Dose-adjusted EPOCH-rituximab combined with fludarabine provides an effective bridge to reduced-intensity allogeneic hematopoietic stem-cell transplantation in patients with lymphoid malignancies.
OBJECTIVE
There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R).


METHODS
One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count < 200/μL) or progressive disease.


RESULTS
Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P < .001), CD4(+) (P < .001), and CD8(+) (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001).


CONCLUSIONS
DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Rachel B
RB
Salit
Daniel H
DH
Fowler
Wyndham H
WH
Wilson
Robert M
RM
Dean
Steven Z
SZ
Pavletic
Kieron
K
Dunleavy
Frances
F
Hakim
Terry J
TJ
Fry
Seth M
SM
Steinberg
Thomas E
TE
Hughes
Jeanne
J
Odom
Kelly
K
Bryant
Ronald E
RE
Gress
Michael R
MR
Bishop
D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity; D005047:Etoposide / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019409:Interleukin-15 / Q000097:blood; D015851:Interleukin-7 / Q000097:blood; D008212:Lymphocyte Depletion; D008223:Lymphoma / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage / Q000633:toxicity; D000069283:Rituximab; D016879:Salvage Therapy / Q000379:methods*; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D014750:Vincristine / Q000008:administration & dosage / Q000633:toxicity
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D019409:Interleukin-15; D015851:Interleukin-7; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine; D011241:Prednisone