Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies.
Pre-clinical data in non-M3 AML supports the use of differentiation therapy, but clinical activity has been limited. Myeloid growth factors can enhance anti-leukemic activity of differentiating agents in vitro. We conducted companion phase II trials investigating sargramostim (GM-CSF) 125μg/m(2)/day plus 1) bexarotene (BEX) 300mg/m(2)/day or 2) entinostat (ENT) 4-8mg/m(2)/week in patients with MDS or relapsed/refractory AML. Primary endpoints were response after at least two treatment cycles and toxicity. 26 patients enrolled on the BEX trial had a median of 2 prior treatments and 24 enrolled on the ENT trial had a median of 1. Of 13 response-evaluable patients treated with BEX, the best response noted was hematologic improvement in neutrophils (HI-N) seen in 4 (31%) patients; none achieved complete (CR) or partial remission (PR). Of 10 treated with ENT, there was 1 (10%) partial remission (PR) and 2 (20%) with HI-N. The secondary endpoint responses of HI-N with each combination were accompanied by a numerical increase in ANC (BEX: 524 to 931 cells/mm(3), p=0.096; ENT: 578 to 1 137 cells/mm(3), p=0.15) without increasing marrow blasts. Shared grade 3-4 non-hematologic toxicities included febrile neutropenia, bone pain, fatigue, and dyspnea. GM-CSF plus either BEX or ENT are well tolerated in resistant and refractory MDS and AML and showed modest clinical and biologic activity, most commonly HI-N.
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Kelly J
KJ
Norsworthy
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Eunpi
E
Cho
Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, United States.
Jyoti
J
Arora
Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, United States.
Jeanne
J
Kowalski
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Hua-Ling
HL
Tsai
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Erica
E
Warlick
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Margaret
M
Showel
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Keith W
KW
Pratz
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Lesley A
LA
Sutherland
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Steven D
SD
Gore
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Anna
A
Ferguson
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Sarah
S
Sakoian
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Jackie
J
Greer
Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, United States.
Igor
I
Espinoza-Delgado
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Richard J
RJ
Jones
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
William H
WH
Matsui
Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States. Electronic address: bdsmith@jhmi.edu.
B Douglas
BD
Smith
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D000077610:Bexarotene; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009504:Neutrophils / Q000166:cytology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012074:Remission Induction; D016879:Salvage Therapy / Q000379:methods*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D020298:U937 Cells
D000970:Antineoplastic Agents; D001549:Benzamides; D011725:Pyridines; D011994:Recombinant Proteins; D013764:Tetrahydronaphthalenes; C118739:entinostat; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000077610:Bexarotene
Acute myeloid leukemia; Bexarotene; Differentiation; Entinostat; Myelodysplastic syndrome