Will radioimmunotherapy replace TBI?

Comment on Nademanee et al, page 2896

Radioimmunoconjugates that target lymphoma-associated antigens may be safely combined with high-dose chemotherapy and autologous stem cell transplantation. The most effective and easiest approach for widespread application remains to be determined.

Radiolabeled antibodies to lymphoma-associated antigens target high doses of irradiation to widespread disease with relative sparing of normal tissues. Their dose-limiting toxicity in the nontransplantation setting is myelosuppression. These properties, as well as their demonstrated effectiveness in the treatment of relapsed and refractory B-cell lymphomas, have led to clinical trials in autologous stem cell transplantation (ASCT). Radioimmunoconjugates (RICs) replace total body irradation (TBI) in some studies, while in others they augment chemotherapy-only regimens.

More than a decade ago, Press and colleagues reported pioneering studies investigating the use of iodine-131 (¹³¹I)–labeled anti-CD20 antibodies. Their phase 1 and 2 studies in NHL established both the safety and efficacy of high-dose ¹³¹I-labeled anti-CD20 RICs administered both alone and in combination with etoposide and cyclophosphamide followed by ASCT.^1,2  Toxicities were no different from those associated with regimens of TBI, etoposide, and cyclophosphamide, while clinical outcomes appeared to be superior.

Today, 2 anti-CD20 RICs, ¹³¹I-tositumomab and yttrium-90 (⁹⁰Y)–ibritumomab tiuxetan, are approved for the treatment of CD20⁺ non-Hodgkin lymphoma (NHL). In this issue, Nadamanee and coinvestigators from the City of Hope report the results of a phase 1/2 trial in which ⁹⁰Y–ibritumomab tiuxetan was combined with etoposide and cyclophosphamide followed by ASCT. In their study, the radioimmunotherapeutic dose was calculated to deliver no more than 1 000 cGy to critical organs and capped at 3.17 × 10⁹ Bq (100 mCi) for practical considerations, significantly less than the 2 500 cGy maximal tolerated dose studied by Press et al.²  Whereas the regimen was well tolerated, it is possible that a much higher RIC dose could have been administered. Whether the use of higher doses would have increased efficacy, however, is unknown. The outcomes, like those reported by Press et al, are excellent, but it is difficult to judge the regimen's impact given the small numbers and heterogeneity of the study population, which included some patients in first remission. Studies limited to a given histologic subset with uniform patient characteristics and risk profiles will be required to more accurately define the effectiveness of this therapeutic strategy.

Some investigators have added RICs to a standard chemotherapy combination, BEAM (carmustine, etoposide, cytarabine, and melphalan), rather than substitute radioimmunotherapy for TBI in a combined modality regimen.^3-5  Results combining BEAM and ⁹⁰Y–ibritumomab tiuxetan at 1.3 × 10⁷ Bq/kg (0.4 mCi/kg), the approved dose for routine treatment, are promising.⁵  However, much higher doses of ⁹⁰Y–ibritumomab tiuxetan can safely be combined with this chemotherapy regimen, as demonstrated in an ongoing phase 1 trial.⁴  In that phase 1 study, patient-specific doses calculated to deliver a prescribed radiation dose (100-1500+ cGy) to critical organs were highly variable, suggesting that dosing based on weight and not dosimetry is likely to result in a wide range of absorbed dose to critical organs and potential toxicity, especially at the higher dose range.

As described, this treatment approach required considerable technologic support and expertise. Treatment was individualized based on dosimetry, the details of which are to be published elsewhere but are described as “quite complicated.” If this approach is to be transported to other centers and widely available, the methodology will need to be simplified. Further investigation of alternative approaches to dosing and ultimately randomized trials will be required to determine if RICs are worth the cost in stem cell transplantation. ▪