Introduction
The level of administered activity in radionuclide therapy is often limited by haematological toxicity resulting from the absorbed dose delivered to the bone marrow. The purpose of these ...EANM guidelines is to provide advice to scientists and clinicians on data acquisition and data analysis related to bone-marrow and whole-body dosimetry.
Materials and methods
The guidelines are divided into sections “Data acquisition” and “Data analysis”. The Data acquisition section provides advice on the measurements required for accurate dosimetry including blood samples, quantitative imaging and/or whole-body measurements with a single probe. Issues specific to given radiopharmaceuticals are considered. The Data analysis section provides advice on the calculation of absorbed doses to the whole body and the bone marrow. The total absorbed dose to the bone marrow consists of contributions from activity in the bone marrow itself (self-absorbed dose) and the cross-absorbed dose to the bone marrow from activity in bone, larger organs and the remainder of the body.
Conclusion
As radionuclide therapy enters an era where patient-specific dosimetry is used to guide treatments, accurate bone-marrow and whole-body dosimetry will become an essential element of treatment planning. We hope that these guidelines will provide a basis for the optimization and standardization of the treatment of cancer with radiopharmaceuticals, which will facilitate single- and multi-centre radionuclide therapy studies.
Radioimmunotherapy with 90-yttrium-ibritumomab tiuxetan (90Y-IT) as first-line treatment in patients with follicular lymphoma (FL) demonstrated promising results with a complete remission (CR) rate ...of 56% and a median progression-free survival (PFS) of 26 months, when initially analyzed after a median follow-up of 30.6 months. The aim of this long-term follow-up was to investigate whether clinical benefits were maintained and new safety signals appeared. Fifty-nine patients, aged ≥ 50 years, with FL grade 1 to 3A in stages II to IV were treated with 90Y-IT as first-line therapy. If CR without evidence of minimal residual disease (MRD), partial response or stable disease was achieved 6 months after treatment, patients were observed without further treatment. Patients with CR but persisting MRD received consolidation therapy with rituximab. The primary endpoint was the clinical response rate. Secondary endpoints were time to progression, safety, and tolerability. After a median follow-up of 9.6 years, median PFS was 3.6 years, and 8-year PFS was 38.3%. Median overall survival (OS) was not reached during the extended follow-up, and 8-year OS amounted to 69.2%. Age 65 years and above or disease progression within 24 months of treatment were significantly associated with shorter OS. An important finding was the lack of new safety signals. In particular, no increase in secondary malignancies or transformation into aggressive lymphoma was observed compared to trials with a similar follow-up. In summary, 90Y-IT as first-line treatment demonstrates a favorable safety profile and long-term clinical activity in a substantial fraction of FL patients in need of therapy. ClinicalTrials.gov Identifier: NCT00772655.
Thorium-227 (
Th) is a long-lived (T
= 18.7 d) α-emitter that has emerged as candidate for radioimmunotherapy. Imaging of patients treated with thorium-227 conjugates is challenging due to the low ...activity administered and to photon emissions with low yields. In addition, the radioactive daughter radium-223 (
Ra) have photon emissions in the same energy range as
Th. The long half-life of
Ra (T
= 11.4 d) and the possibility of redistribution motivates efforts to separate
Th and
Ra. The aim of this study was to investigate the feasibility of imaging of patients treated with
Th-labeled-monoclonal antibody (mAb) and to determine acquisition and image processing parameters to enable discrimination between
Th and
Ra. Imaging was performed with a GE Discovery 670 NM/CT γ-camera. Radionuclide separation with different energy windows (EW) and collimators was studied in images of vials with either
Th or
Ra. Phantom acquisitions with clinically relevant activities were performed to assess image quality and the usefulness of background subtraction and spatial filtering. Two patients treated with
Th-labeled-mAb were imaged. Imaging of vials showed that
Ra can be distinguished from
Th using multiple energy windows. Medium- and high-energy collimators showed similar performance of sensitivity and spatial resolution, whereas the low-energy collimator had higher sensitivity but poor resolution due to collimator penetration. Visually, the image quality was improved with background subtraction and spatial filtering. The patient images exhibited the expected image quality and a possibility to separate
Th and
Ra. γ-Camera imaging of patients treated with
Th-mAb is feasible and
Ra can be distinguished from
Th. Image quality is substantially improved using background subtraction and a spatial smoothing filter. Acquisition settings recommended for planar images are: high-energy general purpose or medium-energy general purpose collimator, 40 min acquisition time and energy windows: (1) 70-100 keV (
Th and
Ra); (2) 215-260 keV (
Th); (3) 260-290 keV (
Ra); (4) 350-420 keV (
Ra).
We report on a multicenter phase II trial of (90)yttrium-ibritumomab-tiuxetan ((90)YIT) as first-line stand-alone therapy for patients with follicular lymphoma (FL).
Fifty-nine patients with CD20(+) ...FL grade 1 to 3a in stages II, III, or IV, age 50 years old or older requiring therapy were enrolled. They received (90)YIT according to standard procedure. If complete response (CR) or unconfirmed complete response (CRu) without evidence for minimal residual disease (MRD) 6 months after application of (90)YIT was achieved, patients were observed without further intervention. The same applied to patients with partial response (PR) or with stable disease (SD). Patients with CR but with persisting MRD were to receive a consolidation treatment with rituximab. Primary end point was the clinical and molecular response rate. Secondary end points were time to progression, safety, and tolerability.
Six months after treatment with (90)YIT, 56% of the patients showed a CR or CRu and 31% achieved a PR. After a median follow-up of 30.6 months, the progression-free survival (PFS) was 26 months. There was a trend for shorter PFS in patients with increased lactate dehydrogenase (LDH). Of the 26 patients who had CR 12 months after (90)YIT, only three had relapsed. Median time to next treatment has not been reached. The most common toxicities were transient thrombocytopenia and leukocytopenia. Nonhematologic toxicities never exceeded grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE v2.0).
(90)YIT is well tolerated and achieves high response rates. Patients with increased LDH tend to relapse earlier, and individuals in remission 1 year after (90)YIT appear to have long- lasting responses.
The treatment of splenic marginal zone lymphoma is debated: splenectomy (the old standard‐of‐care) is better than chemotherapy but maybe not better than rituximab‐containing treatment. We examined ...all 358 patients diagnosed with splenic marginal zone lymphoma in Sweden 2000–2020. The median overall survival was 11.0 years. The median age was 73 years; 61% were women. Age was the only independently prognostic clinical characteristic. Eighty‐six patients were started on wait‐and‐watch, 90 rituximab monotherapy, 47 rituximab‐chemotherapy, 88 splenectomy, 37 chemotherapy, and 10 both systemic therapy and splenectomy. Overall survival was inferior in patients treated with chemotherapy, but equal in patients treated with rituximab, rituximab‐chemotherapy and splenectomy. Patients treated with both systemic therapy and splenectomy showed good outcome, suggesting that surgery can be safely reserved for nonresponders. After adjustment for age, survival did not differ between patients started on wait‐and‐watch and those treated with splenectomy or rituximab‐containing therapy. Over time, rituximab use and survival increased in patients ≥73 years. This is, to our knowledge, the largest population‐based study of splenic marginal zone lymphoma patients treated with upfront rituximab. We conclude that wait‐and‐watch remains the most reasonable option in asymptomatic splenic marginal zone lymphoma patients. Symptomatic patients should be offered single‐agent rituximab in first line.
Objective and methods
The aim of this study was to investigate the effect of season of diagnosis on the outcome of patients with diffuse large B‐cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). In ...this study, we included curatively treated DLBCL (n = 5875) and HL (n = 1693) patients, diagnosed between 2000 and 2011, based on data from the Swedish Lymphoma Register.
Results
Overall survival was significantly better for patients diagnosed with DLBCL during the summer months, but not for patients diagnosed with HL. The difference remained in a multivariable analysis adjusted for age, stage, performance status, number of extra nodal sites and year of diagnosis (HR 1.08; 95% CI 1.02–1.14, P = 0.0069). When analyzing the DLBCL patients according to gender in the multivariable model, the effect of season was shown to be restricted to male patients (HR = 1.09, 95% CI 1.01–1.17, P = 0.0269.
Conclusions
In summary, season of diagnosis was shown to have impact on overall survival in male patients with DLBCL. Possible explanations of our results are the higher vitamin D level during the summer months, the effects of sunlight on the circadian rhythm and the immune system, or the lower risk of infectious disease during the summer. Further investigations are needed to explore these hypotheses.
This feasibility study demonstrates (90)Y quantitative bremsstrahlung imaging of patients undergoing high-dose myeloablative (90)Y-ibritumomab treatment.
The study includes pretherapy (111)In ...SPECT/CT and planar whole-body (WB) imaging at 7 d and therapy (90)Y SPECT/CT at 6 d and (90)Y WB imaging at 1 d. Time-activity curves and organ-absorbed doses derived from (90)Y SPECT images were compared with pretherapy (111)In estimates. Organ activities derived from (90)Y WB images at the first day were compared with corresponding pretherapy estimates.
Pretherapy (111)In images from 3 patients were similar to the (90)Y images. Differences between absorbed-dose estimates from pretherapy (111)In and (90)Y therapy were within 25%, except for the lungs. Corresponding activity differences derived from WB images were within 25%. Differences were ascribed to incomplete compensation methods and real differences in pharmacokinetics between pretherapy and therapy.
Quantitative bremsstrahlung imaging to estimate organ activities and absorbed doses is feasible.
Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a ...useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line-based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitizes DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor FTI-277 or the geranylgeranyl transferase I inhibitor GGTI-298 indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.
T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown.
Using flow ...cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-α2a-rituximab combinations.
In univariate analysis, higher levels of CD3(+), CD4(+), and CD8(+) T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3(+) (P = 0.011) and blood-CD4(+) (P = 0.029) cells were independent. CD4(+) cells were favorable regardless of treatment arm, but CD8(+) cells were favorable only in patients treated with single rituximab, because IFN-α2a improved responses especially in patients with low CD8(+) cell levels. Higher levels of blood-CD3(+) (P = 0.003) and blood-CD4(+) (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8(+) cells longer times to next treatment (P = 0.046).
We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4(+) and CD8(+) cells are both favorable in patients treated with rituximab. IFN-α2a abrogates the negative impact of few CD8(+) cells.
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