Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance.
OBJECTIVE
Rituximab has clinical activity in patients with chronic lymphocytic leukemia (CLL) and has a variety of proposed mechanisms, including apoptosis, complement-dependent cell lysis (CDC), and antibody-dependent cellular cytotoxicity (ADCC). Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy.


METHODS
Pretreatment samples from 21 CLL patients treated on a prospective, single-agent rituximab trial were examined for quantitative expression of apoptotic and CDC regulatory proteins, and the level of expression of these proteins was correlated with clinical outcome.


RESULTS
Of the 21 patents for whom samples were available, 10 attained a partial response and 11 failed to respond to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, and the ratio of Bcl-2/Bax were higher but not statistically increased in nonresponding patients versus those responding to treatment. In contrast, the pretreatment Mcl-1/Bax ratio was significantly elevated (0.82 +/- 0.28 v 0.39 +/- 0.29, P <.016) in nonresponding patients compared with patients responding to rituximab therapy. Although pretreatment expression of CD55 and CD59 was not associated with response to rituximab therapy, significantly higher levels of CD59 were observed in the CLL cells that were not cleared from the blood at completion of therapy than the level observed at baseline levels (P =.02).


CONCLUSIONS
These data indicate that baseline expression of the Mcl-1/Bax ratio, but not CD55 and CD59, predict for clinical response to rituximab therapy in CLL patients. Further study of disrupted apoptosis in CLL as a potential mechanism of resistance to rituximab appears warranted.
Bannerji
Rajat
R
Division of Hematology-Oncology, Starling Loving Hall, The Ohio State University, Columbus, OH 43210, USA. byrd-3@medctr.osu.edu
Kitada
Shinichi
S
Flinn
Ian W
IW
Pearson
Michael
M
Young
Donn
D
Reed
John C
JC
Byrd
John C
JC
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018958:CD55 Antigens / Q000378:metabolism; D018957:CD59 Antigens / Q000378:metabolism; D003165:Complement System Proteins / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism*; D015337:Multicenter Studies as Topic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D000069283:Rituximab; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C494826:BAX protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000069283:Rituximab; D003165:Complement System Proteins