National Cancer Institute®
Last Modified: November 21, 2001
UI - 21443827
AU - Soignet SL; Frankel SR; Douer D; Tallman MS; Kantarjian H; Calleja E;
TI - Stone RM; Kalaycio M; Scheinberg DA; Steinherz P; Sievers EL; Coutre S; Dahlberg S; Ellison R; Warrell RP Jr United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia.
SO - J Clin Oncol 2001 Sep 15;19(18):3852-60
AD - Leukemia and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Joan and Sanford Weill Medical College of Cornell University, New York, NY 10021, USA. firstname.lastname@example.org
PURPOSE: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Forty patients experiencing first (n = 21) or > or = second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study. RESULTS: Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/microL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes. CONCLUSION: This study establishes ATO as a highly effective therapy for patients with relapsed APL.
UI - 21455229
AU - Estey EH
TI - Therapeutic options for acute myelogenous leukemia.
SO - Cancer 2001 Sep 1;92(5):1059-73
AD - Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095, USA. email@example.com
BACKGROUND: General therapeutic options for patients with acute myelogenous leukemia (AML) are reviewed and specific new therapies are described. METHODS: Data in this review came from the published literature and the M. D. Anderson Cancer Center's acute leukemia database. RESULTS: Outcome following standard therapy of AML is so variable that is best to speak of a range of outcomes determined by various prognostic factors. Therapy can (and usually does) fail because of treatment-induced mortality or (more usually) resistance to therapy. Performance status and age are the principal predictors of early death, whereas cytogenetics, a history of abnormal blood counts, and MDR1 expression are predictors of resistance. Using this information, physicians can categorize patients into those in whom 1) standard therapy is indicated, 2) either standard or investigational therapy is appropriate, and 3) investigational therapy is indicated. The majority of even newly diagnosed patients belong to Group 3. The availability of allogeneic or autologous transplantation does not alter this conclusion. Investigational therapies have been developed that are directed against the CD33 surface antigen, the multidrug-resistant MDR1 protein, and other targets. Because of the number of new therapies clinical research in AML should emphasize pilot trials rather than traditionally large Phase III studies. CONCLUSIONS: Most patients with newly diagnosed AML should be offered investigational regimens. Copyright 2001 American Cancer Society.
UI - 21262630
AU - Zhao W; Wang H; Wang X; Wu F; Guo W; Qu B; Shen Z; Wang Z
TI - Effects of all-trans-retinoic acid and arsenic trioxide on the hemostatic disturbance associated with acute promyelocytic leukemia.
SO - Thromb Res 2001 May 1;102(3):197-204
AD - Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197 Rui Jin Road II, 200025, Shanghai, People's Republic of China.
To study the in vivo effect of all-trans-retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) on the expression of tissue factor (TF) and the other hemostatic disturbance, a series of parameters were measured either in bone marrow blasts or plasma from acute promyelocytic leukemia (APL) patients. The plasma parameters were measured by ELISA or chromogenic studies. The TF transcription was assessed using reverse transcription-polymerase chain reaction (RT-PCR) technique. The results indicated that the blast cell procoagulant activity (PCA), TF antigen of APL cell lysate, as well as the transcription of APL TF mRNA elevated at diagnosis, were reduced after ATRA or As(2)O(3) therapy. The plasma level of P-selectin, TF, thrombin-antithrombin complex (TAT), soluble fibrinmonomer complex, thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), plasmin-antiplasmin complex, tissue plasminogen activator (t-PA) activity, urokinase plasminogen activator (u-PA) and its receptor (u-PAR), and D-dimer (D-D) significantly increased. Fibrinogen (Fg), antigen level of protein C (PC), plasminogen (PLG) activity, alpha(2)-plasminogen inhibitor activity (alpha(2)-PI), and plasminogen activator inhibitor (PAI) activity were decreased at diagnosis. The protein C activity (PC:A) and protein S (PS) remained unchanged. All the parameters were restored to normal ranges after complete remission (CR) except elevation of TF and TAT in both groups, as well as PC:A, PS, and t-PA in the ATRA group. In conclusion, there existed activation of platelets and consumption of anticoagulants as well as activation of coagulation and fibrinolytic system before treatment. Both ATRA and As(2)O(3) therapy downregulated the expression of TF mRNA, decreased the PCA and TF level in APL cells, significantly inhibited coagulation activation, corrected secondary hyperfibrinolysis and the other hemostatic abnormalities, and thus greatly improved the bleeding symptom in early stage of the treatment.
UI - 21400380
AU - Cesaro S; Meloni G; Messina C; Pillon M; Proglia A; Lanino E; Caniggia
TI - M; Bagnulo S; Pession A; Locatelli F; Italian Pediatric Group for Bone Marrow Transplantation High-dose melphalan with autologous hematopoietic stem cell transplantation for acute myeloid leukemia: results of a retrospective analysis of the Italian Pediatric Group for Bone Marrow Transplantation.
SO - Bone Marrow Transplant 2001 Jul;28(2):131-6
AD - Clinica di Oncoematologia Pediatrica, Dipartimento di Pediatria, Universita di Padova, Italy.
This retrospective study from the Italian Association of Pediatric Hematology Oncology-Bone Marrow Transplant Group (AIEOP-TMO) reports the results of consolidation with high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1). From 0.11-16.2) were treated in six centers. Eighteen had de novo AML and two had secondary AML. According to BFM criteria, 10 were classified as standard- and 10 as high-risk patients, respectively. The median time from diagnosis to CR1 and from diagnosis to Auto-HSCT were 1.1 months (range 0.8-1.6) and 4.3 months (range 3.1-6.2), respectively. Purging with either mafosfamide (three) or in vivo interleukin-2 (four) was performed in seven of 20 patients. Melphalan was administered at a dosage of 150-220 mg/m(2) (median 180). Median total number of nucleated cells infused was 2.5 x 10(8)/kg (range 1.1-8.9). The myeloablative regimen was well tolerated with no toxic death, veno-occlusive disease or life-threatening complications. All patients had hematopoietic recovery in a median time of 27 days for neutrophils and 44 days for platelets. Eight of 20 patients relapsed after a median time of 7.2 months from transplant (range 5.7-15.9). Six of them died (five of progression of disease and one of sepsis) while the remaining two patients are alive in CR2. The 3-year cumulative probability of survival and event-free-survival (EFS) is 62% and 56%, respectively. This study showed that in pediatric patients with AML consolidation of CR1 with high-dose melphalan allows survival and EFS to be obtained comparable to other auto-HSCT or chemotherapy published series with a potential sparing effect both on duration of treatment (with respect to chemotherapy) and on long-term side-effects (with respect to auto-HSCT with TBI or busulfan containing regimens).
UI - 21437188
AU - Mansson E; Paul A; Lofgren C; Ullberg K; Paul C; Eriksson S; Albertioni
TI - F Cross-resistance to cytosine arabinoside in a multidrug-resistant human promyelocytic cell line selected for resistance to doxorubicin: implications for combination chemotherapy.
SO - Br J Haematol 2001 Sep;114(3):557-65
AD - Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
The pyrimidine analogue cytosine arabinoside (AraC) is one of the most effective drugs used in the treatment of acute leukaemia. Overexpression of the multidrug resistance (MDR-1) gene and its product, P-glycoprotein (P-gp), is associated with cellular resistance to drugs, such as anthracyclines and vinca alkaloids. This resistance can be reversed by cyclosporine analogues or verapamil (ver). We investigated the in vitro cross-resistance to AraC in a doxorubicin-resistant HL60 cell line, with an elevated expression of the MDR-1 gene. The resistant clone showed an eightfold increased resistance to AraC and a two- to fourfold resistance to the other analogues, as measured by cytotoxicity test. There was no significant increase in the activity of 5'-nucleotidase or in the amount of deoxyribonucleotide pools between cell lines. We could, however, detect a reduction in deoxycytidine kinase (dCK) activity (30%, P = 0.021, using deoxycytidine as substrate) and the level of AraC triphosphates was significantly reduced in the resistant cells (70%, P = 0.009). When the cells were exposed to cyclosporin A (CsA) or the cyclosporine analogue PSC 833 (PSC) in combination with AraC, there was more extensive apoptosis, as measured by formation of oligonucleosomal DNA fragmentation and caspase-3-like activity, than with exposure to AraC alone. We also found an increased retention of AraC in the resistant cells when incubated with AraC in combination with CsA. Ver in combination with AraC, failed to increase apoptosis for the resistant cell line. Our data suggests that the resistance to AraC for the P-gp-expressing cells is a result of a reduction of dCK activity and an increase in efflux, the latter possibly depending on P-gp. A combination of CsA or PSC with AraC may improve the effect of AraC in vivo.
UI - 21463157
AU - Au WY; Chan GC; Chim CS; Shek TW; Ooi GC; Ho WK; Kwong YL
TI - Unusual sites of involvement by hematologic malignancies. Case 3. External auditory canal tumor: a rare chloroma in acute promyelocytic leukemia with a complete response to arsenic trioxide.
SO - J Clin Oncol 2001 Oct 1;19(19):3993-5
AD - Queen Mary Hospital, Hong Kong.
UI - 21471001
AU - Asou N; Adachi K; Tamura U; Kanamaru A; Kageyama S; Hiraoka A; Omoto E;
TI - Akiyama H; Tsubaki K; Saito K; Kuriyama K; Oh H; Kitano K; Miyawaki S; Takeyama U; Yamada O; Nishikawa K; Takahashi M; Matsuda S; Ohtake H; Ohno R Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG).
SO - Cancer Chemother Pharmacol 2001 Aug;48 Suppl 1():S65-71
AD - Second Department of Internal Medicine, Kumamoto University School of Medicine, Honjo, Japan. firstname.lastname@example.org
All-trans-retinoic acid (ATRA) has been incorporated in front-line therapy for newly diagnosed acute promyelocytic leukemia (APL). We conducted a multicenter study of differentiation therapy with ATRA alone or in combination with chemotherapy followed by intensive postremission chemotherapy in patients with APL (the JALSG APL92 study), and analyzed prognostic factors to increase the cure rate in our subsequent trial. From 1992 to 1997, adult patients with newly diagnosed APL received oral ATRA 45 mg/m2 daily alone until complete remission (CR) if initial leukocyte counts were < 3.0x10(9)/l, and ATRA daily plus daunorubicin (DNR) 40 mg/m2x3 days plus enocitabine (BHAC) 200 mg/m2x5 days if leukocyte counts were > or =3.0 x 10(9)/l. If peripheral blasts exceeded 1.0x10(9)/l during therapy, DNRx3 days plus BHACx5 days was added. After CR was achieved, three courses of consolidation and six courses of maintenance/intensification chemotherapy were administered. Of 376 patients enrolled, 369 were evaluable (median age 46 years, range 15-86 years; median leukocyte counts 2.0x10(9)/l), and 333 (90%) achieved CR (94% of patients treated with ATRA alone, 88% with ATRA plus later chemotherapy, 89% with ATRA plus initial chemotherapy, and 86% with ATRA plus initial and later chemotherapy). At a median follow-up of 45 months, the predicted 6-year overall and event-free survival (EFS) rates for all patients were 65% and 52%, respectively. Favorable prognostic factors for CR were younger age, no or mild purpura, high serum total protein level, low lactate dehydrogenase level, and no or mild disseminated intravascular coagulation (DIC). Favorable prognostic factors for EFS were leukocyte counts < 10.0x10(9)/l, mild DIC, and no sepsis during induction therapy. In the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or =3.0x10(9)/l, and are randomly testing whether further chemotherapy is required for APL patients with negative PCR for PML/retinoic acid receptor alpha in the maintenance phase.
UI - 21471002
AU - Wang ZY
TI - Arsenic compounds as anticancer agents.
SO - Cancer Chemother Pharmacol 2001 Aug;48 Suppl 1():S72-6
AD - Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Second Medical University, People's Republic of China.
In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.
UI - 21284538
AU - Okamoto Y; Tsuda T; Matsunami M; Hirose T; Sakaguchi R; Katayama N; Ota
TI - K Treatment of acute myeloblastic leukaemia in a patient with Bombay blood type: a case report.
SO - J Int Med Res 2001 Mar-Apr;29(2):140-6
AD - Department of Blood Transfusion Medicine and Clinical Haematology, Wakayama Medical College, Wakayama City, Japan. email@example.com
A 62-year-old female was admitted to our hospital with suspected acute leukaemia and after investigation we diagnosed acute myeloblastic leukaemia (AML-M1). The patient's blood type was found to be the very rare Bombay type and surveillance of her relatives showed the same blood type in her male cousin on her mother's side. Alongside chemotherapy the patient received 4000 ml of frozen Bombay-type red cells, 1400 ml of concentrated red cells in manitol adenine phosphate solutions and 360 units of type O concentrated platelets without marked effects. The anti-H antibody was initially at 128 dilution but for unknown reasons increased to 2048 dilution after remission of AML-M1. About 3 months after hospitalization the patient died of Cryptococcus neoformans pneumonia despite strict precautions against infection. Although AML-M1 is a common adult leukaemia and is chemosensitive to anti-leukaemic drugs, neither AML-M1 in a patient with Bombay-type red cells nor its treatment with chemotherapy and transfusion with type Oh frozen red cells have previously been reported.
UI - 21346270
AU - Takeshita A
TI - [Prognostic factors and treatment of acute myelogenous leukemia based on clinical results obtained by the Japan Adult Leukemia Study Group]
SO - Rinsho Ketsueki 2001 May;42(5):366-71
UI - 21346273
AU - Sakura T
TI - [Indications for allogeneic bone marrow transplantation (BMT) in adult acute myelogenous leukemia: matched-pair analysis in comparison with chemotherapy in patients achieving initial remission]
SO - Rinsho Ketsueki 2001 May;42(5):380-4
UI - 21371225
AU - Ma R; Liu F; Yang J
TI - [Clinical study on effect of Fuzheng Kangbai Granule on long-term survival of patients with acute leukemia]
SO - Zhongguo Zhong Xi Yi Jie He Za Zhi 1998 May;18(5):276-8
AD - Department of Hematology, Xiyuan Hospital, China Academy of TCM, Beijing 100091.
OBJECTIVE: To observe the effect of Fuzheng Kangbai Granule (FZKBG) on event free interval (EFI) and over survival (OS) of patients with acute leukemia, and to study the mechanism of FZKBG. METHODS: FZKBG was used in 90 cases of completely remitted acute leukemia, immune functions of patients before and after using FZKBG were measured. RESULTS: Five year EFI and OS were 64.2% and 77.2% of 90 cases of completely remitted acute leukemia, and the immune functions after using FZKBG have improved significantly. CONCLUSIONS: FZKBG could increase the EFI and OS of patients with acute leukemia, and the improved immune functions may play a role in increasing 5 year EFI and OS.
UI - 21430352
AU - Mathews V; Chandy M; Srivastava A
TI - Arsenic trioxide in the management of acute promyelocytic leukaemia.
SO - Natl Med J India 2001 Jul-Aug;14(4):215-22
AD - Department of Haematology, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India. firstname.lastname@example.org
Arsenical compounds were used as early as 2000 BC, both as medicines as well as poisons. Arsenicals gained importance in the beginning of the last century as the primary mode of treating syphilis. In 1931, Folkner and Scott used an arsenical preparation called Fowler's solution in the treatment of chronic myeloid leukaemia. This continued to be used until the introduction of busulphan in 1953. In the 1970s, arsenic trioxide was introduced for the treatment of acute promyelocytic leukaemia in China and was found to be extremely effective in treating this condition. Since then, numerous in vitro and in vivo studies have confirmed this observation. This article reviews the pathogenesis of acute promyelocytic leukaemia, the possible mechanism of action of arsenic trioxide in this condition and the literature on its use in the treatment, with special reference to the clinical and molecular response rates, toxicity and pharmacology of this compound. It also attempts to address the role of arsenic trioxide in the present algorithm for the treatment of acute promyelocytic leukaemia.
UI - 90331661
AU - Rhodes AM
TI - A minor's refusal of treatment.
SO - MCN Am J Matern Child Nurs 1990 Jul-Aug;15(4):261
AD - Finance and University Services, University of Iowa, Iowa City.
UI - 97393802
AU - Kerridge I; Lowe M; Seldon M; Enno A; Deveridge S
TI - Clinical and ethical issues in the treatment of a Jehovah's Witness with acute myeloblastic leukemia.
SO - Arch Intern Med 1997 Aug 11-25;157(15):1753-7
AD - Health Law and Ethics Program, University of Newcastle, Australia.
We report the first documented case of the use of peripheral blood stem cell autografting in the treatment of a Jehovah's Witness with acute myeloblastic leukemia. This case illustrates the complex ethical and clinical issues that arise in the treatment of such patients.
UI - 21291607
AU - Colita A; Belhabri A; Chelghoum Y; Charrin C; Fiere D; Thomas X
TI - Prognostic factors and treatment effects on survival in acute myeloid leukemia of M6 subtype: a retrospective study of 54 cases.
SO - Ann Oncol 2001 Apr;12(4):451-5
AD - Service d'Hematologie, Hjpital Edouard Herriot, Lyon, France.
classification system of acute myeloid leukemia (AML) which designates it as M6 AML. This report describes the data of 54 patients with newly Median age was 59 years. Pancytopenia was the most common feature at diagnosis. Twenty-six percent of cases presented with secondary AML. Karyotype was successfully performed in 35 cases. Eleven patients presented with normal karyotype, nine with simple karyotypic abnormalities, and fifteen with major karyotypic abnormalities. Fifty of the fifty-four patients received one or two courses of induction chemotherapy combining anthracyclines with cytarabine according to different successive protocols. One elderly patient only received low-dose cytarabine, and three patients died before any chemotherapy could be given. RESULTS: Complete remission (CR) was achieved in 29 cases (54%, 95% confidence interval (CI): 40%-67%). As post-remission therapy, four patients could be allografted, and two underwent autologous transplantation. All other treated patients received continuation chemotherapy. Twenty-one patients have relapsed (72%). Median time to relapse was six months. Among those patients, only eight achieved a second CR (38%). The median disease-free survival (DFS) was eight months (95% CI: 4-10 months) with a five-year survival rate of 17%. Median overall survival (OS) was nine months (95% CI: 5-12 months) with a five-year survival rate of 13%. In univariate analysis, poor prognostic factors for DFS were secondary AML (P = 0.05) and initial platelet count <50 x 109/l (P = 0.02). Poor prognostic factors for OS were age > or = 60 years (P = 0.005), secondary AML (P = 0.05), initial 'blastic' fever (P = 0.0004), and initial haemoglobin level < 90 g/l (P = 0.03). All factors, but haemoglobin level, remained significant in the multivariate analysis. Although it was not statistically significant, there was a trent for a better prognosis of M6 patients presenting with normal karyotype as compared to those displaying chromosomal abnormality. CONCLUSIONS: This retrospective analysis points to a somewhat heterogenous group of AML in terms of clinical and biological features, and outcome. Distinctive subgroups can be identified according to prognostic factors related to survival. A larger multicenter study with well-defined diagnostic criteria is warranted to further clarify treatment effects.
UI - 21445089
AU - Milella M; Kornblau SM; Estrov Z; Carter BZ; Lapillonne H; Harris D;
TI - Konopleva M; Zhao S; Estey E; Andreeff M Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.
SO - J Clin Invest 2001 Sep;108(6):851-9
AD - Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.
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