Feasibility Study of a Novel Experimental Induction Protocol Combining B43-PAP (Anti-CD19) Immunotoxin With Standard Induction Chemotherapy in Children and Adolescents With Relapsed B-Lineage ALL: A Report From the Children's Oncology Group.
BACKGROUND
B43-pokeweed antiviral protein (B43-PAP) is a high-affinity anti-CD19 immunotoxin that is capable of causing apoptotic death in B-lineage leukemic cells with a drug-resistant phenotype. B43-PAP exhibited in vivo antileukemic activity in preclinical studies as well as on a single-agent phase I clinical trial. This pediatric phase I/II study evaluated the toxicity profile and efficacy of B43-PAP immunotoxin in combination with standard induction chemotherapy in children and adolescents with relapsed CD19-positive B-lineage acute lymphoblastic leukemia (B-ALL). Pharmacokinetic profile and immunogenicity of B43-PAP were assessed.


METHODS
B43-PAP in combination with standard 3 and 4-drug induction chemotherapy was administered on days 9-13 and 21-25 of a 28-day treatment course with vincristine, prednisone, L-asparaginase, daunomycin, and intrathecal methotrexate. Thirty patients with relapsed B-ALL were enrolled on study CCG-0957.


RESULTS
Grade III/IV nonhematologic dose-limiting toxicities were encountered in 4 patients evaluable for toxicity and included myalgias, motor dysfunction, pulmonary toxicity, and elevated liver transaminase. Dose-limiting toxicities occurred only with the 4-drug regimen. Fourteen patients achieved a complete remission at the end of induction among the 20 patients evaluable for response.


CONCLUSIONS
B43-PAP in combination with standard induction chemotherapy can be safely administered and exhibits clinical antileukemic activity against relapsed B-ALL.
*Department of Pediatric Hematology-Oncology, Children's National Medical Center, George Washington University School of Medicine and Public Health, Washington, DC †Clinical Investigations Branch, Cancer Therapy Evaluation Program, NCI, Bethesda ¶¶Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD ‡Keck School of Medicine, University of Southern California ¶Division of Hematology-Oncology, Children's Hospital Los Angeles, Los Angeles §Children's Oncology Group, Arcadia ‡‡Department of Pediatrics, City of Hope National Medical Center, Duarte, CA ∥Department of Biostatistics and Bioinformatics, Emory University ∥∥Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta/Emory University, Atlanta, GA #Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN **Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA ††Pediatric Hematology-Oncology, C.S. Mott Children's Hospital, Ann Arbor, MI §§Division of Pediatrics, Children's Cancer Hospital at the University of Texas M.D. Anderson Cancer Center, Houston, TX.
Holly J
HJ
Meany
Nita L
NL
Seibel
Mark
M
Krailo
Doojduen
D
Villaluna
Zhengjia
Z
Chen
Paul
P
Gaynon
Joseph P
JP
Neglia
Julie R
JR
Park
Raymond
R
Hutchinson
Judith K
JK
Sato
Robert J
RJ
Wells
William G
WG
Woods
Gregory
G
Reaman
D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination / Q000379:methods; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000276:immunology*; D060828:Induction Chemotherapy / Q000379:methods; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology*; D054789:Ribosome Inactivating Proteins, Type 1 / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; C024275:pokeweed antiviral protein