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Megadose 90Y-ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma.

ABSTRACT: Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCLs), although outcomes are worse in aggressive disease, and most patients will still experience relapse. Radioimmunotherapy using 90Y-ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that megadoses of 90Y-ibritumomab tiuxetan with reduced-intensity conditioning could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-ibritumomab tiuxetan (1.5 mCi/kg; maximum, 120 mCi), fludarabine, and then 2 Gy total body irradiation before HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy, including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y-ibritumomab tiuxetan activity of 113.6 mCi (range, 71.2-129.2 mCi) was administered, delivering a median of 552 cGy to the liver (range, 499-2411 cGy). The estimated 1- and 5-year progression-free survival was 55% (95% confidence interval [CI], 31-73) and 50% (95% CI, 27-69) with a median progression-free survival of 1.57 years. The estimated 1- and 5-year overall survival was 80% (95% CI, 54-92) and 63% (95% CI, 38-81) with a median overall survival of 6.45 years. Sixteen patients (80%) experienced grade 3 or higher toxicities, although nonrelapse mortality was 10% at 1 year. No patients developed secondary acute myeloid leukemia/myelodysplastic syndrome. Megadose 90Y-ibritumomab tiuxetan, fludarabine, and low-dose total body irradiation followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified end point while producing nonhematologic toxicities comparable to those of standard reduced-intensity conditioning regimens.

SUBMITTER: Chow VA

PROVIDER: S-EPMC8753215 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In the treatment of diffuse large B-cell lymphoma, a persistently positive [18F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan-BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17-20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3-4, 54% bulk, and 54% International Prognostic Index 3-5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257).

Project description:PurposeTherapeutic 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.Experimental designWe 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.ResultsIn 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).ConclusionsThis 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.

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Megadose 90Y-ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma.

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