Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HuM195 is a humanized, unconjugated, anti-CD33 monoclonal antibody. Fifty adult patients with relapsed or refractory AML were randomized to receive HuM195 at a dose of 12 or 36 mg/m(2) by intravenous infusion over 4 h on days 1-4 and 15-18. Patients with stable or responding disease received two additional cycles on days 29-32 and 43-46. HuM195 was given as first salvage therapy in 24 patients and as second or subsequent salvage therapy in 26 patients. Pretreatment blast percentage in the marrow was between 5 and 30% in 20 patients with the others having blast counts greater than 30%. The median age of patients was 62 years (range 26-86) and CD33 was detected in 95% of patients for whom immunophenotyping was available. Of 49 evaluable patients, two complete and one partial remission were observed. All three responses were in patients treated at the 12 mg/m(2) dose level and all had baseline blast percentages less than 30%. Decreases in blast counts ranging from 30 to 74% were seen in nine additional patients. Infusion-related events of fever and chills occurred in the majority of patients and were generally mild and primarily related to the first dose of antibody. No hepatic, renal or cardiac toxicities were observed and other adverse events such as nausea, vomiting, mucositis and diarrhea were uncommon or felt to be unrelated to HuM195. In addition, anti-HuM195 responses were not detected. HuM195 as a single agent has minimal, but observable, anti-leukemic activity in patients with relapsed or refractory AML and activity is confined to patients with low burden disease. No significant differences in clinical efficacy or toxicity were seen between the two dose levels of antibody. HuM195 was well tolerated with infusion-related fevers and chills the predominant toxicities seen. Meaningful clinical efficacy of this unconjugated monoclonal antibody may be realized only in patients with minimal residual disease, or in combination with chemotherapy.
Leukemia 2003 Feb
PMID:Treatment of relapsed or refractory acute myeloid leukemia with humanized anti-CD33 monoclonal antibody HuM195. 1259 28

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for 20% of pediatric leukemia. Although conventional chemotherapy induces clinical remissions in most patients with AML, recurrent leukemia represents the major obstacle to cure. Conventional chemotherapy reinduction is associated with limited efficacy and substantial toxicity. Chemotherapy specifically targeted to leukemic cells by monoclonal antibodies might enable patients to achieve remissions more safely than conventional approaches. After evaluating a series of phase II studies, the U.S. Food and Drug Administration approved Mylotarg (gemtuzumab ozogamicin) for the treatment of patients with CD33-positive AML in first relapse who are 60 years of age or older and who are not considered candidates for other types of cytotoxic chemotherapy. Among 277 adult patients with CD33-positive AML in first relapse, 26% experienced an overall response after Mylotarg monotherapy. Despite the fact that myelosuppression, hyperbilirubinemia, and elevated hepatic transaminases were commonly observed, the incidences of severe infections and mucositis were relatively low in comparison with conventional chemotherapeutic treatment. Preliminary reports in pediatric patients also report Mylotarg to be reasonably well tolerated. Recently, data from study regimens combining Mylotarg and conventional chemotherapy suggest an unusually high remission induction rate in de novo AML patients. Information assembled from prospective, ongoing studies in the United States and the United Kingdom should help us use this novel immunoconjugate in a safe and effective manner.
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PMID:Antibody-targeted chemotherapy of acute myeloid leukemia using gemtuzumab ozogamicin (Mylotarg). 1285 Apr 77

Acute myeloid leukemia is the most common type of leukemia in adults, yet it continues to have the lowest survival rate of all leukemias. Prognosis for the elderly in particular continues to be dismal. This review examines the currently available literature on the epidemiology, etiology, diagnosis and management of acute myeloid leukemia. New therapies and therapeutic strategies must be found to improve survival, especially as the worldwide population ages. Gemtuzumab ozogamicin (Mylotarg) for the treatment of patients with CD33-positive acute myeloid leukemia, selective FLT3 inhibitors currently in advanced development (e.g., SU11248, PKC412, CT53518 and CEP-710) and other targeted compounds (e.g., farnesyl transferase inhibitors, BCL-2 inhibitors and interleukin-2) may present initial opportunities to achieve improved outcomes.
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PMID:Epidemiology and clinical burden of acute myeloid leukemia. 1459 92

Multicenter phase II trials with Gemtuzumab Ozogamicin (GO/Mylotarg), consisting of a CD33 antibody linked to the cytotoxic drug calicheamicin, have shown a 30% overall response rate in relapsed acute myeloid leukemia patients. However, no clear correlation was observed between CD33 expression on leukemic blasts and response to GO therapy. We analyzed the CD33 specificity of GO-induced cell death and the effect of GO on CD33-negative malignancies. We demonstrate that lysis induced by clinically relevant GO concentrations is partially CD33 mediated, and that efficient non-CD33-mediated GO uptake can occur via endocytosis. In agreement with these results, we observed GO-mediated death of human CD33-negative acute lymphoblastic leukemia cells both in vitro and in vivo in an NOD/SCID mouse model. Finally, sensitivity to GO-induced cell death was at least partially determined by the activation status of leukemic cells, with cells in activated phases of the cell cycle being most effective in both CD33-specific GO internalization, renewed expression of CD33 molecules, and non-CD33-mediated GO uptake via endocytosis. In conclusion, these data provide mechanistic insight into the efficacy of GO in CD33-positive as well as in CD33-negative malignancies with endocytic capacity, and provide a rationale for the use of GO in the treatment of malignancies with endocytic capacity.
Leukemia 2004 Feb
PMID:Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity. 1461 14

Treatment options are limited for patients with relapsed acute myelogenous leukemia (AML), particularly when the disease is refractory to standard cytotoxic chemotherapy. Targeted drug therapy offers the advantage of delivering higher doses of non-cross resistant chemotherapy with potentially less systemic toxicity. Gemtuzumab ozogamicin (Mylotarg, Wyeth-Ayerst Laboratories) is an immunoconjugate that consists of humanized anti-CD 33 antibody linked to the potent anti-tumor antibiotic calicheamicin and has been an effective therapy for some patients with relapsed AML. However, the overall utility of gemtuzumab ozogamicin is not well defined. For instance, it is not known how well this antibody will target extramedullary disease. This article reports gemtuzumab treatment of refractory AML in a 32-year-old man. At the time of recurrence, his bone marrow was hypoplastic and without leukemia, but the condition progressed resulting in marked leukemic infiltration of the oral mucosa. This case history raises the possibility that leukemic sanctuary sites may exist, and that monoclonal antibody therapy may have sub-optimal activity in non-medullary sites of disease.
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PMID:Leukemic gingival infiltrate as an indicator of chemotherapeutic failure following monoclonal antibody therapy: a case report. 1465 May 59

Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia. High-dose radioimmunotherapy with beta-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of antileukaemic therapy before bone marrow transplantation. Conversely, alpha-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumour cell kill while sparing surrounding normal cells. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML.
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PMID:Antibody-based treatment of acute myeloid leukaemia. 1468 Apr 72

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.
Leukemia 2004 May
PMID:High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab ozogamicin (Mylotarg) treatment in acute myeloid leukemia patients. 1502 14

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.
Leukemia 2004 Jul
PMID:Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function. 1520 43

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


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