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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.
Smeland E, Funderud S, Ruud E, Kiil Blomhoff H, Godal T. Characterization of two murine monoclonal antibodies reactive with human B cells. Their use in a high-yield, high-purity method for isolation of B cells and utilization of such cells in an assay for B-cell stimulating factor. Scand J Immunol. 1985;21:205–14. CrossRefPubMed
Press OW, Howell-Clark J, Anderson S, Bernstein I. Retention of B-cell-specific monoclonal antibodies by human lymphoma cells. Blood. 1994;83:1390–7. PubMed
Moldenhauer G. Cd37. J Biol Regul Homeost Agents. 2000;14:281–3. PubMed
Dahle J, Repetto-Llamazares AH, Mollatt CS, Melhus KB, Bruland OS, Kolstad A, et al. Evaluating antigen targeting and anti-tumor activity of a new anti-CD37 radioimmunoconjugate against non-Hodgkin's lymphoma. Anticancer Res. 2013;33:85–95. PubMed
Blakkisrud J, Londalen A, Dahle J, Turner S, Holte H, Kolstad A, et al. Red marrow-absorbed dose for non-Hodgkin lymphoma patients treated with 177Lu-lilotomab satetraxetan, a novel anti-CD37 antibody-radionuclide conjugate. J Nucl Med. 2017;58:55–61. https://doi.org/10.2967/jnumed.116.180471. CrossRefPubMed
Blakkisrud J, Londalen A, Martinsen AC, Dahle J, Holtedahl JE, Bach-Gansmo T, et al. Tumor-absorbed dose for non-Hodgkin lymphoma patients treated with the anti-CD37 antibody radionuclide conjugate 177Lu-lilotomab satetraxetan. J Nucl Med. 2017;58:48–54. https://doi.org/10.2967/jnumed.116.173922. CrossRefPubMed
Blakkisrud J, Holtedahl JE, Londalen A, Dahle J, Bach-Gansmo T, Holte H, et al. Biodistribution and dosimetry results from a phase 1 trial of 177Lu-lilotomab satetraxetan antibody-radionuclide conjugate therapy. J Nucl Med. 2017; https://doi.org/10.2967/jnumed.117.195347.
Sgouros G. Bone marrow dosimetry for radioimmunotherapy: theoretical considerations. J Nucl Med. 1993;34:689–94. PubMed
Kulkarni HR, Prasad V, Schuchardt C, Baum RP. Is there a correlation between peptide receptor radionuclide therapy-associated hematological toxicity and spleen dose? Recent Results Cancer Res. 2013;194:561–6. https://doi.org/10.1007/978-3-642-27994-2_33. CrossRefPubMed
Wahl RL. Tositumomab and (131)I therapy in non-Hodgkin's lymphoma. J Nucl Med. 2005;46(Suppl 1):128S–40S. PubMed
Goldsmith SJ. Radioimmunotherapy of lymphoma: Bexxar and Zevalin. Semin Nucl Med. 2010;40:122–35. https://doi.org/10.1053/j.semnuclmed.2009.11.002. CrossRefPubMed
Kolstad A, Madsbu U, Stokke C, Blakkisrud J, Londalen AM, Dahle J, et al. A higher amount of Lilotomab pre-dosing increases the activity-adjusted Auc and has a protective effect against myelosuppression of lutetium ( 177Lu)-lilotomab satetraxetan in indolent NHL patients. Haematologica. 2017;102:468–9.
Wittrup KD, Thurber GM, Schmidt MM, Rhoden JJ. Practical theoretic guidance for the design of tumor-targeting agents. Methods Enzymol. 2012;503:255–68. https://doi.org/10.1016/B978-0-12-396962-0.00010-0. CrossRefPubMedPubMedCentral
Repetto-Llamazares AH, Larsen RH, Patzke S, Fleten KG, Didierlaurent D, Pichard A, et al. Targeted cancer therapy with a novel anti-CD37 Beta-particle emitting radioimmunoconjugate for treatment of non-Hodgkin lymphoma. PLoS One. 2015;10:e0128816. https://doi.org/10.1371/journal.pone.0128816. CrossRefPubMedPubMedCentral
Press OW, Eary JF, Badger CC, Martin PJ, Appelbaum FR, Levy R, et al. Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody. J Clin Oncol. 1989;7:1027–38. https://doi.org/10.1200/JCO.1922.214.171.1247. CrossRefPubMed
- 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
Anne C. T. Martinsen
- Springer Berlin Heidelberg
European Journal of Nuclear Medicine and Molecular Imaging
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089