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

Marina Konopleva, Peter F. Thall, Cecilia Arana Yi, Gautam Borthakur, Andrew Coveler, Carlos Bueso-Ramos, Juliana Benito, Sergej Konoplev, Yongchuan Gu, Farhad Ravandi, Elias Jabbour, Stefan Faderl, Deborah Thomas, Jorge Cortes, Tapan Kadia, Steven Kornblau, Naval Daver, Naveen Pemmaraju, Hoang Q. Nguyen, Jennie FeliuHongbo Lu, Caimiao Wei, William R. Wilson, Teresa J. Melink, John C. Gutheil, Michael Andreeff, Elihu H. Estey, Hagop Kantarjian

Research output: Contribution to journalArticle

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/m2. 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/m2 or 4 g/m2 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.

Original languageEnglish (US)
Pages (from-to)927-934
Number of pages8
JournalHaematologica
Volume100
Issue number7
DOIs
StatePublished - Jul 6 2015
Externally publishedYes

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Prodrugs
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Amines
Leukemia
Enterocolitis
Mechlorethamine
Febrile Neutropenia
Hypoxia
Neutropenia
Thrombocytopenia
Hydroxyl Radical
Anemia
Esters
Therapeutics
Blood Platelets
Bone Marrow
Phosphates
Alcohols
Oxygen

ASJC Scopus subject areas

  • Hematology

Cite this

Konopleva, M., Thall, P. F., Yi, C. A., Borthakur, G., Coveler, A., Bueso-Ramos, C., ... Kantarjian, H. (2015). Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica, 100(7), 927-934. https://doi.org/10.3324/haematol.2014.118455

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

In: Haematologica, Vol. 100, No. 7, 06.07.2015, p. 927-934.

Research output: Contribution to journalArticle

Konopleva, M, Thall, PF, Yi, CA, Borthakur, G, Coveler, A, Bueso-Ramos, C, Benito, J, Konoplev, S, Gu, Y, Ravandi, F, Jabbour, E, Faderl, S, Thomas, D, Cortes, J, Kadia, T, Kornblau, S, Daver, N, Pemmaraju, N, Nguyen, HQ, Feliu, J, Lu, H, Wei, C, Wilson, WR, Melink, TJ, Gutheil, JC, Andreeff, M, Estey, EH & Kantarjian, H 2015, 'Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia', Haematologica, vol. 100, no. 7, pp. 927-934. https://doi.org/10.3324/haematol.2014.118455
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. / Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. In: Haematologica. 2015 ; Vol. 100, No. 7. pp. 927-934.
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AU - Konopleva, Marina

AU - Thall, Peter F.

AU - Yi, Cecilia Arana

AU - Borthakur, Gautam

AU - Coveler, Andrew

AU - Bueso-Ramos, Carlos

AU - Benito, Juliana

AU - Konoplev, Sergej

AU - Gu, Yongchuan

AU - Ravandi, Farhad

AU - Jabbour, Elias

AU - Faderl, Stefan

AU - Thomas, Deborah

AU - Cortes, Jorge

AU - Kadia, Tapan

AU - Kornblau, Steven

AU - Daver, Naval

AU - Pemmaraju, Naveen

AU - Nguyen, Hoang Q.

AU - Feliu, Jennie

AU - Lu, Hongbo

AU - Wei, Caimiao

AU - Wilson, William R.

AU - Melink, Teresa J.

AU - Gutheil, John C.

AU - Andreeff, Michael

AU - Estey, Elihu H.

AU - Kantarjian, Hagop

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