National Cancer Institute®
Last Modified: March 1, 2002
UI - 11820331
AU - Naoe T
TI - Mechanism-based therapy for leukemia: a lesson from ATRA therapy.
SO - Nagoya J Med Sci 2001 Nov;64(3-4):103-8
AD - Department of Infectious Diseases, Nagoya University Graduate School of Medicine, Japan. email@example.com
In the past two decades, there has been a tremendous increase in our understanding of the molecular mechanism of human leukemias. Leukemias are now recognized as a deregulated state of cell proliferation, differentiation and apoptosis, which is induced by gene alterations, including chromosomal translocations. Many of the mechanisms are potentially exploited as new targets for drug development. All-trans retinoic acid therapy for acute promyelocytic leukemia, which was initially developed as a differentiation therapy in an experienced-based manner, is currently known to be the first successful oncoprotein-directed therapy. Basic and clinical research into ATRA-resistance provides new directions for acute myeloid leukemia therapy. Anti-leukemia therapy will continue to lead the field of chemotherapy in the coming decades.
UI - 11806982
AU - Latagliata R; Petti MC; Fenu S; Mancini M; Spiriti MA; Breccia M;
TI - Brunetti GA; Avvisati G; Lo Coco F; Mandelli F Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem.
SO - Blood 2002 Feb 1;99(3):822-4
AD - Department of Human Biotechnologies and Hematology, University La Sapienza of Rome, Cattedra di Ematologia, Via Benevento 6-00161, Rome, Italy. firstname.lastname@example.org
The use of all-trans retinoic acid (ATRA) in combination with chemotherapy has markedly improved the prognosis for patients with acute promyelocytic leukemia (APL); the higher complete remission (CR) and survival rates now reported in this disease almost approach those obtained for other highly curable hematologic malignancies. Of 77 patients with APL who were consecutively treated at a single institution and who achieved CR after induction and consolidation therapy, 5 (6.5%) acquired therapy-related myelodysplasia (tMDS), acute myelogenous leukemia (AML), or both (tMDS-AML). Of these, 3 of 46 (6.5%) patients received front-line chemotherapy with or without ATRA and acquired tMDS-AML while in first remission of APL. Two underwent repeated chemotherapy cycles with ATRA because of APL relapse and acquired tMDS-AML while in the second or third remission of APL. In 2 patients, clinical and biologic characteristics of tMDS-AML were as expected for postalkylating forms (long latency, MDS phase preceding AML, karyotypic aberrations involving chromosomes 5 or 7), even though one of them had not previously received alkylating drugs. Three of the 5 patients died shortly after tMDS-AML diagnosis, one is alive with tMDS, and one is alive and in CR after allogeneic bone marrow transplantation. The occurrence of tMDS-AML after successful therapy for APL is an emerging problem. The availability of prognostic score systems at initial diagnosis and monitoring of residual disease by polymerase chain reaction might allow better tailoring of treatment intensity in APL to spare unnecessary toxicity and to minimize the risk for tMDS-AML in patients who are presumably cured.
UI - 11841402
AU - Usuki K; Urabe A; Masaoka T; Ohno R; Mizoguchi H; Hamajima N; Miyazaki
TI - T; Niitsu Y; Yoshida Y; Miura A; Shibata A; Abe T; Miura Y; Ikeda Y; Nomura T; Nagao T; Saitou H; Shirakawa S; Ohkuma M; Matsuda T; Nakamura T; Horiuchi A; Kuramoto A; Kimura I; Irino S; Niho Y; Takatsuki K; Tomonaga M; Uchino H; Takaku F; Gran AML Study Group Efficacy of granulocyte colony-stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study.
SO - Br J Haematol 2002 Jan;116(1):103-12
AD - Division of Hematology, NTT Kanto Medical Center, Tokyo, Japan.
To investigate the efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in patients with acute myelogenous leukaemia, a leukaemia were randomized to G-CSF or control groups after remission induction therapy. The G-CSF group received G-CSF (Filgrastim) from 48 h after the completing chemotherapy until the absolute neutrophil count exceeded 1.5 x 10(9)/l. The control group did not receive G-CSF unless severe infection occurred. There were 245 evaluable patients (120 and 125 in the G-CSF and control groups respectively). The complete remission rate was similar in the G-CSF and control groups (80.8% versus 76.8%), as was the 5-year probability of disease-free survival (34.5% versus 33.6%) and overall survival (42.7% versus 35.6%). Neutrophil recovery was significantly faster in the G-CSF group than in the control group (12 d versus 18 d, P = 0.0001). The median duration of febrile neutropenia was significantly shorter in the G-CSF group than in the control group (3 d versus 4 d, P = 0.0001). In conclusion, prophylactic administration of G-CSF after remission induction therapy for acute myelogenous leukaemia is safe and useful even in patients without infection on completing chemotherapy.
UI - 11858371
AU - Tunc B; Oner AF; Hicsonmez G
TI - The effect of short-course high-dose methylprednisolone on peripheral blood CD34+ progenitor cells of children with acute leukemia during remission induction therapy.
SO - Turk J Pediatr 2002 Jan-Mar;44(1):1-4
AD - Department of Pediatrics, Suleyman Demirel University Faculty of Medicine, Isparta, Turkey.
This study was undertaken to determine the effect of short-course high-dose methylprednisolone (HDMP) treatment on peripheral blood (PB) CD34+ progenitor cells during remission induction treatment in 11 children with newly diagnosed acute leukemia (7 with ALL, 4 with AML) whose bone marrow (BM) cells expressed fewer than 5% CD34 at the time of diagnosis. All children who had no infection were given HDMP as a single daily oral dose of 30 mg/kg for the first four days of induction therapy. The number of CD34+ progenitor cells were determined by flow cytometry before and after four days of HDMP treatment. While the number of PB blast cells significantly decreased after only a four-day course of HDMP treatment, the number of PB CD34+ progenitor cells increased in all patients. In addition, after four days of HDMP treatment polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC) increased significantly (p < 0.05). We suggest that the potential beneficial effects of HDMP in the induction treatment of acute leukemia may occur partly by the stimulation of PB CD34+ hematopoietic progenitor cells in a short period of time.
UI - 11535988
AU - Nabhan C; Mehta J; Tallman MS
TI - The role of bone marrow transplantation in acute promyelocytic leukemia.
SO - Bone Marrow Transplant 2001 Aug;28(3):219-26
AD - Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Robert H Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA.
Acute promyelocytic leukemia (APL) is characterized by a specific gene rearrangement and the generation of the PML-RARalpha fusion transcript which results from a translocation between chromosomes 15 and 17. Targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy results in an apparent cure in 70-80% of patients. Both allogeneic (ALLO) and autologous (AUTO) hematopoietic stem cell transplantation (HSCT) are effective in acute myeloid leukemia (AML), but their role in APL is not clear given the excellent outcome with ATRA and chemotherapy. Several retrospective studies have analyzed the outcome of patients undergoing AUTO or ALLO-HSCT in first (CR1) or second (CR2) complete remission. Most of these studies have shown significant transplant-related mortality (TRM) with ALLO-HSCT, but a reduction in relapse rate compared with AUTO-HSCT. The high TRM with ALLO-HSCT and the excellent outcome with ATRA and chemotherapy do not justify recommending this procedure for the majority of patients in CR1. The role of AUTO-HSCT in CR1 also is unclear. A small subset of patients at high risk of relapse, possibly identifiable by a high white blood cell count at presentation may benefit from HSCT. Most patients with relapsed disease achieve CR2 with ATRA, arsenic trioxide, or combination therapy. However, it is not known if these responses are sustained or if consolidation with HSCT has a place in this setting. The outcome of AUTO-HSCT in CR2 using stem cells that are negative for PML-RARalpha is excellent. It is unclear whether ALLO-HSCT from an HLA-identical sibling is superior to AUTO-HSCT with PML-RARalpha-negative cells in CR2 since the former would be associated with graft-versus-leukemia effects and the latter with lower TRM. Alternatively, arsenic trioxide or re-treatment with ATRA, followed by intensive chemotherapy may also be effective. A randomized prospective clinical trial, or a retrospective analysis of the available data would be useful in answering this critical question.
UI - 11803362
AU - Trisolini R; Bandini G; Stanzani M; Chilosi M; Cancellieri A; Boaron M;
TI - Poletti V Morphologic changes leading to bronchiolitis obliterans in a patient with delayed non-infectious lung disease after allogeneic bone marrow transplantation.
SO - Bone Marrow Transplant 2001 Dec;28(12):1167-70
AD - Department of Thoracic Diseases, Maggiore Hospital, Largo Nigrisoli 2, 40100 Bologna, Italy.
A 37-year-old man developed delayed non-infectious lung disease after undergoing bone marrow transplantation (BMT) for acute myeloid leukaemia. Over a 15-month period, the progression of morphologic changes from cellular interstitial pneumonia to bronchiolitis obliterans organizing pneumonia and cicatricial bronchiolitis obliterans was documented. Pulmonary function tests, high-resolution CT, bronchoalveolar lavage, lung biopsy and extensive microbiological studies were used as diagnostic tools either at onset and during the follow-up. This represents the first reported case in which a model--supported by longitudinal biopsy results--for the evolution of histologic lesions toward bronchiolitis obliterans after BMT is suggested; therapeutic implications are discussed.
UI - 10673689
AU - Seo S; Kami M; Honda H; Kashima T; Matsumura T; Moriya A; Machida U;
TI - Kanda Y; Chiba S; Hirai H Extramedullary relapse in the so-called 'sanctuary' sites for chemotherapy after donor lymphocyte infusion.
SO - Bone Marrow Transplant 2000 Jan;25(2):226-7
UI - 11706877
AU - Milligan DW
TI - The diagnosis and management of acute myeloid leukaemia.
SO - Clin Med 2001 Sep-Oct;1(5):358-61
AD - Birmingham Heartlands Hospital. email@example.com
Significant advances have been made in the management of AML in younger patients in the last 20 years, and it is easier to identify individual risk groups and stratify treatment accordingly. Results remain discouraging in the elderly, except for the minority with favourable risk factors, and new approaches are needed for most of these patients.
UI - 11890109
AU - Wang ZY
TI - Mechanism of action of all-trans retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia.
SO - Gan To Kagaku Ryoho 2002 Feb;29 Suppl 1():214-8
AD - Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Second Medical University, Shanghai 200025, China.
Treatment of APL with ATRA or As2O3 alone or in combination with chemotherapy yields a complete remission as high as 85%-95%, but their mechanisms of action remain unclear. The mechanisms of action underlying ATRA treatment are (1) relocalization of the PML restoration of normal structure of nuclear bodies and degradation of PML-RAR alpha protein via caspase-mediated cleavage and proteosome-dependent degradation; (2) conversion of PML-RAR alpha from a transcription repressor (CoR) to a transcription activator (CoA) under therapeutic concentration of ATRA (3) coordinated genes expression induced by ATRA resulting in an elegant and intricate cellular program for the commitment to differentiation. 169 genes were modulated to express, with 100 genes up-regulated and 69 down-regulated. As2O3 exerts its action by dual dose-dependent manner. At higher concentration (1-2 microns/l), it induces apoptosis of the leukemic cells associated with disruption of mitochondrial membrane potential, elevation of caspase-3 and other caspases activity and decline of Bcl-2 expression. At lower concentration (0.1-0.5 micron/l), it triggers differentiation with elevation of CD11b expression accompanied by morphologically partial differentiation. At both concentrations, As2O3 causes degradation of PML-RAR alpha protein implicated probably in its mechanisms of action.
UI - 11860447
AU - Mishra SK; Melinkeri SR; Dabadghao S
TI - Benign thymic hyperplasia after chemotherapy for acute myeloid leukemia.
SO - Eur J Haematol 2001 Oct;67(4):252-4
AD - Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Thymic hyperplasia can occur after cytotoxic therapy for various malignancies. The possible cause could be rebound enlargement after initial atrophy caused by these drugs. During the treatment of hematological malignancies this could be a cause of great concern. We report here a case of thymic hyperplasia after chemotherapy for acute myeloid leukemia. Awareness of this unusual side-effect may prevent needless investigation and therapy.
UI - 11841431
AU - Fassas A; Buffels R; Anagnostopoulos A; Gacos E; Vadikolia C; Haloudis
TI - P; Kaloyannidis P Safety and early efficacy assessment of liposomal daunorubicin (DaunoXome) in adults with refractory or relapsed acute myeloblastic leukaemia: a phase I-II study.
SO - Br J Haematol 2002 Feb;116(2):308-15
AD - Department of Haematology, George Papanicolaou General Hospital, Exokhi, Thessaloniki, Greece. firstname.lastname@example.org
We have conducted a phase I/II trial to determine the maximum tolerated dose, early safety and efficacy of single-agent liposomal daunorubicin in relapsed or refractory acute myeloid leukaemia (AML). Successive cohorts of six patients received escalated doses of 75, 100, 125 or 150 mg/m2 of DaunoXome for three consecutive days. Responding patients received a further consolidation cycle of DaunoXome at a dose identical to the one inducing complete or partial remission at the various dose levels. Twenty-eight patients with a median age of 50.5 years were enrolled. A maximum tolerated dose was determined at 150 mg/m2. Twelve patients received the second cycle. DaunoXome was well tolerated at all administered levels; dose-limiting toxicities included nausea and vomiting, mucositis and two episodes of cardiotoxicity resulting in the death of two patients. The overall response rate was 46% with a median duration of response of 180 d and a median duration of survival of 208 d. Ten patients demonstrated a complete response following cycle 1, and a further four entered partial response with the first cycle (marrow blasts between 5% and 10%). Of these, three attained complete response with the second cycle (total complete response 13/28). Our results indicate that DaunoXome at a dose of 150 mg/m2 displays acceptable toxicity in a 3-d regimen followed by a 3-d consolidation course at 100 mg/m2/d. At this dose schedule, interestingly high remission rates were achieved, justifying further evaluation of DaunoXome for the treatment of relapsed or refractory AML patients.
UI - 11757771
AU - Hirayama Y; Koyama R; Nagai T; Ohta H; Kondo A; Ishikawa K; Ishitani K;
TI - Matsunaga T; Sakamaki S; Niitsu Y Successful treatment of a case of relapsed acute promyelocytic leukemia with arsenic trioxide.
SO - Intern Med 2001 Nov;40(11):1136-9
AD - Hokkaido Prefectural Sapporo Kitano Hospital.
We report a patient with an initial relapse of acute promyelocytic leukemia (APL) who achieved a second complete remission (CR) after treatment with arsenic trioxide. The patient, a 66-year-old woman diagnosed as having relapsed APL, received arsenic trioxide intravenously at a dose of 10 mg/day. At day 36, the patient achieved a second CR. The side effects were slight neuralgia and mild skin erythematous changes, which improved following cessation of the drug. Although arsenic trioxide may be effective for relapsed APL, it should be used with caution because of various complications.
UI - 11821446
AU - Gandhi V; Plunkett W; Du M; Ayres M; Estey EH
TI - Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia.
SO - J Clin Oncol 2002 Feb 1;20(3):665-73
AD - Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. email@example.com
PURPOSE: To determine the maximum tolerated duration of infusions at the fixed gemcitabine dose rate of 10 mg/m(2)/min and to analyze the pharmacodynamic actions in leukemia blasts during gemcitabine therapy. PATIENTS AND METHODS: The study was conducted in a phase I trial by escalating the duration of gemcitabine infusion at a fixed-dose rate of 10 mg/m(2)/min. Patients with relapsed or refractory acute myelogenous leukemia (AML) received gemcitabine for 8.0 (n = 3), 10.0 (n = 3), 12.5 (n = 8), 15.5 (n = 3), or 18.0 hours (n = 2). Pharmacokinetic and pharmacodynamic investigations were undertaken in circulating AML blasts. RESULTS: Gemcitabine was infused for up to 18 hours at the fixed-dose rate. Four patients had grade 3 toxicities at longer infusion schedules. One patient had a partial remission; two others had a reduction in blasts and concomitant rise in neutrophils. Gemcitabine triphosphate was detectable in AML cells even at 1 hour after the start of infusion in eight patients. The concentration ranged from 130 to 900 micromol/L at the end of the infusion. Consistently, there was a rapid decline in DNA synthesis, which remained suppressed at 85% to 95% during and for at least 10 hours after the end of the infusion. Compared with levels in cells measured before therapy, at 8 hours after the start of the infusion, there was a decline in the cellular purine deoxynucleotide pools. CONCLUSION: At the fixed-dose rate of 10 mg/m(2)/min, gemcitabine could be administered for longer than 12 hours without untoward toxicity. The favorable toxicity profile and pharmacokinetic and pharmacodynamic features warrant combination with DNA-damaging agents.
UI - 11721417
AU - Song Y; Wang G; Wan D
TI - [Successful treatment of AML by HLA-compatible sibling umbilical cord blood stem cell transplantation--the first case report in China]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Aug;20(8):399-401
AD - First Affiliated Hospital, Henan Medical University, Zhengzhou 450052.
OBJECTIVE: To apply umbilical cord blood stem cell transplantation (UCBSCT) to the treatment of hematological malignancies, and to observe the persistent hematopoietic reconstitution, graft-versus-host disease (GVHD) and transplantation-related complications. METHODS: An 11-year-old patient with acute myeloid leukemia in complete remission (CR) received UCBSCT from a HLA-compatible sibling. The conditioning regimen was BU/CY (busulfan 4 mg.kg-1.d-1 x 4, cyclophosphamide 60 mg.kg-1.d-1 x 2). CsA was given for prophylaxis of acute GVHD. The patient received 0.35 x 10(8) nucleated cells/kg, including 1.82 x 10(4) CFU-GM/kg and 2.04 x 10(5) CD34+ cells/kg. RESULTS: The recipient showed hematopoietic reconstitution on day 14 post-transplantation; ANC > 1.0 x 10(9)/L on day 21; DNA fingerprinting showed engraftment on day 60, the blood type of the patient changed from O group to B group. In the follow-up of 330 days, the patient was in good condition without acute or chronic GVHD. CONCLUSION: It is the first case reported in China that have succeeded in the treatment of acute myeloid leukemia by allogeneic UCBSCT.
UI - 11721423
AU - Wu B; Sun J; Meng F
TI - [Allogeneic peripheral stem cell transplantation (PBSCT) for hematological malignancies]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Aug;20(8):420-3
AD - Nanfang Hospital, First Military Medical University, Guangzhou 510515.
OBJECTIVE: To evaluate the efficacy of allo-PBSCT in hematological malignancies. METHODS: Sixteen patients with hematological malignancies were treated by allo-PBSCT, started from march 1997. Five of them were ALL (CR1 4, CR2 1), 2 ANLL (CR1), 8 CML(CP 5, AP 3), and one NHL(PR). The median age was 33(18-49) years. Conditioning regimen was TBI 9-10 Gy + CTX 120 mg/kg, or TBI 10 Gy + CTX 120 mg/kg + Vp16 500 mg. A combination of cyclosporine and methotrexate was administered to prevent acute GVHD. All donors received G-CSF 5 micrograms.kg-1.d-1 for 5 to 6 days. One or three leukapheresis procedures were performed by CS 3000 plus blood cell separator to collect a median mononuclear cells of 9 x 10(8)/kg recipient weight [range(5.79-13.7) x 10(8)/kg], including a median CD34+ cells 13.9 x 10(6)/kg [range(5.69-49.00) x 10(6)/kg]. RESULTS: All patients were engrafted and hematopoietic reconstitution was rapid: neutrophils achieving 0.5 x 10(9)/L on day 12 (range, 10-15), platelets > 30 x 10(9)/L on day 13 (range, 8-24). More than grade II aGVHD occurred in 3(18.7%), and localized cGVHD in 3 patients. Leukemia relapse occurred in one patients. The median follow-up duration was 13 months. Eleven patients were alive in disease-free situation. CONCLUSION: Allo-PBSCT can rapidly reconstitute hematopoiesis with incidences of aGVHD and cGVHD not more than that in BMT.
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