Arne Kolstad | Theragnostic Imaging

Radioimmunotherapy of Non-Hodgkin B-cell Lymphoma: An update

Mon, 01 May 2023 00:00:00 +0000

Systemic radioimmunotherapy (RIT) is arguably the most effective and least toxic anticancer treatment for non-Hodgkin lymphoma (NHL). In treatment-naïve patients with indolent NHL, the efficacy of a single injection of RIT compares with that of multiple cycles of combination chemotherapy. However, 20 years following the approval of the first CD20-targeting radioimmunoconjugates ⁹⁰Y-Ibritumomab-tiuxetan (Zevalin) and ¹³¹I-tositumomab (Bexxar), the number of patients referred for RIT in western countries has dramatically decreased. Notwithstanding this, the development of RIT has continued. Therapeutic targets other than CD20 have been identified, new vector molecules have been produced allowing for faster delivery of RIT to the target, and innovative radionuclides with favorable physical characteristics such as alpha emitters have been more widely available. In this article, we reviewed the current status of RIT in NHL, with particular focus on recent clinical and preclinical developments.

FDG PET/CT and Dosimetric Studies of 177Lu-Lilotomab Satetraxetan in a First-in-Human Trial for Relapsed Indolent non-Hodgkin Lymphoma-Are We Hitting the Target?

Sat, 01 Oct 2022 00:00:00 +0000

[¹⁷⁷Lu]Lu-lilotomab satetraxetan, a novel CD37 directed radioimmunotherapy (RIT), has been investigated in a first-in-human phase 1/2a study for relapsed indolent non-Hodgkin lymphoma. In this study, new methods were assessed to calculate the mean absorbed dose to the total tumor volume, with the aim of establishing potential dose-response relationships based on 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) parameters and clinical response. Our second aim was to study if higher total tumor burden induces reduction in the ¹⁷⁷Lu-lilotomab satetraxetan accumulation in tumor. Fifteen patients with different pre-dosing (non-radioactive lilotomab) regimens were included and the cohort was divided into low and high non-radioactive lilotomab pre-dosing groups for some of the analyses. ¹⁷⁷Lu-lilotomab satetraxetan was administered at dosage levels of 10, 15, or 20 MBq/kg. Mean absorbed doses to the total tumor volume (tTAD) were calculated from posttreatment single-photon emission tomography (SPECT)/computed tomography (CT) acquisitions. Total values of metabolic tumor volume (tMTV), total lesion glycolysis (tTLG) and the percent change in these parameters were calculated from FDG PET/CT performed at baseline, and at 3 and 6 months after RIT. Clinical responses were evaluated at 6 months as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD). Significant decreases in tMTV and tTLG were observed at 3 months for patients receiving tTAD ≥ 200 cGy compared to patients receiving tTAD < 200 cGy (p = .03 for both). All non-responders had tTAD < 200 cGy. Large variations in tTAD were observed in responders. Reduction in ¹⁷⁷Lu-lilotomab satetraxetan uptake in tumor volume was not observed in patients with higher baseline tumor burden (tTMV). tTAD of ≥ 200 cGy may prove valuable to ensure clinical response, but further studies are needed to confirm this in a larger patient population. Furthermore, this work indicates that higher baseline tumor burden (up to 585 cm³) did not induce reduction in radioimmunoconjugate accumulation in tumor.

Myelosuppression in patients treated with 177Lutetium-lilotomab satetraxetan can be predicted with absorbed dose to the red marrow as the only variable

Mon, 01 Nov 2021 00:00:00 +0000

The aim of this study was to investigate dosimetry data and clinical variables to predict hematological toxicity in non-Hodgkin lymphoma (NHL) patients treated with [¹⁷⁷Lutetium]Lu-lilotomab satetraxetan. A total of 17 patients treated with [¹⁷⁷Lu]Lu-lilotomab satetraxetan in a first-in-human phase 1/2a study were included. Absorbed dose to the red marrow was explored using SPECT/CT-imaging of the lumbar vertebrae L2-L4 over multiple time points. Percentage reduction of thrombocytes and neutrophils at nadir compared to baseline (PBN) and time to nadir (TTN) were chosen as indicators of myelosuppression and included as dependent variables. Two models were applied in the analysis, a multivariate linear model and a sigmoidal description of toxicity as a function of absorbed dose. A total of 10 independent patient variables were investigated in the multivariate analysis. Absorbed dose to the red marrow ranged from 1 to 4 Gy. Absorbed dose to the red marrow was found to be the only significant variable for PBN for both thrombocytes and neutrophils. The sigmoid function gave similar results in terms of accuracy when compared to the linear model. Myelosuppression in the form of thrombocytopenia and neutropenia in patients treated with [¹⁷⁷Lu]Lu-lilotomab satetraxetan can be predicted from the SPECT/CT-derived absorbed dose estimate to the red marrow.

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Tue, 01 Jun 2021 00:00:00 +0000

¹⁷⁷Lu-lilotomab satetraxetan targets the CD37 antigen and has been investigated in a first-in-human phase 1/2a study for relapsed non-Hodgkin lymphoma (NHL). Tumor dosimetry and response evaluation can be challenging after radioimmunotherapy (RIT). Changes in FDG PET/CT parameters after RIT and correlations with tumor-absorbed doses has not been examined previously in patients with lymphoma. Treatment-induced changes were measured at FDG PET/CT and ceCT to evaluate response at the lesion level after treatment, and correlations with tumor-absorbed doses were investigated. Forty-five tumors in 16 patients, with different pre-treatment and pre-dosing regimens, were included. Dosimetry was performed based on multiple SPECT/CT images. FDG PET/CT was performed at baseline and at 3 and 6 months. SUV_max, MTV, TLG, and changes in these parameters were calculated for each tumor. Lesion response was evaluated at 3 and 6 months (PET_3months and PET_6months) based on Deauville criteria. Anatomical changes based on ceCT at baseline and at 6 and 12 months were investigated by the sum of perpendiculars (SPD). Tumor-absorbed doses ranged from 35 to 859 cGy. Intra- and interpatient variations were observed. Mean decreases in PET parameters from baseline to 3 months were ΔSUV_max-3months 61%, ΔMTV_3months 80%, and ΔTLG_3months 77%. There was no overall correlation between tumor-absorbed dose and change in FDG PET or ceCT parameters at the lesion level or significant difference in tumor-absorbed doses between metabolic responders and non-responders after treatment. Our analysis does not show any correlation between tumor-absorbed doses and changes in FDG PET or ceCT parameters for the included lesions. The combination regimen, including cold antibodies, may be one of the factors precluding such a correlation. Increased intra-patient response with increased tumor-absorbed doses was observed for most patients, implying individual variations in radiation sensitivity or biology. ClinicalTrials.gov Identifier (NCT01796171). Registered December 2012.

Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

Tue, 08 Sep 2020 00:00:00 +0000

For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20-based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the "cold" anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

Pre-dosing with lilotomab prior to therapy with 177Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients

Sun, 01 Jul 2018 00:00:00 +0000

¹⁷⁷Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses. Two of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m² BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq ¹⁷⁷Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student’s t tests were used for all statistical analyses. Organs with distinct uptake of ¹⁷⁷Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1-4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p = 0.04) and arm 4 (p = 0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p < 0.01). Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1-4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p = 0.05 and p = 0.02). No statistically significant difference between arms 1 and 4 was found. RM is the primary dose-limiting organ for ¹⁷⁷Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m² was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab.

Biodistribution and Dosimetry Results from a Phase 1 Trial of Therapy with the Antibody-Radionuclide Conjugate 177Lu-Lilotomab Satetraxetan

Sun, 01 Apr 2018 00:00:00 +0000

¹⁷⁷Lu-lilotomab satetraxetan is a novel antibody-radionuclide conjugate currently in a phase 1/2a first-in-humans dose escalation trial for patients with relapsed CD37-positive indolent non-Hodgkin lymphoma. The aim of this study was to investigate biodistribution and absorbed doses to organs at risk.

Methods: In total, 7 patients treated with ¹⁷⁷Lu-lilotomab satetraxetan were included for dosimetry. Patients were grouped on the basis of 2 different predosing regimens (with and without predosing with 40 mg of lilotomab) and were treated with different levels of activity per body weight (10, 15, and 20 MBq/kg). All patients were pretreated with rituximab. Serial planar and SPECT/CT images were used to determine time-activity curves and patient-specific masses for organs with ¹⁷⁷Lu-lilotomab satetraxetan uptake. Doses were calculated with OLINDA/EXM.

Results: The organs (other than red bone marrow and tumors) with distinct uptake of ¹⁷⁷Lu-lilotomab satetraxetan were the liver, spleen, and kidneys. The highest uptake was found in the spleen, with doses ranging from 1.54 to 3.60 mGy/MBq. The liver received 0.70-1.15 mGy/MBq. The kidneys received the lowest dose of the source organs investigated, 0.16-0.79 mGy/MBq. No statistically significant differences in soft-tissue absorbed doses were found between the two predosing regimens. The whole-body dose ranged from 0.08 to 0.17 mGy/MBq.

Conclusion: The biodistribution study for patients treated with ¹⁷⁷Lu-lilotomab satetraxetan revealed the highest physiologic uptake to be in the liver and spleen (besides the red marrow). For all treatment levels investigated, the absorbed doses were found to be modest when compared with commonly assumed tolerance limits.

Red Marrow-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with 177Lu-Lilotomab Satetraxetan, a Novel Anti-CD37 Antibody-Radionuclide Conjugate

Sun, 01 Jan 2017 00:00:00 +0000

Red marrow (RM) is often the primary organ at risk in radioimmunotherapy; irradiation of marrow may induce short- and long-term hematologic toxicity. ¹⁷⁷Lu-lilotomab satetraxetan is a novel anti-CD37 antibody-radionuclide conjugate currently in phase 1/2a. Two predosing regimens have been investigated, one with 40 mg of unlabeled lilotomab antibody (arm 1) and one without (arm 2). The aim of this work was to compare RM-absorbed doses for the two arms and to correlate absorbed doses with hematologic toxicity. Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin lymphoma were included for RM dosimetry. Hybrid SPECT and CT images were used to estimate the activity concentration in the RM of L2-L4. Pharmacokinetic parameters were calculated after measurement of the ¹⁷⁷Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The mean absorbed doses to RM were 0.9 mGy/MBq for arm 1 (lilotomab+) and 1.5 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arms 1 and 2 (Student t test, P = 0.02). Total RM-absorbed doses ranged from 67 to 127 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve was higher with lilotomab predosing than without (P = 0.001), whereas the volume of distribution and the clearance of ¹⁷⁷Lu-lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging-based, method underestimated the RM dose and did not show any correlation with toxicity. Predosing with lilotomab reduces the RM-absorbed dose for ¹⁷⁷Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematologic toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images.

Tumor-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with the Anti-CD37 Antibody Radionuclide Conjugate 177Lu-Lilotomab Satetraxetan

Sun, 01 Jan 2017 00:00:00 +0000

¹⁷⁷Lu-lilotomab satetraxetan is a novel antibody radionuclide conjugate currently tested in a phase 1/2a first-in-human dosage escalation trial for patients with relapsed CD37+ indolent non-Hodgkin lymphoma. The aim of this work was to develop dosimetric methods and calculate tumor-absorbed radiation doses for patients treated with ¹⁷⁷Lu-lilotomab satetraxetan. Patients were treated at escalating injected activities (10, 15 and 20 MBq/kg) of ¹⁷⁷Lu-lilotomab satetraxetan and with different predosing, with or without 40 mg of unlabeled lilotomab. Eight patients were included for the tumor dosimetry study. Tumor radioactivity concentrations were calculated from SPECT acquisitions at multiple time points, and tumor masses were delineated from corresponding CT scans. Tumor-absorbed doses were then calculated using the OLINDA sphere model. To perform voxel dosimetry, the SPECT/CT data and an in-house-developed MATLAB program were combined to investigate the dose rate homogeneity. Twenty-six tumors in 8 patients were ascribed a mean tumor-absorbed dose. Absorbed doses ranged from 75 to 794 cGy, with a median of 264 cGy across different dosage levels and different predosing. A significant correlation between the dosage level and tumor-absorbed dose was found. Twenty-one tumors were included for voxel dosimetry and parameters describing dose-volume coverage calculated. The investigation of intratumor voxel doses indicates that mean tumor dose is correlated to these parameters. Tumor-absorbed doses for patients treated with ¹⁷⁷Lu-lilotomab satetraxetan are comparable to doses reported for other radioimmunotherapy compounds. Although the intertumor variability was considerable, a correlation between tumor dose and patient dosage level was found. Our results indicate that mean dose may be used as the sole dosimetric parameter on the lesion level.