Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
J Clin Oncol ; 19(18): 3852-60, 2001 Sep 15.
Article in English | MEDLINE | ID: mdl-11559723

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Adolescent , Adult , Arsenic Trioxide , Arsenicals/adverse effects , Electrocardiography , Female , Humans , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/pathology , Leukocytosis/chemically induced , Male , Middle Aged , Nervous System Diseases/chemically induced , Oxides/adverse effects , Pilot Projects , Platelet Count , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , Syndrome
2.
Oncologist ; 6 Suppl 2: 11-6, 2001.
Article in English | MEDLINE | ID: mdl-11331435

ABSTRACT

Acute promyelocytic leukemia (APL) has unique clinical, cytogenetic, and molecular features and is one of the most potentially curable human malignancies. The current standard treatment given to patients with newly diagnosed APL consists of all-trans retinoic acid and anthracycline-based cytotoxic chemotherapy, which is highly effective for remission induction. However, despite the potential for cure with existing treatments, approximately 20%-30% of patients relapse and require salvage therapy. Reports of the safety and efficacy of arsenic trioxide from centers in China led to a pivotal trial of this agent in the United States for patients with relapsed APL. In an initial pilot study, 11 of 12 patients experienced a complete response, and a subsequent multicenter trial confirmed the efficacy and safety of arsenic trioxide for remission induction in this patient population. Additional trials are under way to evaluate the use of this agent alone or as part of a chemotherapy regimen for consolidation and maintenance of patients with APL.


Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Arsenic Trioxide , Clinical Trials as Topic , Humans , Neoplasm Recurrence, Local
3.
Oncologist ; 6 Suppl 2: 29-32, 2001.
Article in English | MEDLINE | ID: mdl-11331438

ABSTRACT

Approximately 20%-30% of patients with acute promyelocytic leukemia (APL) who are treated with the current standard all-trans retinoic acid and anthracycline-based chemotherapy regimen suffer relapse. In the mid-1990s, studies from China reported the effective use of arsenic trioxide in achieving complete remission in patients with APL. In the United States, a multicenter trial of this agent in 40 patients with relapsed APL following conventional therapy confirmed the positive safety and efficacy outcomes of a smaller 12-patient pilot study. Common adverse events were hyperleukocytosis, APL differentiation syndrome, prolonged QT interval on electrocardiogram, skin rash, and hyperglycemia.


Subject(s)
Antineoplastic Agents , Arsenicals , Leukemia, Promyelocytic, Acute/drug therapy , Oxides , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Arsenic Trioxide , Arsenicals/adverse effects , Arsenicals/therapeutic use , Humans , Neoplasm Recurrence, Local , Oxides/adverse effects , Oxides/therapeutic use , Risk Assessment
4.
Blood ; 96(4): 1525-30, 2000 Aug 15.
Article in English | MEDLINE | ID: mdl-10942401

ABSTRACT

Arsenic trioxide (As(2)O(3)) has recently been used successfully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro. However, the mechanism by which As(2)O(3) exerts its antileukemic effect remains uncertain. Emerging data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that activated endothelial cells release cytokines that may stimulate leukemic cell growth. Leukemic cells, in turn, can release endothelial growth factors, such as vascular endothelial growth factor (VEGF). On the basis of these observations, we hypothesized that As(2)O(3) may interrupt a reciprocal loop between leukemic cells and the endothelium by direct action on both cell types. We have shown that treatment of proliferating layers of human umbilical vein endothelial cells (HUVECs) with a variety of concentrations of As(2)O(3) results in a reproducible dose- and time-dependent sequence of events marked by change to an activated morphology, up-regulation of endothelial cell adhesion markers, and apoptosis. Also, treatment with As(2)O(3) caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVECs with As(2)O(3) prevented capillary tubule and branch formation in an in vitro endothelial cell-differentiation assay. In conclusion, we believe that As(2)O(3 )interrupts a reciprocal stimulatory loop between leukemic cells and endothelial cells by causing apoptosis of both cell types and by inhibiting leukemic cell VEGF production. (Blood. 2000;96:1525-1530)


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Arsenicals/pharmacology , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Oxides/pharmacology , Arsenic Trioxide , Cells, Cultured , Dose-Response Relationship, Drug , Humans , Leukemia/drug therapy , Leukemia/pathology , Neovascularization, Pathologic/drug therapy , Time Factors
5.
J Clin Oncol ; 18(13): 2620-5, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10893295

ABSTRACT

PURPOSE: Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. PATIENTS AND METHODS: Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. RESULTS: Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37). CONCLUSION: Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.


Subject(s)
Antineoplastic Agents/adverse effects , Arsenicals/adverse effects , Leukemia, Promyelocytic, Acute/drug therapy , Leukocytosis/chemically induced , Oxides/adverse effects , Tretinoin/adverse effects , Arsenic Trioxide , Dyspnea/chemically induced , Fever/chemically induced , Humans , Pleural Effusion/chemically induced , Syndrome
6.
Clin Cancer Res ; 6(5): 1731-5, 2000 May.
Article in English | MEDLINE | ID: mdl-10815891

ABSTRACT

Retinoids mediate their biological response by binding to specific nuclear receptors, including retinoic acid receptors and/or retinoid X receptors. LGD1550 is a high-affinity ligand for all three retinoic acid receptors (alpha, beta, and gamma isoforms) and a potent inhibitor of AP-1, a protein that is closely linked with trophic responses and malignant transformation. We conducted a dose ranging study to evaluate the pharmacokinetics, safety, clinical tolerance, and potential efficacy of this drug in patients with advanced cancer. Twenty-seven patients received oral doses of LGD1550 once per day at doses ranging from 20-400 microg/m2. Skin toxicity was the dose-limiting reaction at the 400 microg/m2 daily dose level. Less prominent reactions included nausea and headache. No major antitumor effects were observed. Pharmacokinetic studies in 15 patients at five dose levels showed that the peak plasma concentration (Cmax) and areas under the plasma concentration-time curve on day 1 were dose-proportional and were similar to values obtained on days 15, 29, and 84. Unlike other retinoids, LGD1550 did not induce its own metabolism, and there was little evidence of drug accumulation. The t1/2 was approximately 5 h after both the initial and repeated doses. We conclude that once-daily doses of LGD1550 of up to 300 microg/m2 are relatively well tolerated. Additional clinical explorations are warranted, especially in patients with cancers of the prostate, thyroid, head and neck, and cervix.


Subject(s)
Fatty Acids, Unsaturated/therapeutic use , Neoplasms/drug therapy , Receptors, Retinoic Acid/agonists , Adult , Aged , Area Under Curve , Binding, Competitive , Dose-Response Relationship, Drug , Fatty Acids, Unsaturated/adverse effects , Fatty Acids, Unsaturated/pharmacokinetics , Humans , Ligands , Middle Aged , Neoplasms/pathology , Treatment Outcome
7.
Cancer Chemother Pharmacol ; 44(5): 417-21, 1999.
Article in English | MEDLINE | ID: mdl-10501916

ABSTRACT

Inorganic arsenic trioxide (As(2)O(3)) induces a high proportion of complete remissions in relapsed patients with acute promyelocytic leukemia (APL). Previously, we have shown that both As(2)O(3 )and melarsoprol, an organic arsenical used for the treatment of trypanosomiasis, exhibit broad antileukemic activity against both chronic and acute myeloid and lymphoid leukemia cell lines. Given the breadth of this activity, we initiated a clinical study to evaluate the pharmacokinetics, safety, and potential efficacy of melarsoprol in patients with refractory or resistant leukemia. Using the antitrypanosomal dose and schedule, patients received escalating intravenous doses daily for 3 days, repeated weekly for 3 weeks. Doses were 1 mg/kg on day 1, 2 mg/kg on day 2, and 3.6 mg/kg on day 3 and on all days thereafter, up to a maximum daily dose of 200 mg. Eight patients [6 AML (2 morphologic APL), 1 CML, 1 CLL] were treated. Mean peak plasma concentrations of the parent drug were obtained immediately after injection, ranged from 1.2 microg/ml on day 1 to 2.4 microg/ml on day 3, were dose proportional, and decayed with a t(1/2) congruent with 15 min. A minor clinical response (regression of splenomegaly and lymphadenopathy) was observed in a patient with chronic lymphocytic leukemia. Central nervous system (CNS) toxicity proved limiting on this dose and schedule. Three patients experienced generalized grand mal seizures during the second week of therapy. We concluded that this dose and schedule of melarsoprol is associated with excessive CNS toxicity and that verification of the striking preclinical activity in patients with leukemia will require developing an alternative dose and schedule.


Subject(s)
Leukemia/drug therapy , Melarsoprol/adverse effects , Adult , Aged , Area Under Curve , Female , Humans , Injections, Intravenous , Leukemia/blood , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid, Acute/drug therapy , Male , Melarsoprol/administration & dosage , Melarsoprol/blood , Melarsoprol/pharmacokinetics , Middle Aged
8.
N Engl J Med ; 339(19): 1341-8, 1998 Nov 05.
Article in English | MEDLINE | ID: mdl-9801394

ABSTRACT

BACKGROUND: Two reports from China have suggested that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL). We evaluated this drug in patients with APL in an attempt to elucidate its mechanism of action. METHODS: Twelve patients with APL who had relapsed after extensive prior therapy were treated with arsenic trioxide at doses ranging from 0.06 to 0.2 mg per kilogram of body weight per day until visible leukemic cells were eliminated from the bone marrow. Bone marrow mononuclear cells were serially monitored by flow cytometry for immunophenotype, fluorescence in situ hybridization, reverse-transcription-polymerase-chain-reaction (RT-PCR) assay for PML-RAR-alpha fusion transcripts, and Western blot analysis for expression of the apoptosis-associated proteins caspases 1, 2, and 3. RESULTS: Of the 12 patients studied, 11 achieved complete remission after treatment that lasted from 12 to 39 days (range of cumulative doses, 160 to 495 mg). Adverse effects were relatively mild and included rash, lightheadedness, fatigue, and musculoskeletal pain. Cells that expressed both CD11b and CD33 (antigens characteristic of mature and immature cells, respectively), and which were found by fluorescence in situ hybridization to carry the t(15;17) translocation, increased progressively in number during treatment and persisted in the early phase of complete remission. Eight of 11 patients who initially tested positive for the PML-RAR-alpha fusion transcript by the RT-PCR assay later tested negative; 3 other patients, who persistently tested positive, relapsed early. Arsenic trioxide induced the expression of the proenzymes of caspase 2 and caspase 3 and activation of both caspase 1 and caspase 3. CONCLUSIONS: Low doses of arsenic trioxide can induce complete remissions in patients with APL who have relapsed. The clinical response is associated with incomplete cytodifferentiation and the induction of apoptosis with caspase activation in leukemic cells.


Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Adolescent , Adult , Aged , Antigens, CD/analysis , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Apoptosis , Arsenic Trioxide , Arsenicals/administration & dosage , Arsenicals/adverse effects , Bone Marrow Cells/immunology , Caspases , Cell Differentiation , Child , Humans , Immunophenotyping , Leukemia, Promyelocytic, Acute/immunology , Leukemia, Promyelocytic, Acute/pathology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Middle Aged , Neoplasm Proteins/analysis , Neoplasm Proteins/drug effects , Oncogene Proteins, Fusion/analysis , Oncogene Proteins, Fusion/drug effects , Oxides/administration & dosage , Oxides/adverse effects , Recurrence , Remission Induction/methods
9.
Leukemia ; 12(10): 1518-21, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9766493

ABSTRACT

The use of all-trans retinoic acid (RA) for remission induction markedly increases survival of patients with acute promyelocytic leukemia (APL) compared to patients treated solely with cytotoxic chemotherapy. However, clinical resistance to this agent develops rapidly, which has been associated with a progressive decline in plasma drug concentrations. Previous studies suggested that 9-cis RA, a retinoid receptor 'pan agonist' did not induce its own catabolism to the same extent as all-trans RA. Therefore, we conducted a dose-ranging study of this compound in patients with both relapsed and newly diagnosed APL. We treated 18 patients with morphologically diagnosed APL (13 relapsed, five newly diagnosed). The daily dose of 9-cis RA ranged from 30 to 230 mg/m2/day given as a single oral dose. Four of 12 (33%) relapsed patients (three of whom were previously treated with all-trans RA) and four of five (80%) newly diagnosed patients achieved complete remission. The sole failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translocation had substantial hematologic improvement. The drug was generally well tolerated; headache and dry skin were the most common adverse reactions. Three patients were treated with corticosteroids for signs of incipient 'RA syndrome.' These preliminary data suggest that 9-cis RA is an effective agent for remission induction and deserves further investigation in patients with retinoid-sensitive APL.


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Tretinoin/therapeutic use , Adolescent , Adult , Aged , Alitretinoin , Antineoplastic Agents/adverse effects , Child , Child, Preschool , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 9 , Dose-Response Relationship, Drug , Female , Humans , Infant , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/genetics , Leukocyte Count/drug effects , Male , Middle Aged , Platelet Count/drug effects , Recurrence , Translocation, Genetic , Tretinoin/adverse effects
SELECTION OF CITATIONS
SEARCH DETAIL
...