Phase I II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33 positive myeloid leukemias and myelodysplastic syndrome

• Published in: Leukemia Vol. 22; no. 2; pp. 258 - 264
• Main Authors: de Lima, M, Champlin, R E, Thall, P F, Wang, X, Martin, T G, Cook, J D, McCormick, G, Qazilbash, M, Kebriaei, P, Couriel, D, Shpall, E J, Khouri, I, Anderlini, P, Hosing, C, Chan, K W, Andersson, B S, Patah, P A, Caldera, Z, Jabbour, E, Giralt, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2008; Nature Publishing; Nature Publishing Group
• Subjects: Adolescent; Adult; Aged; Aminoglycosides - administration & dosage; Aminoglycosides - toxicity; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - toxicity; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - toxicity; Biological and medical sciences; Cancer Research; Care and treatment; Complications and side effects; Critical Care Medicine; Disease-Free Survival; Dosage and administration; Female; Fludarabine; Gemtuzumab ozogamicin; Genetic aspects; Graft Survival; Graft-versus-host reaction; Hematologic and hematopoietic diseases; Hematology; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic Stem Cell Transplantation - mortality; Hematopoietic stem cells; Humans; Immunotoxins; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid - mortality; Leukemia, Myeloid - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Medicine; Medicine & Public Health; Melphalan; Melphalan - administration & dosage; Methotrexate; Middle Aged; Myelocytic leukemia; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - mortality; Myelodysplastic Syndromes - therapy; Nonlymphoid leukemia; Oncology; original-article; Patients; Prophylaxis; Remission; Remission Induction; Sialic Acid Binding Ig-like Lectin 3; Stem cell transplantation; Stem cells; Survival Rate; Tacrolimus; Toxicity; Transplantation; Transplantation, Homologous; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives; United States; myeloid leukemia; toxicity; unrelated donor transplant; phase I; allogeneic transplantation; gemtuzumab ozogamicin; Antineoplastic agent; High risk; Immunochemotherapy; Toxicity; Stem cell; allogeneix transplantation; Hematopoietic cell; Homograft; Transplantation; Nucleotide analog; Monoclonal antibody; Ozogamicin; Myelodysplastic syndrome; Myeloproliferative syndrome; Surgery; Phase II trial; Melphalan; Graft; Purine nucleotide; Hematology; Unrelated donor; Gemtuzumab; Chronic myelogenous leukemia; Malignant hemopathy; gemtuzumab orgamicin; Alkylating agent; Chemotherapy; Fludarabine; Treatment; Antimetabolic; Nitrogen mustard; Phase I trial; Fluorine Organic compounds; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2405014

We investigated the hypothesis that gemtuzumab ozogamicin (GO), an anti-CD33 immunotoxin would improve the efficacy of fludarabine/melphalan as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. Toxicity was defined as grades III–IV organ damage, engraftment failure or death within 30 days. ‘Response’ was engraftment and remission (CR) on day +30. We sought to determine the GO dose (2, 4 or 6 mg m −2 ) giving the best trade-off between toxicity and response. All patients were not candidates for myeloablative regimens. Treatment plan: GO (day −12), fludarabine 30 mg m −2 (days −5 to −2), melphalan 140 mg m −2 (day −2) and HSCT (day 0). GVHD prophylaxis was tacrolimus and mini-methotrexate. Diagnoses were AML ( n =47), MDS ( n =4) or CML ( n =1). Median age was 53 years (range, 13–72). All but three patients were not in CR. Donors were related ( n =33) or unrelated ( n =19). Toxicity and response rates at 4 mg m −2 were 50% ( n =4) and 50% ( n =4). GO dose was de-escalated to 2 mg m −2 : 18% had toxicity ( n =8) and 82% responded ( n =36). 100-day TRM was 15%; one patient had reversible hepatic VOD. Median follow-up was 37 months. Median event-free and overall survival was 6 and 11 months. GO 2 mg m −2 can be safely added to fludarabine/melphalan, and this regimen merits further evaluation.