The combined administration of daniplestim and Mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression.
This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl-L) administration in nonhuman primates following severe, radiation-induced myelosuppression. Rhesus monkeys were total body x-irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post-TBI, animals were s.c. administered daniplestim (100 microg/kg bid; n = 4), Mpl-L (10 microg/kg qd; n = 3), daniplestim (100 microg/kg bid) plus Mpl-L (10 microg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT <20,000/microl) was significantly decreased by the administration of daniplestim (6.5 d, p = .01), Mpl-L (3.0 d, p = .003) and the coadministered daniplestim/Mpl-L (1.3 d, p = .001) compared to controls (10.4 d). As monotherapy Mpl-L but not daniplestim significantly improved the PLT nadir (21,000/microl, p = .023 and 5,000/microl, p = .266, respectively) compared to the control (3,000/microl). The combined administration of daniplestim and Mpl-L significantly improved the PLT nadir (28,000/microl, p = .007) compared to both the control cohort (3,000/microl) and the daniplestim only cohort (5,000/microl, p = .043). Recovery of PLT to preirradiation values occurred earlier in the daniplestim only (d 21) or the daniplestim/Mpl-L cohorts (d 18) than in the Mpl-L only or control cohorts (d 28, d 29, respectively). The administration of daniplestim or Mpl-L alone neither shortened the duration of neutropenia (ANC<500/microl) compared to the controls (15.8 d, 16.0 d versus 16.2 d, respectively), nor improved the recovery time of neutrophils to baseline values (d 22, d 25, and d 23, respectively). The ANC nadir was significantly improved by daniplestim alone but not Mpl-L administration (76/microl, p = .001 and 50/microl, p = .093, respectively) compared to the controls (8/microl). Coadministration of daniplestim and Mpl-L significantly improved the ANC nadir (196/microl, p = .001) compared to either the AS- or the monotherapy-treated cohorts. Also the duration of neutropenia observed in the AS-controls (16.2 d) was significantly reduced in the daniplestim/Mpl-L cohort (10.8 d, p = .002). The combined administration of daniplestim and Mpl-L significantly improved hematopoietic recovery and further enhanced the stimulatory effect of cytokine monotherapy, as well as reducing clinical support requirements after radiation-induced bone marrow myelosuppression.
Farese
A M
AM
Greenebaum Cancer Center, University of Maryland, Baltimore, USA.
MacVittie
T J
TJ
Lind
L B
LB
Smith
W G
WG
McKearn
J P
JP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001803:Blood Transfusion; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology*; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D007165:Immunosuppression Therapy / Q000379:methods; D007377:Interleukin-3 / Q000031:analogs & derivatives; D008253:Macaca mulatta; D008297:Male; D009503:Neutropenia / Q000188:drug therapy / Q000503:physiopathology; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013921:Thrombocytopenia / Q000188:drug therapy / Q000503:physiopathology; D013926:Thrombopoietin / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004338:Drug Combinations; D007377:Interleukin-3; D010446:Peptide Fragments; D010455:Peptides; C093340:daniplestim; D013926:Thrombopoietin