title: Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.
abstract: 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.
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA mkonople@mdanderson.org.
authors: Marina
authors: M
authors: Konopleva
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Peter F
authors: PF
authors: Thall
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Cecilia Arana
authors: CA
authors: Yi
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Gautam
authors: G
authors: Borthakur
authors: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
authors: Andrew
authors: A
authors: Coveler
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Carlos
authors: C
authors: Bueso-Ramos
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Juliana
authors: J
authors: Benito
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Sergej
authors: S
authors: Konoplev
authors: Auckland Cancer Society Research Centre, University of Auckland, NZ, USA.
authors: Yongchuan
authors: Y
authors: Gu
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Farhad
authors: F
authors: Ravandi
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Elias
authors: E
authors: Jabbour
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Stefan
authors: S
authors: Faderl
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Deborah
authors: D
authors: Thomas
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jorge
authors: J
authors: Cortes
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Tapan
authors: T
authors: Kadia
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Steven
authors: S
authors: Kornblau
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Naval
authors: N
authors: Daver
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Naveen
authors: N
authors: Pemmaraju
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Hoang Q
authors: HQ
authors: Nguyen
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jennie
authors: J
authors: Feliu
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Hongbo
authors: H
authors: Lu
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Caimiao
authors: C
authors: Wei
authors: Auckland Cancer Society Research Centre, University of Auckland, NZ, USA.
authors: William R
authors: WR
authors: Wilson
authors: Proacta Inc., La Jolla, CA, USA.
authors: Teresa J
authors: TJ
authors: Melink
authors: Proacta Inc., La Jolla, CA, USA.
authors: John C
authors: JC
authors: Gutheil
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Michael
authors: M
authors: Andreeff
authors: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
authors: Elihu H
authors: EH
authors: Estey
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Hagop
authors: H
authors: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D004760:Enterocolitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D009593:Nitroimidazoles / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009588:Nitrogen Mustard Compounds; D009593:Nitroimidazoles; C522381:PR-104; D011355:Prodrugs; C033815:pimonidazole; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases