyotypes, for example, t(9;22) or t(4;11), were adverse features contributing to the identification of 3 prognostic risk groups with 0, 1, and 2 adverse features, respectively: standard (47%), intermediate (36%), and high (17%). The 10-year cumulative incidences of relapse (20%, 48%, 85%; P <.0001) and probabilities of DFS (72%, 41%, 10%; P =.0003) were significantly different among these groups. In Cox analysis of the 71 patients alive and well 120 days after transplantation, those receiving 2 or 3 maintenance chemotherapy agents had significantly lower relapse rates and superior DFS compared with those receiving 0 or 1 agent. Our data suggest that maintenance chemotherapy improves the outcome of patients with ALL undergoing autografting. However, it is unlikely that autograft-based strategies are optimal for the high-risk group of patients who should be considered for alternative-donor allograft procedures.
UI - 12176906
AU - Mori N; Yamada Y; Ikeda S; Yamasaki Y; Tsukasaki K; Tanaka Y; Tomonaga
TI - M; Yamamoto N; Fujii M Bay 11-7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells.
SO - Blood 2002 Sep 1;100(5):1828-34
AD - Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Japan. email@example.com
Human T-cell leukemia virus type I (HTLV-I) is the causative agent of an aggressive form of leukemia designated adult T-cell leukemia (ATL). We have previously demonstrated that all T-cell lines infected with HTLV-I and primary leukemic cells from ATL patients display constitutively high activity of transcription factor NF-kappaB. In this study we showed that Bay 11-7082, an inhibitor of NF-kappaB, induced apoptosis of HTLV-I-infected T-cell lines but only negligible apoptosis of HTLV-I-negative T cells. Bay 11-7082 rapidly and efficiently reduced the DNA binding of NF-kappaB in HTLV-I-infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-x(L), regulated by NF-kappaB, whereas it had little effect on the DNA binding of another transcription factor, AP-1. Although the viral protein Tax is an activator of NF-kappaB, Bay 11-7082-induced apoptosis of HTLV-I-infected cells was not associated with reduced expression of Tax. Furthermore, Bay 11-7082- induced apoptosis of primary ATL cells was more prominent than that of normal peripheral blood mononuclear cells, and apoptosis of these cells was also associated with down-regulation of NF-kappaB activity. Our results indicate that NF-kappaB plays a crucial role in the pathogenesis and survival of HTLV-I-infected leukemic cells and that it is a suitable target for the prevention and treatment of ATL.
UI - 12211194
AU - Pinheiro JP; Lanvers C; Wurthwein G; Boos J
TI - Pharmacology of PEG-asparaginase in childhood acute lymphoblastic leukemia (ALL).
SO - Blood 2002 Sep 1;100(5):1923-4; discussion 1924-5
UI - 11697515
AU - Kishi Y; Kami M; Oki Y; Hamaki T; Kanda Y; Machida U; Miyakoshi S;
TI - Ueyama J; Morinaga S; Muto Y Successful bone marrow transplantation for adult T-cell leukemia from a donor with oligoclonal proliferation of T-cells infected with human T-cell lymphotropic virus.
SO - Leuk Lymphoma 2001 Aug;42(4):819-22
AD - Department of Hematology, Toranomon Hospital, Tokyo, Japan.
We describe a patient who underwent successful BMT from her sibling for the treatment of adult T-cell leukemia/lymphoma. Pre-transplant examination of the donor revealed oligoclonal integration of HTLV-I proviruses within the germ line, and our concern was that clinical sequelae of HLTV-I infection might become evident in the setting of post-transplant immunosuppression. However, the patient has been in complete remission for 14 months after transplantation, and no clonality of HTLV-I provirus was detected in the peripheral blood cells using southern blotting analysis. Our experience supports the possibility of transplantation from HTLV-I positive donors.
UI - 12015642
AU - Erler T; Schmidt K; Klaber HG; Wischniewski E; Holfeld E
TI - [Successful surfactant therapy of ARDS in an immunodepressed child]
SO - Klin Padiatr 2002 May-Jun;214(3):109-12
AD - Klinik fur Kinder, und Jugendmedizin, Abteilung Neonatologie, Padiatrische Intensivmedizin, Carl-Thiem-Klinikum Cottbus, Lehrkrankenhaus der Universitatsklinik Charite zu Berlin, Germany. firstname.lastname@example.org
The acute respiratory distress syndrome in childhood is a rare disease, but as in the past still plagued with a high mortality rate. It is caused by severe pneumoniaes or infectious diseases with multiorgan failure, aspiration, trauma or immunodepression. There are no therapeutic guidelines based on controlled studies. Therefore different therapies i. e. high frequency oscillatory ventilation, nitric oxide application, surfactant therapy, extracorporal membrane oxygenation or a combination of these methods are used. We present the case of a 4 (3)/ 12 year old boy, who suffered from an acute lymphatic leukaemia. Caused by immunosuppressive therapy he got a severe broncho-pneumonia. During ventilation therapy an acute respiratory distress syndrome occurred. Due to a surfactant application over 7 days with a doses of 360 mg/kg body weight this RDS could be dominated. The extubation was possible after 17 days of ventilatory support. 3 weeks later the lung function was normalized and the chemotherapy resumed.
UI - 12210452
AU - Chunikhovskiy SP; Zelterman D; van Hoff J
TI - Treatment of childhood acute lymphoblastic leukemia at a regional non-academic center in Belarus.
SO - Med Pediatr Oncol 2002 Sep;39(3):202-6
AD - Mogilev Regional Children's Hospital, Mogilev, Belarus.
The outlook for children with cancer is improving in the less privileged nations of the world. This report from Belarus is representative of results that can be achieved. Copyright 2002 Wiley-Liss, Inc.
UI - 11874159
AU - Nyhlen A; Ljungberg B; Nilsson-Ehle I; Nord CE
TI - Impact of combinations of antineoplastic drugs on intestinal microflora in 9 patients with leukaemia.
SO - Scand J Infect Dis 2002;34(1):17-21
AD - Department of Infectious Diseases, University Hospital of Lund, Sweden.
The impact of antineoplastic drugs on the intestinal microflora was studied in 9 patients with acute leukaemia during chemotherapy and in 5 patients also during chemotherapy-induced neutropenia. Quantitative and qualitative microbiological analyses of faecal samples obtained before and during chemotherapy showed significantly increased counts of Bacteroides spp. in 3/9 patients and, during neutropenia, significantly increased counts of yeasts in 2/5 patients; however, the intestinal microflora was stable in most patients.
UI - 9080116
AU - Anderegg B; Horstmann M; Kabisch H
TI - Effects of anti-tal-1 oligodeoxynucleotides in T-ALL cell lines.
SO - Cancer Gene Ther 1997 Mar-Apr;4(2):84-90
AD - Department of Hematology/Oncology, Children's Hospital, Clinical Center for the University of Hamburg, Germany. email@example.com
Rearrangement of the gene tal-1 leads to transcriptional dysregulation and contributes to the formation of childhood T-cell acute lymphoblastic leukemia. Therefore, we tried to interfere with the transcription of the SIL/tal-1 fusion gene, the most common form of aberrant tal-1, by treatment with antisense oligodeoxynucleotides (ODNs). The potential of two different strategies was investigated, one targeting the cell line specific SIL/tal-1 fusion region, the other using an ODN complementary to tal-1 sequence downstream of the region not affected by any of the known types of tal-1 rearrangement. With both approaches a single-dose application of 3 mumol of ODN led to a significant antiproliferative effect of a about 25-60% in two T-ALL cell lines characterized by the SIL/tal-1 fusion gene. Investigation of the tal-1 mRNA level by reverse transcription-polymerase chain reaction was in concordance with these results: In both cell lines clearly less of the tal-1-specific fragment was generated after incubation with the antisense ODN tal-1 common than in the control experiments with a mismatched ODN or no ODN at all. Neither the antiproliferation antisense effect nor the downregulation of the steady state tal-1 mRNA level was observed in control cell lines bearing wildtype tal-1.
UI - 11532632
AU - Baron F; Frere P; Fillet G; Beguin Y
TI - Treatment of leukemia relapse after allogeneic hematopoietic stem cell transplantation by donor lymphocyte infusion and STI-571.
SO - Haematologica 2001 Sep;86(9):993-4
UI - 11721977
AU - Tabayashi T; Masuda K; Yamada K; Takeuchi M; Matsue K
TI - Successful eradication of residual bcr-abl-positive clones by donor leukocyte transfusion in a patient with philadelphia chromosome-positive acute lymphoblastic leukemia after peripheral blood stem cell transplantation.
SO - Int J Hematol 2001 Oct;74(3):354-6
UI - 12098004
AU - Styczynski J; Wysocki M; Balwierz W; Rokicka-Milewska R; Matysiak M;
TI - Balcerska A; Kowalczyk A; Wachowiak J; Sonta-Jakimczyk D; Chybicka A In vitro comparative antileukemic activity of various glucocorticoids in childhood acute leukemia.
SO - Neoplasma 2002;49(3):178-83
AD - Department of Pediatric Hematology and Oncology; Medical University Bydgoszcz, Bydgoszcz, 85-094 Poland. firstname.lastname@example.org
Resistance to glucocorticoids is nowadays one of the strongest adverse risk factors in the treatment of childhood acute lymphoblastic leukemia (ALL). Differential in vitro antileukemic activity of various glucocorticoids and their cross-resistance pattern in childhood acute lymphoblastic and myeloblastic leukemia was determined by means of the MTT assay in 49 successfully tested samples of childhood acute leukemia. The equivalent antileukemic concentrations of respective drugs against lymphoblasts in de novo ALL samples were: 35 microM of hydrocortisone; 8 microM of prednisolone; 1.6 microM of methylprednisolone; 0.47 microM of dexamethasone and 0.23 microM of betamethasone. In comparison to initial ALL samples, the group of relapsed ALL was more resistant to: prednisolone (38-fold, p=0.004), dexamethasone (>32-fold, p=0.004), methylprednisolone (37-fold, p=0.039), betamethasone (38-fold, p=0.018) and hydrocortisone (33-fold, p=0.030). The group of acute myeloid leukemia (AML) samples were resistant to: prednisolone (>83-fold, p<0.001), dexamethasone (>32-fold, p<0.004), methylprednisolone (>65-fold, p=0.003), betamethasone (>66-fold, p=0.004) and hydrocortisone (61-fold, p=0.007), when compared to ALL at presentation. A significant cross-resistance between all used glucocorticoids as well as between glucocorticoids and other tested anti-leukemic drugs was found. In some individual cases in vitro glucocorticoid cross-resistance was less pronounced and relatively good antileukemic activity of betamethasone was observed.
UI - 12200979
AU - Bhatnagar S; Chandra J; Narayan S
TI - Hematological changes and predictors of bone marrow recovery in patients with neutropenic episodes in acute lymphoblastic leukemia.
SO - J Trop Pediatr 2002 Aug;48(4):200-3
AD - Department of Pediatrics, Kalawati Saran Children Hospital, India. email@example.com
A total of 30 episodes of neutropenia in 16 patients of acute lymphoblastic leukemia, aged between 1 and 12 years were studied prospectively. In the initial treatment phase (induction of remission, consolidation and CNS prophylaxis) 92.8 per cent episodes were prolonged (> 7 days) and 85.7 per cent of them had profound neutropenia (absolute neutrophil counts < 0.200 x 10(9)/l). In contrast, in the maintenance phase, only 64.2 per cent were of prolonged duration; of them 57.1 per cent had profound neutropenia. Most patients in neutropenia of prolonged duration had anemia (Hb < 8 g/100 ml) and thrombocytopenia (platelet < 100 x 10(9)/l). Regularly increasing trends were seen in total leucocyte counts (TLC), absolute monocyte counts (AMC) and platelet counts from 4 days prior to recovery of absolute neutrophil counts (ANC). Of all the parameters, platelet count (> 100 x 10(9)/l) and AMC (> 0.1 x 10(9)/l) recovered 4 and 1 days, respectively, prior to recovery of ANC above 0.5 x 10(9)/l. Recovery of platelet counts (4 days prior to recovery of ANC) and possibly AMC can be considered early predictors of bone marrow recovery. These parameters can be used in conjunction with clinical condition to decide about early discharge of leukemia patients with neutropenia, especially in developing countries where prolonged stay can result in hospital acquired infections.
UI - 12200696
AU - Harasawa H; Yamada Y; Kudoh M; Sugahara K; Soda H; Hirakata Y; Sasaki H;
TI - Ikeda S; Matsuo T; Tomonaga M; Nobori T; Kamihira S Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL).
SO - Leukemia 2002 Sep;16(9):1799-807
AD - Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAP-negative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5'-deoxyadenosine, however, also caused the undesirable rescue of MTAP-negative ATL cell lines. 5'-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5'-deoxyadenosine rescue in MTAP-deficient ATL.
UI - 11753557
AU - Chatterjee R; Kottaridis PD; McGarrigle HH; Papatryphonos A; Goldstone
TI - AH Hypogonadotrophism fails to prevent severe testicular damage induced by total body irradiation in a patient with beta-thalassaemia major and acute lymphoblastic leukaemia.
SO - Bone Marrow Transplant 2001 Nov;28(10):989-91
AD - Department of Obstetrics and Gynaecology, University College London Hospitals, UK.
Radiation and chemotherapeutic drugs for cancer produce prolonged and often irreversible gonadal damage. To determine whether total body irradiation (TBI)-induced gonadal damage can be prevented by suppression of pituitary gonadotrophin levels, we studied a patient with transfusion dependent homozygous beta-thalassaemia and acute lymphoblastic leukaemia (ALL) who underwent one-antigen mismatched related bone marrow transplantation (BMT). Our data showed that despite having hypogonadotrophic hypogonadism (HH) prior to BMT, the patient developed primary testicular failure following the procedure, indicating that hypogonadotrophism failed to offer protection against TBI-induced testicular damage in this patient. Although this is an interesting case report, no firm conclusions can be drawn from a single patient.
UI - 12060979
AU - Mann G; Gadner H
TI - Curability of cancer in childhood and adolescence: acute lymphoblastic leukemia.
SO - Wien Klin Wochenschr 2002 Feb 28;114(4):141-2
UI - 12060981
AU - Attarbaschi A; Mann G; Dworzak M; Urban C; Fink FM; Dieckmann K; Riehm
TI - H; Gadner H; Austrian Cooperative Study Group Treatment results of childhood acute lymphoblastic leukemia in Austria--a report of 20 years' experience.
SO - Wien Klin Wochenschr 2002 Feb 28;114(4):148-57
AD - St. Anna Children's Hospital, Vienna.
Between 1981 and 1999, 890 Austrian children with acute lymphoblastic leukemia (ALL) were treated in 5 consecutive trials using protocols from the Berlin-Frankfurt-Munster (BFM) Group. In the trials BFM-A (Austria) 81 and ALL A 84, treatment stratification was performed using a risk factor, which was calculated from the initial peripheral blast cell count, and size of liver and spleen. In the following studies (BFM-A 86, 90 and 95) early response to a 7-day systemic mono-therapy with prednisone (as measured by the peripheral blast cell count) was used as an overriding stratification factor; in order to reduce the need for cranial radiotherapy, all patients received high-dose methotrexate (5 g/m2) for preventive central nervous system treatment. Event-free survival (EFS) rates increased from study BFM-A 81 (n = 141, probability (p) of EFS: 59% +/- 4%) and study ALL A 84 (n = 127, pEFS: 67% +/- 4%) to 77% +/- 4% in trial BFM-A 86 (n = 142), 79% +/- 3% in trial BFM-A 90 (n = 256), and 84% +/- 3% in trial BFM-A 95 (n = 224). However, the prognosis for high-risk patients has not significantly improved within the last 20 years (pEFS: 50%). Furthermore, conventional risk factors such as leukocyte count and age at time of diagnosis, could not be used to indicate patients in the low and intermediate risk group who might eventually relapse. Thus, in trial BFM-A 2000, detection of minimal residual disease by polymerase chain reaction-based methods after 5 and 12 weeks of therapy was introduced for treatment stratification. Minimal residual disease was prospectively shown to predict relapses more precisely and, as a matter of fact, may allow a more exact definition of which patients are at risk and which patients belong to the subgroup with a good prognosis despite reduced treatment.
UI - 12139731
AU - Chessells JM; Harrison G; Richards SM; Gibson BE; Bailey CC; Hill FG;
TI - Hann IM; Medical Research Council Working Party On Childhood Leukaemia Failure of a new protocol to improve treatment results in paediatric lymphoblastic leukaemia: lessons from the UK Medical Research Council trials UKALL X and UKALL XI.
SO - Br J Haematol 2002 Aug;118(2):445-55
AD - Molecular Haematology Unit, Camelia Botnar Laboratories, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. firstname.lastname@example.org
The impact of various types of intensification therapy was examined in a cohort of 3617 children aged 1-14 years with acute lymphoblastic leukaemia (ALL) enrolled in the Medical Research Council (MRC) UKALL X (1985-90) and UKALL XI (1990-97) trials. UKALL XI was modified in 1992 to incorporate the "best arm" of UKALL X with two 5-d intensification blocks at 5 and 20 weeks, and an additional randomization in respect of a third intensification at 35 weeks but omission of two consecutive injections of daunorubicin during induction. All children were eligible for randomization irrespective of risk group. The impact of the various types of intensification therapy was examined in a stratified analysis. At a median follow up of 102 months, both trials had an identical event-free survival of 61% (95% CI 58-63%) at 8 years. Survival at 8 years in UKALL XI was significantly better in than in UKALL X, 81% (79-83%) compared with 74% (72-76%) (P = < 0.001), owing