Prospective SPECT-CT organ dosimetry-driven radiation-absorbed dose escalation using the In-111 (111In)/yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin ®) theranostic pair in patients with lymphoma at myeloablative dose levels

PURPOSE: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin\u27s lymphoma using the theranostic pair of 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 \u3e 75,000/mm 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 CONCLUSIONS: Patient-specific outpatien

Initial Experience with Tositumomab and I-131-Labeled Tositumomab for Treatment of Relapsed/Refractory Hodgkin Lymphoma.

PurposeTo determine the maximum tolerated dose (MTD) of [131I]tositumomab in patients with refractory/recurrent Hodgkin lymphoma (HL) and to preliminarily determine if [131I]tositumomab has activity against HL and if positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]DG) performed 6 weeks post-therapy predicted 12-week response.ProceduresSeparate dose-finding studies were performed for patients with and without prior transplant. A single therapeutic total body radiation dose (TBD) of [131I]tositumomab was administered. TBD was escalated/de-escalated based on dose-limiting hematologic toxicity (DLT) using a modified continual reassessment method. [18F]DG-PET/CT scans were performed at baseline and 6 and 12 weeks post therapy.ResultsTwelve patients (nine classical HL, three lymphocyte-predominant [LP] HL) completed two dosing levels (n = 3 each) in the post-transplant (55 cGy, 79 cGy) and no transplant (75 cGy, 87 cGy) groups. Hematologic toxicities were common and transient. Twelve weeks after [131I]tositumomab, 10 patients progressed and two with LPHL achieved complete response. [18F]DG-PET/CT at 6 weeks post therapy appeared more predictive than CT at 6 weeks of a response at 12 weeks.ConclusionsTositumomab and [131I]tositumomab was well-tolerated in patients with relapsed/refractory HL. Complete responses in LPHL support a therapeutic effect in this subtype. Early metabolic response assessments by [18F]DG-PET in HL after radioimmunotherapy appear to be more predictive than purely anatomic assessments

Prospective SPECT-CT Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using the In-111 (111In)/Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Theranostic Pair in Patients with Lymphoma at Myeloablative Dose Levels

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

Comparison of organ residence time estimation methods for radioimmunotherapy dosimetry and treatment planning—patient studies

The estimation of organ residence time is essential for high-dose myeloablative regimens in radioimmunotherapy (RIT). Frequently, this estimation is based on a series of simple planar scans and planar processing. The authors previously performed a simulation study which demonstrated that the accuracy of this methodology is limited compared to a hybrid planar∕SPECT residence time estimation method. In this work the authors applied this hybrid method to data from a clinical trial of high-dose myeloablative yttrium-90 ibritumomab tiuxetan therapy. Image data acquired from 18 patients were comprised of planar scans at five time points ranging from 1 to 144 h postinjection and abdominal and thoracic SPECT∕CT scans obtained at 24 h postinjection. The simple planar processing method used in this work was based on the geometric mean method with energy window based scatter compensation. No explicit background subtraction nor object or source thickness corrections were performed. The SPECT projections were reconstructed using iterative reconstruction with compensations for attenuation, scatter, and full collimator-detector response. Large differences were observed when residence times were estimated using the simple planar method compared to the hybrid method. The differences were not constant but varied in magnitude and sign. For the dose-limiting organ (liver), the average difference was −18% and variation in the difference was 19%, similar to the differences observed in a previously reported simulation study. The authors also looked at the relationship between the weight of the patient and the liver residence time and found that there was no meaningful correlation for either method. This indicates that weight would not be an adequate proxy for an experimental estimate of residence time when choosing the activity to administer for therapy. The authors conclude that methods such as the simple planar method used here are inadequate for RIT treatment planning. More sophisticated methods, such as the hybrid SPECT∕planar method investigated here, are likely to be better predictors of organ dose and, as a result, organ toxicities