Abstract
Background: MCL is an aggressive and prognostically unfavorable subtype of B-cell NHL, with a 5-yr survival rate <20%. Standard chemotherapy for MCL includes fludarabine, cyclophosphamide, and mitoxatrone (FCM). Addition of rituximab (R) to FCM increases overall response rate (ORR) from 46% to 58%. Conventional non-myeloablative RIT has been unsuccessful in MCL patients because tumor burdens were large and because of the “sink phenomenon.” It was hypothesized that fludarabine sensitizes MCL to the radiotoxic effects of RIT, and RIT applied after appropriate tumor size reduction would consolidate the FCM effect and prolong PFS. The Polish Lymphoma Research Group Trial (PLRG MCL1) assessed whether 90Y-Zevalin consolidates the response achieved from FCM±R and provide better ORRs and longer TTP.
Methods: Eighteen MCL pts (stage III-IV) not suitable for SCTs were enrolled in 8 PLRG centers: 9 pts had MCL at diagnosis, 6 pts had a PR after 1st-line therapy of MCL, and 3 MCL pts were in 1st relapse. Tumor burden was reduced by treating all pts with a minimum of 3, and a maximum of 6, 3-wk cycles of FCM±R (375 mg/m2) and staged after the 3rd and subsequent cycles to assess tumor regression. Pts with a CR or PR, <25% bone marrow (BM) infiltration, <30 mm lymph node diameter, <12 cm spleen diameter, no massive extranodular involvement, PMNs >1500/ml, PLTs >100,000/ml, and no BM hypoplasia were in the 90Y-Zevalin consolidation step. These pts received 250 mg/m2 of R and 1 wk later a 2nd dose of R+90Y-Zevalin (11 or 15 MBq=0.3 or 0.4 mCi/Kg, based on initial PLT count; max dose=32 mCi). ORR (CR+PR) and hematologic toxicity were determined. Therapeutic response is being monitored at 6 wks, 3 mo, and 3-mo intervals for up to 2 yrs to assess TTP. Another 7 pts have been enrolled; 4 pts will receive 90Y-Zevalin, but 3 will not due to inadequate response (1) or cytopenias (2) after FCM±R.
Results: Following 90Y-Zevalin consolidation, 13 of the 15 pts achieved a CR (no palpable lymph nodes or measurable masses on CT scans) and 12 of the 13 shifted from a PR after FCM±R to a CR. One pt achieved a greater PR after 90Y-Zevalin. Of these 12 PRàCR pts, 10 are in CR 3-6 mo after receiving 90Y-Zevalin, 1 pt progressed at 3 mo, and another progressed immediately despite 90Y-Zevalin. Response and toxicity data of all pts and preliminary TTP results will be reported at ASH. In most pts, WBC and PLT values ↓ 4–5 wks after 90Y-Zevalin and cytopenias lasted 5–7 wks (2 wks longer compared to follicular pts given 90Y-Zevalin w/o fludarabine; P=NS). In 3 of 15 pts, the time for PMN >1000/ml was 7–12 wks and for PLT levels >50,000/ml was >20 wks and were transfusion dependent. No pt developed serious infections.
Conclusions: 90Y-Zevalin consolidated the therapeutic benefit of FCM±R in 13 MCL pts. Fludarabine, a known radiosensitizer, can reduce tumor burden before RIT and enhance the therapeutic benefit of non-myeloablative doses of 90Y-Zevalin, but may also ↑ the toxicity from RIT. Although we have shown 90Y-Zevalin has negative effects on stem and early progenitor cells, 90Y-Zevalin can be safely given after fludarabine-based therapy to MCL pts.
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