RIT D-2214

Radioimmunotherapy (RIT) is a safe and active treatment available for non-Hodgkin lymphomas (NHLs). In particular, two monoclonal antibodies raised against CD20, that is Zevalin (90Y-ibritumomab-tiuxetan) and Bexxar (131I-tositumomab) received FDA approval for the treatment of relapsing/refractory indolent or transformed NHLs. RIT is likely the most effective and least toxic anticancer agent in NHLs. However, its use in the clinical setting is still debated and, in case of relapse after optimized rituximab-containing regimens, the efficacy of RIT at standard dosage is suboptimal. Thus, clinical trials were based on the hypothesis that the inclusion of RIT in myeloablative conditioning would allow to obtain improved efficacy and toxicity profiles when compared to myeloablative total-body irradiation and/or high-dose chemotherapy regimens. Standard-activity RIT has a safe toxicity profile, and the utility of pretherapeutic dosimetry in this setting can be disputed. In contrast, dose-escalation clinical protocols require the assessment of radiopharmaceutical biodistribution and dosimetry before the therapeutic injection, as dose constrains for critical organs may be exceeded when RIT is administered at high activities. The aim of the present study was to review and discuss the internal dosimetry protocols that were adopted for non-standard RIT administration in the myeloablative setting before hematopoietic stem cell transplantation in patients with NHLs.

Background: Although ABO-incompatible (ABOi) kidney transplantation (KT) has been performed successfully, a standard preconditioning regimen has not been established. Based on the initial antidonor ABO antibody titers, an individualized preconditioning regimen is developed, and this study explored the efficacy and safety of the regimen. Methods: From September 1, 2014, to September 1, 2020, we performed 1668 consecutive living-donor KTs, including 100 ABOi and 1568 ABO-compatible (ABOc) KTs. ABOi KT recipients (KTRs) with a lower antibody titer (≤1:8) were administered oral immunosuppressive drugs (OIs) before KT, while patients with a medium titer (1:16) received OIs plus antibody-removal therapy (plasma exchange/double-filtration plasmapheresis), patients with a higher titer (≥1:32) were in addition received rituximab (Rit). Competing risk analyses were conducted to estimate the cumulative incidence of infection, acute rejection (AR), graft loss, and patient death. Results: After propensity score analyses, 100 ABOi KTRs and 200 matched ABOc KTRs were selected. There were no significant differences in graft and patient survival between the ABOi and ABOc groups (P = 0.787, P = 0.386, respectively). After using the individualized preconditioning regimen, ABOi KTRs showed a similar cumulative incidence of AR (10.0% υs . 10.5%, P = 0.346). Among the ABOi KTRs, the Rit-free group had a similar cumulative incidence of AR ( P = 0.714) compared to that of the Rit-treated group. Multivariate competing risk analyses revealed that a Rit-free regimen reduced the risk of infection (HR: 0.31; 95% CI: 0.12-0.78, P = 0.013). Notably, antibody titer rebound was more common in ABOi KTRs receiving a Rit-free preconditioning regimen ( P = 0.013) than those receiving Rit. ABOi KTRs with antibody titer rebound had a 2.72-fold risk of AR (HR: 2.72, 95% CI: 1.01-7.31, P = 0.048). ABOi KTRs had similar serum creatinine and estimated glomerular filtration rate compared to those of ABOc KTRs after the first year. Conclusions: An individualized preconditioning regimen can achieve comparable graft and patient survival rates in ABOi KT with ABOc KT. Rit-free preconditioning effectively prevented AR without increasing the risk of infectious events in those with lower initial titers; however, antibody titer rebound should be monitored.

Polatuzumab vedotin (Pola) is an antibody-drug conjugate that targets the B-cell antigen CD79b and delivers monomethyl auristatin E (MMAE). It is approved in combination with bendamustine and rituximab (Rit) for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Understanding the molecular basis of Pola combination therapy with Rit, the key component for the treatment of DLBCL, is important to establish the effective treatment strategies against r/r DLBCL. Here, we examined the rationale for the combination of Pola with Rit using Pola-refractory cells. We found that treatment with Pola increased CD20 expression and sensitivity to Rit-induced complement-dependent cytotoxicity (CDC) in several Pola-refractory cells. Pola treatment increased phosphorylation of AKT and ERK and both AKT- and MEK-specific inhibitors attenuated the Pola-induced increase of CD20 and CDC sensitivity, suggesting that these phosphorylation events were required for this combination efficacy. It was revealed that anti-CD79b antibody increased the phosphorylation of AKT but inhibited the phosphorylation of ERK. In contrast, MMAE potentiated phosphorylation of ERK but slightly attenuated the phosphorylation of AKT. Pola also increased CD20 expression on Pola-refractory xenografted tumours and significantly enhanced antitumour activity in combination with Rit. In conclusion, these results could provide a novel rationale for the combination of Pola plus Rit.