Abstract
Simple SummaryWe prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin’s lymphoma using the theranostic pair of 111In and 90Y anti-CD20 ibritumomab tiuxetan (Zevalin®) at myeloablative radiation-absorbed doses with autologous stem cell support. Unlike most routine dose escalation approaches, our approach used patient-individualized measurements of organ radiation absorbed dose from the tracer study, with patient-specific adjustments of the injected therapy dose to deliver a pre-specified radiation absorbed dose to the liver. Our approach was feasible, stem cell engraftment was swift, resulted in an 89% tumor response rate in treated patients, demonstrated over 3 fold variability in liver dosimetry/injected activity among patients, allowed us to exceed the FDA approved administered activity by over 5 fold and demonstrated the normal liver maximum tolerated dose to exceed 28 Gy. Dose escalation was not continued due to lack of drug availability. With modern dosimetry approaches, patient specific dosimetry-driven radiation dose escalation is feasible, allows adjustment of administered activity for heterogeneous pharmacokinetics and allows marked dose escalation vs. non-dosimetry driven approaches.Purpose: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin’s lymphoma using the theranostic pair of 111In and 90Y anti-CD20 ibritumomab tiuxetan (Zevalin®) at myeloablative radiation-absorbed doses with autologous stem cell support. We also assessed acute non-hematopoietic toxicity and early tumor response in this two-center outpatient study. Methods: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm3, and <35% tumor involvement in the marrow were treated with Rituximab (375 mg/m2) weekly for 4 consecutive weeks, then one dose of cyclophosphamide 2.5 g/m2 with filgrastim 10 mcg/kg/day until stem cell collection. Of these, 18 patients with successful stem cell collection (at least 2 × 106 CD34 cells/kg) proceeded to RIT. A dosimetric administration of 111In ibritumomab tiuxetan (185 MBq) followed by five sequential quantitative planar and one SPECT/CT scan was used to determine predicted organ radiation-absorbed dose. Two weeks later, 90Y ibritumomab tiuxetan was administered in an outpatient setting at a cohort- and patient-specific predicted organ radiation-absorbed dose guided by a Continuous Response Assessment (CRM) methodology with the following cohorts for dose escalation: 14.8 MBq/kg, and targeted 18, 24, 28, and 30.5 Gy to the liver. Autologous stem cell infusion occurred when the estimated marrow radiation-absorbed dose rate was predicted to be <1 cGy/h. Feasibility, short-term toxicities, and tumor response were assessed. Results: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of 90Y (range: 12.1–41.4 MBq/kg)) of ibritumomab tiuxetan that was required to deliver 10 Gy to the liver. Infused stem cells engrafted rapidly. The most common treatment-related toxicities were hematological and were reversible following stem cell infusion. No significant hepatotoxicity was seen. One patient died from probable treatment-related causes—pneumonia at day 27 post-transplant. One patient at dose level 18 Gy developed myelodysplastic syndrome (MDS), 4 patients required admission post-90Y RIT for febrile neutropenia, 16/18 patients receiving 90Y ibritumomab tiuxetan (89%) responded to the therapy, with 13 CR (72%) and 3/18 PR (17%), at 60 days post-treatment. Two patients had progressive disease at sixty days. One patient was lost to follow-up. Median time to progression was estimated to be at least 13 months. MTD to the liver is greater than 28 Gy, but the MTD was not reached as the study was terminated due to unexpected discontinuation of availability of the therapeutic agent. Conclusions: Patient-specific outpatient 90Y ibritumomab tiuxetan RIT with myeloablative doses of RIT up to a targeted 30.5 Gy to the liver is feasible, guided by prospective SPECT/CT + planar imaging with the theranostic pair of 111In and 90Y anti-CD20, with outpatient autologous stem cell transplant support. Administered activity over 5 times the standard FDA-approved activity was well-tolerated. The non-hematopoietic MTD in this study exceeds 28 Gy to the liver. Initial tumor responses were common at all dose levels. This study supports the feasibility of organ dosimetry-driven patient-specific dose escalation in the treatment of NHL with stem cell transplant and provides additional information on the radiation tolerance of the normal liver to radiopharmaceutical therapy.
Highlights
Anti-CD20-targeted monoclonal antibodies, both unlabeled and radiolabeled, are active agents in the treatment of B-cell lymphomas [1,2]
The study was performed as a prospective, two-center, dose-escalation study of ibritumomab tiuxetan, with dose escalation based on prospective patient-specific organ dosimetry determined from 111 In ibritumomab tiuxetan imaging
The primary operational goal of the study was to determine if precision, prospective, SPECT-CT organ dosimetry-based outpatient myeloablative radioimmunotherapy, with autologous stem cell transplantation (ASCT), in a two-center study was logistically feasible
Summary
Anti-CD20-targeted monoclonal antibodies, both unlabeled and radiolabeled, are active agents in the treatment of B-cell lymphomas [1,2]. The. FDA has approved two anti-CD20 radio-immunotherapies for follicular lymphomas: 131 I tositumomab plus unlabeled tositumomab (Bexxar® , Philadelphia, PA, USA) and rituximab plus 90 Y ibritumomab tiuxetan (Zevalin® , East Windsor, NJ, USA). FDA has approved two anti-CD20 radio-immunotherapies for follicular lymphomas: 131 I tositumomab plus unlabeled tositumomab (Bexxar® , Philadelphia, PA, USA) and rituximab plus 90 Y ibritumomab tiuxetan (Zevalin® , East Windsor, NJ, USA) Their administered radioactivity doses, and quite likely their efficacy, are limited by hematopoietic toxicity, predominantly thrombocytopenia [5]. While anti-CD20 radio-immunotherapies are effective and safe, their utilization at non-myeloablative doses has been relatively limited given the availability of other therapeutic approaches and other factors, with only 44 treatments reported for Zevalin in a European therapy survey in 2015 [7,8]. Bexxar is no longer commercially available, mainly due to low commercial sales
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