The novel expanded porphyrin, motexafin gadolinium, combined with [90Y]ibritumomab tiuxetan for relapsed/refractory non-Hodgkin's lymphoma: preclinical findings and results of a phase I trial.
OBJECTIVE
Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation.


METHODS
We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [(90)Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma.


RESULTS
In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time-to-treatment failure of 10 months (1-48+ months) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time-to-treatment failure of 14 months (2-48+ months).


CONCLUSIONS
This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [(90)Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.
Evens
Andrew M
AM
Lymphoma Program, Division of Hematology/Oncology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Chicago, IL 60611, USA. a-evens@northwestern.edu
Spies
William G
WG
Helenowski
Irene B
IB
Patton
David
D
Spies
Stewart
S
Jovanovic
Borko D
BD
Miyata
Sarah
S
Hamilton
Elizabeth
E
Variakojis
Daina
D
Chen
Jun
J
Naumovski
Louie
L
Rosen
Steven T
ST
Winter
Jane N
JN
Miller
Richard A
RA
Gordon
Leo I
LI
D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000532:radiotherapy*; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016499:Radioimmunotherapy; D012008:Recurrence; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D008665:Metalloporphyrins; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D015021:Yttrium Radioisotopes; C422802:ibritumomab tiuxetan; C437683:motexafin gadolinium