Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma.
Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production.
Lonial
Sagar
S
Winship Cancer Institute, Emory University, Atlanta, GA, USA. sloni01@emory.edu
Waller
Edmund K
EK
Richardson
Paul G
PG
Jagannath
Sundar
S
Orlowski
Robert Z
RZ
Giver
Cynthia R
CR
Jaye
David L
DL
Francis
Dixil
D
Giusti
Sara
S
Torre
Claire
C
Barlogie
Bart
B
Berenson
James R
JR
Singhal
Seema
S
Schenkein
David P
DP
Esseltine
Dixie-Lee W
DL
Anderson
Jessica
J
Xiao
Hugh
H
Heffner
Leonard T
LT
Anderson
Kenneth C
KC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001897:Boronic Acids / Q000009:adverse effects*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D011719:Pyrazines / Q000009:adverse effects*; D012008:Recurrence; D012307:Risk Factors; D013921:Thrombocytopenia / Q000139:chemically induced*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib