Radioimmunotherapy in allogeneic nonmyeloablative conditioning for B-cell lymphoma: Should we use it more often?

In this issue of Biology of Blood and Marrow Transplantation, Cassaday and coworkers reported improved survival rates in patients with indolent B-cell lymphomas who underwent anti-CD-20 radioimmunotherapy using yttrium-90-ibrutinib tiuxetan (⁹⁰YIT) with their nonmyeloablative transplant conditioning regimen.¹ All these patients had been exposed to rituximab. The authors compared their results to those of a historical control group of patients who did not receive ⁹⁰YIT.¹ After adjusting for imbalances in patients’ characteristics including chemoresistant and bulky disease, thrombocytopenia and Hematopoietic Cell Transplant Comorbidity Index Scores of ≥ 3, favoring the control group, the 3-year adjusted estimates of overall survival and progression-free survival in the ⁹⁰YIT were 87% and 71%, vs 59% and 44% in the non-⁹⁰YIT group.

The authors acknowledge the limitation of the small number of patients studied (n=18), which was even smaller after adjusting for high-risk disease features described above. Nevertheless, their findings further confirm that RIT improves the outcome of patients with relapsed or refractory high-risk indolent lymphoma who have been considered for nonmyeloablative allogeneic transplantation. They are also in agreement with those of an earlier report from our center of a 3-year progression-free survival rate of 80% in refractory follicular lymphoma patients after allogeneic transplantation and ⁹⁰YIT.²

Nonmyeloablative conditioning has been the cornerstone of adoptive allogeneic immunotherapy for B-cell indolent lymphoma that has failed to respond to conventional treatment. Pre-transplantation chemosensitivity vs refractoriness has been an important determinant of outcomes,³ and how to treat refractory disease without inducing additional toxicity has been a challenge. One strategy to enhance initial disease control is to incorporate novel agents into allogeneic conditioning regimens that are effective against lymphoma; remission can later be sustained via the graft-versus-lymphoma effect. One of the most compelling of these agents is ⁹⁰YIT, which is used as targeted therapy in indolent lymphomas.

The known sensitivity of B-cell indolent lymphomas to conventional radiotherapy makes them an attractive target for RIT. In the United States, ⁹⁰YIT (Zevalin; Spectrum Pharmaceuticals, Henderson, NV) has been approved for the treatment of relapsed low-grade and follicular lymphomas. In 2009, the drug received an additional indication for use as consolidation after initial chemotherapy.^{4 90}YIT uses the antibody to mediate complement-mediated cytotoxicity, along with the delivery of high-energy, short path-length (5 mm) beta irradiation from ⁹⁰Y to both CD20-lymphoma cells and neighboring tumor cells that are inaccessible to the antibody or have insufficient antigen expression as a result of a cross-fire effect, with little effect on other solid organs.

Of note, positive results were found in this study in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (10 of 18 patients), while the degree of marrow involvement and cytopenia were not factored into eligibility criteria to receive ⁹⁰YIT. RIT is not known to be active as a single agent, without transplantation, in these histologic types. In a study at MD Anderson, ⁹⁰YIT was administered to 14 patients with relapsed CLL that was in partial (but with < 25% marrow involvement) or complete remission but with persistent minimal residual disease (MRD) after chemotherapy.⁵ Patients were required to have a platelet count of > 100,000/mm³. Of the 13 patients evaluable for response, only 1 patient achieved an MRD-negative remission but soon thereafter had Richter transformation. Grade ≥ 3 hematological toxicity was seen in 12 of the 13 evaluable patients. In view of this contrast in responses and safety, further exploration is needed of the mechanism of action of ⁹⁰YIT in these diseases in the context of allogeneic transplantation.

How can the information in the Cassaday et al study be used in clinical practice? The results of the current study confirm that the type of conditioning used in nonmyeloablative transplantation strategies matters and that one size does not fit all. The results of this study and the study at our center suggest that ⁹⁰YIT should be more frequently administered to patients with active or refractory indolent lymphoma before transplantation. However, patients should be treated in clinical trials. The CLL results are intriguing and need to be confirmed in other studies. Contrary to previous findings in mouse models,⁶ it appears that prior exposure to rituximab does not affect the efficacy or safety of transplantation with ⁹⁰YIT.

Finally, this study does not address the lingering question in allogeneic transplantation: the incidence of graft-versus-host disease (GVHD). Over 70% of patients in this study developed acute II-IV GVHD. This incidence appears to be higher (23%) than the one observed in our transplantation study with ⁹⁰YIT,² suggesting that the difference is related to the GVHD prophylaxis used rather than to the innate conditioning regimen. In this era of novel B-cell receptor pathway-targeted agents such as ibrutinib and idelalisib, it is paramount that the safety of allogeneic transplantation be enhanced to encourage referrals from the community.