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

Mylotarg (gemtuzumab zogamicin) is a conjugated monoclonal antibody that has recently become available for use in patients with relapsing or refractory acute myeloid leukemia. Reversible hepatotoxicity is common after administration. We describe the first report of hepatic veno-occlusive disease (HVOD) developing after Mylotarg infusion in a patient who underwent hematopoietic stem cell transplantation 8 months earlier. Certain antineoplastic agents have been implicated as a cause of HVOD, but the disease is most commonly seen within 30 days after hematopoietic stem cell transplantation. The possible association between Mylotarg infusion and HVOD is discussed.
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PMID:Development of hepatic veno-occlusive disease after Mylotarg infusion for relapsed acute myeloid leukemia. 1178 39

CD33 is expressed by acute myeloid leukemia (AML) cells in >80% of patients but not by normal hematopoietic stem cells, suggesting that elimination of CD33(+) cells may be therapeutically beneficial. A conjugate of a calicheamicin hydrazide derivative attached via hydrazone formation to the oxidized carbohydrates of the anti-CD33 murine antibody P67.6 had been chosen for use in AML prior to humanization of this antibody. However, the CDR-grafted humanized P67.6 could not be used to make the carbohydrate conjugate because of the unexpected sensitivity of this antibody to periodate oxidation. Exploration of a series of bifunctional linkers resulted in a new class of calicheamicin conjugates, termed the hybrid conjugates, that allows for the attachment of the calicheamicin to lysines but incorporates the site of hydrolytic release, a hydrazone, previously shown to be required for activity. The optimized conjugate chosen for clinical trials, gemtuzumab ozogamicin ("gem-ozo", Mylotarg, formerly designated CMA-676), was significantly more potent and selective than the carbohydrate conjugate it replaced. It was selectively cytotoxic to HL-60 leukemia cells in tissue culture with an IC(50) in the low to sub-pg cal/mL range (cal = calicheamicin equivalents). Doses of gem-ozo as low as 50 microg cal/kg given three times to mice bearing HL-60 xenografts routinely resulted in long-term, tumor-free survivors, while a nonbinding control conjugate was relatively inactive. Gem-ozo at a concentration of 2 to 10 ng cal/mL selectively inhibited leukemia colony formation by marrow cells from a significant proportion of AML patients. Gem-ozo has also shown significant activity against AML in Phase II trials and is the first antibody-targeted chemotherapeutic agent approved by the FDA.
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PMID:Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. 1179 78

The anti-CD33 antibody, P67.6, has been chosen to target the potently cytotoxic calicheamicin antitumor antibiotics to acute myeloid leukemia (AML) due to the presence of CD33 on >80% of patient samples and its lack of expression outside the myeloid cell lineages, especially its lack of expression on pluripotent stem cells. Previous calicheamicin conjugates relied on the attachment of a hydrazide derivative to the oxidized carbohydrates that occur naturally on antibodies. This results in a "carbohydrate conjugate" capable of releasing active drug by hydrolysis of a hydrazone bond in the lysozomes where the pH is low. Conjugates have now been made that are formed by reacting a calicheamicin derivative containing an activated ester with the lysines of antibodies. This results in an "amide conjugate" that is stable to hydrolysis, leaving the disulfide that is present in all calicheamicin conjugates as the likely site of drug release from the conjugate. In this article, these two classes of calicheamicin-antibody conjugates are compared for potential use in AML with the anti-CD33 antibody P67.6. Conjugates of P67.6 are shown to require the site of hydrolytic release afforded by the carbohydrate conjugates in order to retain good potency and selectivity in vitro, in vivo, and ex vivo. The P67.6 carbohydrate conjugate of calicheamicin is selectively cytotoxic at <0.006 ng/mL of calicheamicin equivalents (cal equiv) toward HL-60 promyelocytic leukemia cells in tissue culture. Long-term, tumor-free survivors are seen in xenograft models when mice bearing HL-60 subcutaneous tumors are treated with the P67.6 carbohydrate conjugate at a dose of 300 microg/kg cal equiv given three times. This conjugate also selectively inhibits the formation of colonies from AML marrow samples at 2 ng/mL cal equiv. The P67.6 carbohydrate conjugate of calicheamicin therefore appears to have promise as an antibody-targeted chemotherapeutic agent for CD33-positive diseases such as AML.
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PMID:An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker. 1179 77

Gemtuzumab ozogamicin (Mylotarg) targets leukemia cells expressing the CD33 receptor by means of a monoclonal antibody conjugated to a cytotoxic agent, calicheamicin. Treatment of acute myeloid leukemia (AML) with gemtuzumab ozogamicin may result in liver injury. We reviewed the course of 23 patients who were given gemtuzumab ozogamicin for AML that had relapsed after hematopoietic cell transplantation. Liver toxicity was assessed through physical examination, serum tests, histologic examination, and hepatic venous pressure measurements. Liver injury developed in 11 patients after gemtuzumab ozogamicin administration; it was manifested as weight gain, ascites, and jaundice in 7 patients. Seven patients died with persistent liver dysfunction and either multiorgan failure or sepsis at a median of 40 days after gemtuzumab ozogamicin infusion. Portal pressure measurements were elevated in 2 patients. Results of liver histologic examination in 5 patients showed sinusoidal injury with extensive sinusoidal fibrosis, centrilobular congestion, and hepatocyte necrosis. Six patients experienced AML remission that was sustained for at least 60 days after gemtuzumab ozogamicin infusion. In summary, hepatic sinusoidal liver injury developed after gemtuzumab ozogamicin infusion. Histology showed striking deposition of sinusoidal collagen, suggesting that gemtuzumab ozogamicin targets CD33(+) cells residing in hepatic sinusoids as the mechanism for its hepatic toxicity.
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PMID:Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. 1189 61

Acute myeloid leukemia (AML) is the most common adult leukemia and has historically been treated with intensive multiagent chemotherapy. In May 2000, the U.S. Food and Drug Administration approved a new agent, gemtuzumab ozogamicin (Mylotarg) to treat patients who are 60 years and older in first relapse with CD33+ AML and not considered candidates for chemotherapy. Gemtuzumab is an antibody-targeted agent that binds specifically to the CD33 antigen that is found on the surface of more than 80% of patients with AML. The agent is administered via i.v. over two hours, and premedication with acetaminophen and diphenhydramine is recommended. Side effects include fever, chills, neutropenia and thrombocytopenia, and asymptomatic hypotension. Clinical remissions have been observed with gemtuzumab, and additional trials with this new agent currently are being conducted.
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PMID:Mylotarg approved for patients with CD33+ acute myeloid leukemia. 1189 26

Recently, monoclonal antibody(MoAb) therapies which direct at antigens such as CD33, CD45 and GM-CSF receptors on myeloid leukemia cells have been in progress. There are three major MoAb therapies against acute myeloid leukemia(AML), which include unconjugated MoAb, MoAb conjugated with chemotherapy or toxins, and MoAb conjugated with radioisotopes. Gemtuzumab ozogamicin is consisting of an engineered human anti-CD33 antibody linked with the potent anti-tumor antibiotic calicheamicin, which is the most effective for AML. However, recent studies suggested that calicheamicin was also pumped out by multi-drug resistance(MDR) related P-glycoprotein. The combination therapy with MDR modifiers may improve the effect of gemtuzumab ozogamicin.
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PMID:[Antibody directed therapy for leukemia]. 1190 67

Monoclonal antibodies have become an important modality for cancer therapy. The genetically engineered, humanized anti-CD33 antibody HuM195 has demonstrated modest activity against overt relapsed acute myeloid leukemia (AML) and more substantial activity against minimal residual disease in acute promyelocytic leukemia. Radioimmunotherpay with beta-particle-emitting isotopes has eliminated large leukemic burdens while minimizing radiation exposure to normal tissues in both nonmyeloablative and myeloablative regimens. Targeted beta-particle immunotherapy with agents such as bismuth 213-labeled HuM195 offers the possibility of a more selective tumor cell kill with less damage to surrounding normal cells. Directed chemotherapy using the anti-CD33-calicheamicin conjugate gemtuzumab ozogamicin (Mylotarg) has produced remissions in patients with relapsed AML.
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PMID:Antibody therapy in acute myeloid leukemia: current status and future directions. 1197 Jul 65

Relapsed acute myeloid leukemia (AML) carries a poor prognosis. Treatment options are limited, and their toxicities are substantial. There is an urgent need for novel therapies that are effective and have acceptable side effects. Gemtuzumab ozogamicin (Mylotarg) is an immunoconjugate targeted against CD33, which is expressed on more than 90% of myeloid leukemic blasts. The antibody is attached to calicheamicin, a potent cytotoxic enediyne antibiotic that inhibits DNA synthesis and induces apoptosis. In vitro studies showed excellent activity of gemtuzumab ozogamicin in leukemic cell lines and encouraged the evaluation of this agent in patients. In this review, early phase I/II studies that led to the US Food and Drug Administration approval of this immunoconjugate for older patients with relapsed AML are discussed. Potential adverse events reported with this agent, particularly the recent data of possible veno-occlusive disease and increased hepatotoxicity, are addressed. This agent is currently being investigated in many clinical trials as a front-line approach in previously untreated individuals, and it is likely that it will have many more indications in the near future.
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PMID:Early phase I/II trials with gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia. 1197 Jul 66

Gemtuzumab ozogamicin (Mylotarg) is an immunoconjugate composed of a recombinant humanized murine anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. The aim of this review is to summarize ongoing trials with gemtuzumab ozogamicin in combination with chemotherapy in acute myeloid leukemia (AML) patients. The studies include determination of safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy in previously untreated as well as relapsed and refractory AML patients. These studies also determine gemtuzumab ozogamicin's activity in patients with other CD33+ neoplastic diseases such as myelodysplastic syndrome, acute promyelocytic leukemia, chronic myeloid leukemia, and certain subsets of acute lymphocytic leukemia. Moreover, trials are exploring the use of gemtuzumab ozogamicin with novel targeted agents such as Bcl-2 antisense molecules. Gemtuzumab ozogamicin is associated with an acceptable toxicity profile as a single agent; however, the incidence of veno-occlusive disease remains a concern with the use of gemtuzumab ozogamicin in combination with chemotherapy.
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PMID:Trials with gemtuzumab ozogamicin (Mylotarg) combined with chemotherapy regimens in acute myeloid leukemia. 1197 Jul 67

Gemtuzumab ozogamicin (Mylotarg) targets leukemia cells that express CD33 by means of a humanized anti-CD33 monoclonal antibody conjugated to a modified antitumor antibiotic, calicheamicin. The effects of gemtuzumab ozogamicin (given intravenously at a dose of 9 mg/m2 for 2 doses separated by 2 weeks) have been evaluated in 3 phase II studies involving patients (n = 188) with acute myeloid leukemia (AML) in first relapse. Interim analysis has revealed that 30% of patients achieved remission, characterized by < or = 5% blasts in the marrow, neutrophil count > or = 1500/microL, hemoglobin > or = 9 g/dL, and independence from red blood cell and platelet transfusion. Grade 3/4 acute toxicities included nausea or vomiting (11%); elevated serum aminotransferase enzyme (16%) and bilirubin (26%) levels; and infusion-related chills (9%), fever (6%), and hypotension (5%). As predicted with CD33-targeted therapy, most patients had neutropenia (98%) and thrombocytopenia (99%). However, the incidence of grade 3/4 bleeding events (14%) and infection rates (pneumonia, 7%; sepsis, 15%) was low. No patients were reported to have treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Veno-occlusive disease (VOD) after gemtuzumab ozogamicin treatment (but prior to other therapies) occurred in 2% of patients (4/188), and the VOD-related death rate was < 1% (1/188). Prior hematopoietic stem cell transplant may be a risk factor for VOD (P = 0.002, univariate analysis). Gemtuzumab ozogamicin is a safe and effective treatment in carefully selected patients with AML in first relapse.
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PMID:Acute and long-term toxicities associated with gemtuzumab ozogamicin (Mylotarg) therapy of acute myeloid leukemia. 1197 Jul 68


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