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)

Treatment of patients with therapeutic monoclonal antibodies (mAbs) such as rituximab (Rituxan), an anti-CD20 mAb, or trastuzumab (Herceptin), an anti-HER2 mAb, have shown efficacy in clinical trials and have gained approval from the Food and Drug Administration (FDA). Mylotarg, an anti-CD33 mAb conjugated with the antibiotic calicheamicin has proven efficacious in the treatment of patients with acute myeloid leukemia and has also received FDA approval. However, the use of radionuclides to either augment inherent activity or to exploit the specific targeting properties has been a major development in mAb therapeutics. Radionuclide- bearing mAbs have recently been approved by the FDA; Zevalin, an anti-CD20 mAb armed with (90)Y and Bexxar, an anti-CD20 mAb armed with (131)I. This overview presents some background and some of the strategies pertaining to radiolabeled monoclonal antibody therapies with a focus on experiences reported for radiolabeled mAbs as evaluated in clinical trials.
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PMID:Targeting of radio-isotopes for cancer therapy. 1497 24

Gemtuzumab ozogamicin (Mylotarg) induces remission in approximately 30% of relapsed AML patients. We previously demonstrated that gemtuzumab infusion results in near-complete CD33 saturation in peripheral blood, and that saturating gemtuzumab levels result in continuous binding and internalization of gemtuzumab due to renewed CD33 expression. We now demonstrate that a high CD33-antigen load in peripheral blood is an independent adverse prognostic factor, likely due to peripheral consumption of gemtuzumab. Indeed, CD33 saturation in bone marrow is significantly reduced (40-90% saturation) as compared with CD33 saturation in corresponding peripheral blood samples (>90%). In vitro, such reduced CD33 saturation levels were strongly related with reduced cell kill. Apparently, high CD33-antigen loads in blood consume gemtuzumab and thereby limit its penetration into bone marrow. Consequently, CD33 saturation in bone marrow is reduced, which hampers efficient cell kill. Therefore, gemtuzumab should be administered at higher or repeated doses, or, preferably, after reduction of the leukemic cell burden by classical chemotherapy.
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PMID:High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab ozogamicin (Mylotarg) treatment in acute myeloid leukemia patients. 1502 14

Acute promyelocytic leukemia (APL) has become the most curable subtype of acute myeloid leukemia in adults. It represents the only established example of successful differentiation therapy. With current therapy which includes all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy for induction, anthracycline-based consolidation and maintenance with ATRA and/or low-dose chemotherapy, approximately 75-85% of patients with acute promyelocytic leukemia (APL) remain alive and disease-free at 5 years, and most patients are likely to be cured, an unprecedented achievement in the field of hematologic malignancies. However, several causes for failure to be cured need to be addressed. The first is early death which occurs in approximately 10% and is frequently attributable to hemorrhage due to the characteristic coagulopathy. The second is relapse, particularly in intermediate- and high-risk patients. Analyses of new prognostic factors may permit refinement of current risk classification and identify patients warranting alternative therapy. Finally, long-term consequences of current treatment will be important to recognize, including delayed cardiomyopathy, extramedullary relapse related to sanctuary sites, and the potential for second malignancies. For patients who do relapse, arsenic trioxide appears to be the treatment of choice since the majority of patients achieve a second complete morphologic, cytogenetic, and even molecular remission. While some patients achieving a second complete remission have prolonged disease-free survival with consolidation and maintenance arsenic, high-dose chemotherapy with autologous hematopoietic stem cell transplantation appears to offer the highest likelihood of cure. Such a strategy or anti-CD33 antibodies, recently shown to be active in APL, might be considered for high-risk patients in first remission.
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PMID:Curative therapeutic approaches to APL. 1512 85

Eight elderly patients with relapsed or refractory acute myeloid leukemia were treated sequentially with recombinant human granulocyte colony-stimulating factor with rhG-CSF and Mylotarg. Priming with rhG-CSF in vivo induced an increase in the proportion of CD33+ cycling blasts. Four patients (50% ) achieved a complete remission, 2 patients had a partial remission and the other 2 were resistant.
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PMID:In vivo priming with granulocyte colony-stimulating factor possibly enhances the effect of gemtuzumab-ozogamicin in acute myeloid leukemia: results of a pilot study. 1513 40

Agnogenic myeloid metaplasia (AMM) is one of the myeloproliferative disorders, and is usually accompanied by extramedullary hematopoiesis (EMH) in various organs, mainly in the liver, spleen and lymph nodes. Extramedullary hematopoiesis and/or leukemic transformation of EMH in the pleura is a rare occurrence and is usually asymptomatic. Pleural involvement is usually diagnosed on postmortem examination. Herein we describe a 71-year-old man with newly diagnosed agnogenic myeloid metaplasia who was evaluated for progressively worsening dyspnea, pulmonary hypertension and bilateral pleural effusions. EMH involving the lungs and pleura was suspected. A sulfur colloid technetium 99m bone marrow scan performed to detect extramedullary hematopoiesis was negative. The diagnostic thoracentesis yielded bloody fluid that contained a large population of myeloblasts, indicating pleural leukemic transformation. The patient received 100 cGy to the whole lung for treatment of pulmonary hypertension due to EMH. This was followed by 1500 cGy total dose of radiation to the left lung for pleural extramedullary leukemic transformation. Pleural effusions resolved and repeat echocardiography showed reduction of the pulmonary artery pressure. Three months later he had leukemic transformation involving the skin and lymph nodes. Four months after radiation therapy, he had full-blown acute myeloid leukemia. He received 2 cycles of Gemtuzumab ozogamicin (Mylotarg), allopurinol and hydroxyurea. Three months after initiation of chemotherapy, he deteriorated and received salvage chemotherapy of prednisone, VP-16 and imatinib mesylate (Gleevec). He was hospitalized for neutropenic fever and was diagnosed to have pulmonary aspergillosis. He died of multisystem failure 8 1/2 months after being diagnosed with AMM.
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PMID:Agnogenic myeloid metaplasia with pleural extramedullary leukemic transformation. 1516 Sep 62

Bi-specific anti-CD33 x anti-CD64 antibodies (BsAb) mediated more potent and longer-lasting inhibition of proliferation of human leukemia cell lines and primary acute myeloid leukemia (AML) samples compared to mono-specific anti-CD33 mAb. There were no differences between these two antibodies in cellular internalization over time. The inhibitory effect of BsAb was mimicked by a mouse IgG2a subclass mono-specific anti-CD33 mAb. These findings indicate that enhanced inhibition of proliferation was caused by simultaneous ligation of both CD33 and CD64 molecules. We conclude that inhibition of leukemia cell growth initiated by BsAb during prolonged exposure may have therapeutic value for the treatment of AML.
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PMID:Inhibition of acute myeloid leukemia cell growth by mono-specific and bi-specific anti-CD33 x anti-CD64 antibodies. 1520 80

Data on breast cancer resistance protein (BCRP, MXR, ABCG2) expression in acute myeloid leukemia (AML) have been inconsistent, possibly due to use of different assays in different studies. BCRP mRNA was studied by the reverse-transcription polymerase chain reaction and BCRP protein expression (BXP-21, BXP-34 or anti-ABCG2 antibody, with anti-CD34 and anti-CD33) and function (fumitremorgin C modulation of mitoxantrone retention) by flow cytometry in eight cell lines and in pretreatment blasts from 31 AML patients. BCRP mRNA levels, antibody staining and function correlated strongly in cell lines (Pearson r values, 0.73-0.97), but not in AML samples. AML sample BCRP mRNA levels were between those in parental 8226 and 35-fold mitoxantrone-resistant 8226/MR20 cells in all but one case, and BCRP mRNA had the wild-type sequence at codon 482 in all. In AML, unlike in cell lines, BCRP protein expression or function, when present, was only detected in small subpopulations. BCRP mRNA and protein expression did not correlate, nor did staining with different BCRP antibodies, and function did not correlate with mRNA nor protein expression. Presence of BCRP only in subpopulations and discordance among BCRP measurements suggest complex biology of BCRP in AML and incomplete modeling by cell lines.
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PMID:Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function. 1520 43

Antibody-targeted chemotherapy is a promising approach in patients with hematological malignancies. In particular, gemtuzumab ozogamicin (GO, formerly CMA-676), an anti-CD33 antibody linked to calicheamicin, has been approved for the treatment of elderly patients with acute myeloid leukemia (AML) in relapse. Nevertheless, no data are until now available concerning the possible efficacy of GO for myeloid sarcomas (MS). We treated with GO 24 AML patients, in 5 cases presenting with myeloid sarcomas of the skin or bones. The overall complete response rate was 21%. The median duration of response was 6 months. Four out of the 5 patients with myeloid sarcoma showed a regression of the masses, in two cases also obtaining a clearance of marrow blasts. The most common adverse events included thrombocytopenia, neutropenia, infections, elevation of bilirubin and hepatic transaminases. Notably, severe bleeding occurred in 5 cases (21%). VOD was documented in 1 case. We conclude that GO is effective as a single agent in AML and myeloid sarcomas. Further data are required to clarify the possible correlation between GO administration and occurrence of bleeding.
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PMID:Gemtuzumab ozogamicin for relapsed and refractory acute myeloid leukemia and myeloid sarcomas. 1522 37

Recently, anti-cancer antibodies have been launched in Japan and also immunoconjugates with a cytotoxic compound or a radioisotope have been launched in the USA. Gemtuzumab ozogamicin is a conjugate of anti-CD33 antibody and a cytotoxic calicheamicin derivative. After binding the CD33-positive leukemia cells, gemtuzumab ozogamicin is internalized and releases the calicheamicin derivative. The calichemicin derivative breaks DNA and kills the cells. Gemtuzumab ozogamicin was effective and well tolerated in clinical trials in patients with acute myeloid leukemia (AML) in relapse. It was approved in 2000 by the FDA, and Wyeth K.K. has submitted it as an anti-tumor drug for CD33 positive AML. Two kinds of immunoconjugates, anti-CD20 antibodies with radioisotopes, recently have been launched in the USA for CD20-positive non-Hodgkin's lymphoma. These conjugates showed efficacy in patients who are refractory to the conventional chemotherapies. Targeted therapy with the immunoconjugate that can deliver cytotoxic compounds to specific cells is promising for use in oncology.
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PMID:[Gemtuzumab ozogamicin and targeted cancer therapy]. 1522 19

Gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody conjugated to calicheamicin, is effective as single agent in the treatment of poor risk acute myeloid leukaemia (AML) patients. We treated with GO in combination with cytarabine as continuous perfusion nine elderly AML patients, either untreated (five cases), or with relapsed/refractory disease (four cases). Five patients achieved a complete remission (CR), four were resistant. One patient died while in CR due to CNS haemorrhage, two relapsed and two are still in CR. The median CR duration was 10 months. The median overall survival was 6 months (1-19 months). The most common adverse event was myelosuppression, as expected. No hepatic veno-occlusive disease was recorded. Notably, in four cases we observed a grade III/IV bleeding, including gasto-intestinal bleeding, epistaxis, CNS haemorrhage, and ocular bleeding. Larger prospective studies are now warranted in order to better define the possible role of this regimen in the treatment of elderly AML patients.
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PMID:First experience with gemtuzumab ozogamicin plus cytarabine as continuous infusion for elderly acute myeloid leukaemia patients. 1523 77


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