Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD33 antigen is a 67-kd glycosylated transmembrane protein of the sialic acid-binding immunoglobulinlike lectin (siglec) family with immunoreceptor tyrosine-based inhibitory motifs. It is expressed on the surface of normal mature and immature myeloid cells, including colony-forming progenitor cells, and on leukemic blasts from the majority of patients with acute myeloid leukemia (AML). CD33 is not expressed by the normal stem cells, suggesting that in vivo ablation of CD33-bearing normal and leukemic myeloid cells might lead to the establishment of normal hematopoiesis by the remaining normal stem cells. However, whether there are significant numbers of CD33- leukemic stem cells is controversial. Therapeutic trials using unmodified anti-CD33 antibodies have, thus far, met with limited success. Studies with a radiolabeled anti-CD33 antibody have demonstrated rapid saturation of, and internalization by, leukemic blast cells after intravenous administration, suggesting the possibility of using an anti-CD33 antibody to deliver a cytotoxic drug. Using gemtuzumab ozogamicin (Mylotarg, a humanized anti-CD33 antibody conjugated with calicheamicin, the effectiveness of in vivo ablation of CD33+ cells to treat patients with AML was borne out by the portion of patients who achieved remission. To what extent CD33- leukemic precursors are responsible for failure to respond or for relapse following gemtuzumab ozogamicin therapy remains to be determined.
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PMID:CD33 as a target for selective ablation of acute myeloid leukemia. 1197 Jul 70

Gemtuzumab ozogamicin (CMA-676), a calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, has recently been introduced clinically as a promising drug for the treatment of patients with acute myeloid leukemia (AML), more than 90% of which express CD33 antigen. However, our recent study suggested that CMA-676 was excreted by a multi- drug-resistance (MDR) mechanism in P-glycoprotein (P-gp)-expressing leukemia cell lines. We analyzed the in vitro effects of CMA-676 on leukemia cells from 27 AML patients in relation to the amount of P-gp, MDR-associated protein 1 (MRP1), CD33 and CD34, using a multi-laser-equipped flow cytometer. The cytocidal effect of CMA-676, estimated by the amount of hypodiploid portion on cell cycle, was inversely related to the amount of P-gp estimated by MRK16 monoclonal antibody (P = 0.004), and to the P-gp function assessed by intracellular rhodamine-123 accumulation in the presence of PSC833 or MS209 as a MDR modifier (P = 0.0004 and P = 0.002, respectively). In addition, these MDR modifiers reversed CMA-676 resistance in P-gp-expressing CD33(+) leukemia cells (P = 0.001 with PSC833 and P = 0.0007 with MS209). In CD33(+) AML cells from 13 patients, CMA-676 was less effective on CD33(+)CD34(+) than CD33(+)CD34(-) cells (P = 0.002). PSC833 partially restored the effect of CMA-676 in CD33(+)CD34(+) cells. These results suggest that the combined use of CMA-676 and a MDR modifier will be more effective on CD33(+) AML with P-gp-related MDR.
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PMID:Reduced effect of gemtuzumab ozogamicin (CMA-676) on P-glycoprotein and/or CD34-positive leukemia cells and its restoration by multidrug resistance modifiers. 1198 41

Conventional cytotoxic therapy of hematologic malignancies is often associated with significant morbidity. This morbidity is often due to the lack of specificity for hematopoietic cells. Therefore, the concept of targeted therapy for patients with hematologic malignancies has received attention for many years. The goal of monoclonal antibody therapy is to target specific cell surface antigens on malignant hematopoietic cells, while sparing normal cells and tissues. Currently, monoclonal antibodies are being evaluated for their cytotoxic effects as well as their ability to deliver toxic agents or radiation. Rituximab, a chimeric anti-CD20 antibody, has shown response rates of approximately 50% with minimal toxicity in patients with refractory indolent lymphoma. Campath-1H (anti-CD52) has shown encouraging results in patients previously treated for chronic lymphocytic leukemia, with response rates up to 33%, although with significant toxicity. Anti-CD33 antibodies are being used to deliver cytotoxic agents, such as calicheamicin to patients with acute myeloid leukemia with response rates up to 30%. In addition, anti-CD33 and anti-CD45 antibodies have been used to deliver radiation directly to leukemic cells. (131)I-labeled anti-CD45 antibodies are being studied in combination with conventional preparative regimens in patients receiving bone marrow transplantation. Lastly, the therapeutic agent STI571 (signal transduction inhibitor 571) has demonstrated the capability of targeting specific molecular abnormalities seen in hematologic malignancies. STI571 targets the tyrosine kinase activity of the bcr-abl fusion protein seen in chronic myeloid leukemia. STI571 has induced complete hematologic responses in up to 98% of patients evaluated in clinical trials.
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PMID:Cell surface antigen and molecular targeting in the treatment of hematologic malignancies. 1200 80

The outcomes of treatment with gemtuzumab ozogamicin compared with those of conventional chemotherapy for relapse of acute myelogenous leukemia (AML) were studied. The gemtuzumab ozogamicin group consisted of 104 patients treated in 15 U.S. and 25 European centers for first relapse of AML between May 1997 and December 1998. Conventional chemotherapy recipients consisted of 22 historical control patients who received treatment for their first occurrence of AML at a Boston teaching hospital between January 1991 and December 1994 and who subsequently underwent conventional inpatient reinduction chemotherapy for relapse. Patients in the gemtuzumab ozogamicin group received a two-hour i.v. infusion of 9 mg/m2 for up to three doses with at least two weeks between doses, while the historical controls received conventional chemotherapy, usually consisting of continuous-infusion cytarabine (days 1-7) plus mitoxantrone. Outcomes evaluated included differences in survival and hospitalization (occurrence and duration) for up to six weeks. Both stratified and multivariate regression methods were used in making comparisons. Adjusting for baseline differences, six-week survival rates were similar in the two groups (95% for the historical control group versus 89% for the gemtuzumab ozogamicin group). However, gemtuzumab ozogamicin recipients had significantly fewer total hospital days (adjusted mean, 19 days, versus 35 days), which was consistent with the higher prevalence of outpatient chemotherapy in this group (43% versus 0% among the historical controls). The difference in the number of hospital days was consistent across various baseline and demographic factors. Gemtuzumab ozogamicin appeared to be associated with equivalent survival and fewer total days of hospitalization than conventional chemotherapy in adults with relapsed AML.
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PMID:Outcomes in patients treated with gemtuzumab ozogamicin for relapsed acute myelogenous leukemia. 1204 Jul 33

Gemtuzumab ozogamicin (GO) (Mylotarg, CMA-676) is a novel chemotherapeutic agent consisting of an anti-CD33 monoclonal antibody linked to calicheamicin, and is associated with a 30% response rate in patients with CD33-positive acute myeloid leukemia (AML) in first relapse. GO therapy has a 20% incidence of grade 3 or 4 hepatotoxicity, and has recently been associated with hepatic veno-occlusive disease (VOD). The efficacy and toxicity of GO in patients with AML who have relapsed after hematopoietic stem cell transplant (HSCT) is unknown, as this population was largely excluded from phase II studies. We reviewed the outcomes of eight consecutive patients with AML who received GO following relapse after HSCT. Two (25%) had responses to GO. One patient, who had had two previous HSCT and prior hyperbilirubinemia, developed severe VOD and died 14 days after GO therapy. The other seven patients did not meet diagnostic criteria for VOD. We conclude that GO can be safe and effective in patients who relapse following HSCT, but that caution is warranted in patients with multiple risk factors for VOD.
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PMID:Gemtuzumab ozogamicin (Mylotarg) monotherapy for relapsed AML after hematopoietic stem cell transplant: efficacy and incidence of hepatic veno-occlusive disease. 1210 73

Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans.
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PMID:Targeted alpha particle immunotherapy for myeloid leukemia. 1214 3

Options for treatment of poor-prognosis or relapsed acute myeloid leukemia (AML) remain limited. Gemtuzumab ozogamicin (Mylotarg, Wyeth-Ayerst, Philadelphia, PA) is an immunoconjugate composed of recombinant humanized murine anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Phase II trials have shown the efficacy of gemtuzumab ozogamicin in the treatment of relapsed AML. Trials exploring this agent in other CD33+ hematologic malignancies and in combination with other agents for AML are ongoing. Gemtuzumab ozogamicin is associated with acceptable toxicity as a single agent. However, the incidence of veno-occlusive disease of the liver remains a concern when this agent is used in combination with chemotherapy or in the context of hematopoietic stem cell transplant.
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PMID:Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. 1216 10

Acute promyelocytic leukemia (APL) has become the most potentially curable subtype of acute myeloid leukemia (AML) in adults. With current treatment strategies that incorporate all-trans retinoic acid (ATRA), long-term disease-free survival and potential cure rates of 70% to 80% can be expected. Such progress reflects what can be accomplished with insights into the molecular pathogenesis of leukemia, identification of a molecular target, and rapid accrual to a series of clinical trials. The leukemic promyelocytes from patients with APL are uniquely susceptible to a variety of novel agents in addition to ATRA, including arsenic trioxide, and in preliminary studies, gemtuzumab ozogamicin, the immunoconjugate comprised of an anti-CD33 monoclonal antibody linked to the potent cytotoxic agent calicheamicin. Incorporation of such agents into the treatment of patients with high-risk disease may be an important future direction to pursue.
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PMID:Management of acute promyelocytic leukemia. 1216 11

Treatment of patients with unconjugated MAb such as rituximab (Rituxan) the anti-CD20 MAb or trastuzumab (Herceptin) the anti-Her2 MAb, have shown efficacy in clinical trials and have gained approval from the Food and Drug Administration (FDA) has a result. Likewise, an anti-CD33 MAb conjugated with the antibiotic calicheamicin (Mylotarg) has proven efficacious in the treatment of patients with acute myeloid leukemia and has also been approved by the FDA. This overview presents some of the monoclonal antibody (MAb)-guided strategies with a focus on some of the experiences reported for MAb evaluated in clinical trials.
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PMID:Monoclonal antibody-based therapy strategies: providing options for the cancer patient. 1217 46

We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor antibiotic) in the treatment of 101 patients > or =60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m(2) for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.
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PMID:Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). 1220 Jun 74


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