Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia

• Published in: Haematologica (Roma) Vol. 100; no. 7; pp. 927 - 934
• Main Authors: Konopleva, Marina, Thall, Peter F, Yi, Cecilia Arana, Borthakur, Gautam, Coveler, Andrew, Bueso-Ramos, Carlos, Benito, Juliana, Konoplev, Sergej, Gu, Yongchuan, Ravandi, Farhad, Jabbour, Elias, Faderl, Stefan, Thomas, Deborah, Cortes, Jorge, Kadia, Tapan, Kornblau, Steven, Daver, Naval, Pemmaraju, Naveen, Nguyen, Hoang Q, Feliu, Jennie, Lu, Hongbo, Wei, Caimiao, Wilson, William R, Melink, Teresa J, Gutheil, John C, Andreeff, Michael, Estey, Elihu H, Kantarjian, Hagop
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01-07-2015
• Subjects: Adult; Aged; Anemia - chemically induced; Anemia - genetics; Anemia - metabolism; Anemia - pathology; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - metabolism; Biomarkers - metabolism; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; Carbonic Anhydrase IX; Carbonic Anhydrases - genetics; Carbonic Anhydrases - metabolism; Enterocolitis - chemically induced; Enterocolitis - genetics; Enterocolitis - metabolism; Enterocolitis - pathology; Female; Gene Expression; Humans; Hypoxia - complications; Hypoxia - drug therapy; Hypoxia - genetics; Hypoxia - pathology; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Leukemia, Myeloid, Acute - complications; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Male; Middle Aged; Neutropenia - chemically induced; Neutropenia - genetics; Neutropenia - metabolism; Neutropenia - pathology; Nitrogen Mustard Compounds - administration & dosage; Nitrogen Mustard Compounds - adverse effects; Nitrogen Mustard Compounds - metabolism; Nitroimidazoles - pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - metabolism; Recurrence; Remission Induction; Thrombocytopenia - chemically induced; Thrombocytopenia - genetics; Thrombocytopenia - metabolism; Thrombocytopenia - pathology
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2014.118455

We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided a rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104; dose ranged from 1.1 to 4 g/m(2). The most common treatment-related grade 3/4 adverse events were myelosuppression (anemia 62%, neutropenia 50%, thrombocytopenia 46%), febrile neutropenia (40%), infection (24%), and enterocolitis (14%). Ten of 31 patients with acute myeloid leukemia (32%) and 2 of 10 patients with acute lymphoblastic leukemia (20%) who received 3 g/m(2) or 4 g/m(2) had a response (complete response, n=1; complete response without platelet recovery, n=5; morphological leukemia-free state, n=6). The extent of hypoxia was evaluated by the hypoxia tracer pimonidazole administered prior to a bone marrow biopsy and by immunohistochemical assessments of hypoxia-inducible factor alpha and carbonic anhydrase IX. A high fraction of leukemic cells expressed these markers, and PR104 administration resulted in measurable decrease of the proportions of hypoxic cells. These findings indicate that hypoxia is a prevalent feature of the leukemic microenvironment and that targeting hypoxia with hypoxia-activated prodrugs warrants further evaluation in acute leukemia. The trial is registered at clinicaltrials.gov identifier: 01037556.