Fractionated radioimmunotherapy targeting CD22 may substantially improve responses and outcome in non-Hodgkin's lymphoma (NHL).
A multicenter trial evaluated two or three weekly infusions of yttrium-90 ((90)Y) epratuzumab tetraxetan (humanized anti-CD22 antibody) in 64 patients with relapsed/refractory NHL, including 17 patients who underwent prior autologous stem-cell transplantation (ASCT). Objective (OR) and complete responses (CR/complete response unconfirmed [CRu]), as well as progression-free survival (PFS), were determined.
At the maximum total (90)Y dose of 45 mCi/m(2) (1,665 MBq/m(2)), grade 3 to 4 hematologic toxicities were reversible to grade 1 in patients with less than 25% bone marrow involvement. The overall OR rate and median PFS for all 61 evaluable patients was 62% (CR/CRu, 48%) and 9.5 months, respectively. Patients without prior ASCT obtained high OR rates of 71% (CR/CRu, 55%) across all NHL subtypes and (90)Y doses, even in poor-risk categories (refractory to last anti-CD20-containing regimen, 73% [CR/CRu, 60%]; bulky disease: 71% [CR/CRu, 43%]). Patients with prior ASCT received lower doses, but achieved an OR rate of 41% (CR/CRu, 29%). For patients with follicular lymphoma (FL), OR rates and median PFS increased with total (90)Y-dose, reaching 100% (CR/CRu, 92%) and 24.6 months, respectively, at the highest dose levels (> 30 mCi/m(2) total (90)Y-dose [1,110 MBq/m(2)]). Further, patients with FL refractory to prior anti-CD20-containing regimens achieved 90% (nine of 10 patients) OR and CR/CRu rates and a median PFS of 21.5 months.
Fractionated anti-CD22 radioimmunotherapy provides high total doses of (90)Y, yielding high rates of durable CR/CRus in relapsed/refractory NHL, resulting in 20 mCi/m(2) x 2 weeks as the recommended dose for future studies.
"In a preliminary study, we had demonstrated that an injected activity of 3.7 MBq [213Bi]-anti-mCD138 efficiently eradicates tumor cells in mice engrafted with MM . This study showed that 60% of the animals treated with an injected activity of 3.7 MBq were still alive at 300 days with a bone marrow irradiation that can be monitored . From the results obtained in the previous study we wanted to compare alpha-RIT to standard MM treatment based on Melphalan and to evaluate the efficacy of a treatment combining alpha-RIT and this drug. "
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a MM model. In order to define where alpha-RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha-RIT using a [213Bi]-anti-mCD138 antibody in a syngeneic MM mouse model.
C57BL/KaLwRij mice were grafted with 1×10(6) 5T33 murine MM cells. Luciferase transfected 5T33 cells were used for in vivo localization. The first step of the study was to assess the dose-response of Melphalan 21days after engraftment. The second step consisted in therapeutic combination: Melphalan followed by RIT at day 22 or day 25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone, RIT alone at day 22 or day 25 (3.7MBq of [213Bi]-anti-CD138) and Melphalan combined with alpha-RIT.
Fifty percent of untreated mice died by day 63 after MM engraftment. In mice treated with Melphalan alone, only the 200μg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at day 22 after tumor engraftment with only slight and reversible hematological radiotoxicity. No therapeutic effect was observed with alpha-RIT 25days after engraftment. Melphalan and alpha-RIT combination does not improve overall survival compared to RIT alone, and results in increased leukocyte and red blood cell toxicity.
Alpha-RIT seems to be a good alternative to Melphalan. Association of these two treatments provides no benefit. The perspectives of this work would be to evaluate RIT impact on the regimens incorporating the novel agents bortezomide, thalidomide and lenalidomide.
Nuclear Medicine and Biology 05/2014; 41S:e30-e35. DOI:10.1016/j.nucmedbio.2014.02.008 · 2.41 Impact Factor
"Yttrium-90 (half-life, 64 h) is a radionuclide used in targeted radionuclide therapy, particularly for radioimmunotherapy (RAIT), peptide receptor radionuclide therapy (PRRT), and selective internal radiotherapy (SIRT). Promising clinical results have been obtained for the treatment of B-cell lymphomas with anti-CD20 and anti-CD22 monoclonal antibodies [1,2], while the treatment of neuroendocrine tumors with somatostatin analogues has proven its benefit in the last decade [3,4]. One RAIT product labeled with 90Y has been already approved by the regulatory authorities (Zevalin®, Bayer Corporation, Pittsburgh, USA). "
[Show abstract][Hide abstract] ABSTRACT: Despite the early theoretical prediction of the 0+-0+ transition of 90Zr, 90Y-PET underwent only recently a growing interest for the development of imaging radioembolization of liver tumors. The aim of this work was to determine the minimum detectable activity (MDA) of 90Y by PET imaging and the impact of time-of-flight (TOF) reconstruction on detectability and quantitative accuracy according to the lesion size.
The study was conducted using a Siemens Biograph® mCT with a 22 cm large axial field of view. An IEC torso-shaped phantom containing five coplanar spheres was uniformly filled to achieve sphere-to-background ratios of 40:1. The phantom was imaged nine times in 14 days over 30 min. Sinograms were reconstructed with and without TOF information. A contrast-to-noise ratio (CNR) index was calculated using the Rose criterion, taking partial volume effects into account. The impact of reconstruction parameters on quantification accuracy, detectability, and spatial localization of the signal was investigated. Finally, six patients with hepatocellular carcinoma and four patients included in different 90Y-based radioimmunotherapy protocols were enrolled for the evaluation of the imaging parameters in a clinical situation.
The highest CNR was achieved with one iteration for both TOF and non-TOF reconstructions. The MDA, however, was found to be lower with TOF than with non-TOF reconstruction. There was no gain by adding TOF information in terms of CNR for concentrations higher than 2 to 3 MBq mL−1, except for infra-centimetric lesions. Recovered activity was highly underestimated when a single iteration or non-TOF reconstruction was used (10% to 150% less depending on the lesion size). The MDA was estimated at 1 MBq mL−1 for a TOF reconstruction and infra-centimetric lesions. Images from patients treated with microspheres were clinically relevant, unlike those of patients who received systemic injections of 90Y.
Only one iteration and TOF were necessary to achieve an MDA around 1 MBq mL−1 and the most accurate localization of lesions. For precise quantification, at least three iterations gave the best performance, using TOF reconstruction and keeping an MDA of roughly 1 MBq mL−1. One and three iterations were mandatory to prevent false positive results for quantitative analysis of clinical data.
http://IDRCB 2011-A00043-38 P101103
EJNMMI Research 02/2013; 3(1):11. DOI:10.1186/2191-219X-3-11
"The activity of Zevalin in conjunction with rituximab in paediatric B-NHL was investigated in a phase I COG trial with no identified dose limiting toxicity, warranting further investigation (Cooney-Qualter et al, 2007). The radioisotopeconjugated form of epratuzumab, 90 Y-epratuzumab, has also been evaluated in a phase I/II trial that resulted in a high percentage of durable responses (Morschhauser et al, 2010). "
[Show abstract][Hide abstract] ABSTRACT: Leukaemia is the single most common childhood malignancy. With modern treatment regimens, survival in acute lymphoblastic leukaemia (ALL) approaches 90%. Only about 70% of children with acute myeloid leukaemia (AML) achieve long term survival. Patients who relapse have a dismal prognosis. Novel therapeutic approaches are needed to improve treatment outcomes in newly-diagnosed patients with a poor prognosis and for patients with relapsed/refractory disease that have limited treatment options. One promising approach in treating haematological malignancies has been the use of monoclonal antibodies to target cell surface antigens expressed on malignant cells. Most success with monoclonal antibody therapy in the treatment of haematological malignancies has come in the setting of adult B-cell non-Hodgkin lymphoma with the addition of the anti-CD20 monoclonal antibody rituximab to standard treatment regimens. In order to further advance treatment of haematological malignancies, novel monoclonal antibodies continue to be developed that target a variety of cell surface antigens. Several antibodies continue to be investigated in childhood leukaemias. This review will discuss the development of monoclonal antibodies that target a variety of cell surface antigens for the treatment of childhood ALL and the use of the anti-CD33 antibody gemtuzumab ozogamicin in the treatment of childhood AML.
British Journal of Haematology 08/2012; 159(1):3-17. DOI:10.1111/bjh.12002 · 4.71 Impact Factor
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