Splenic marginal zone lymphoma in Sweden 2000-2020: Increasing rituximab use and better survival in the elderly.

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.

90-yttrium-ibritumomab tiuxetan as first-line treatment for follicular lymphoma: updated efficacy and safety results at an extended median follow-up of 9.6 years.

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.

227Th-Labeled Anti-CD22 Antibody (BAY 1862864) in Relapsed/Refractory CD22-Positive Non-Hodgkin Lymphoma: A First-in-Human, Phase I Study.

Background: BAY 1862864 is an α-particle emitting 227Th-labeled CD22-targeting antibody. This first-in-human dose-escalation phase I study evaluated BAY 1862864 in patients with CD22-positive relapsed/refractory B cell non-Hodgkin lymphoma (R/R-NHL). Materials and Methods: BAY 1862864 intravenous injections were administered at the starting 227Th radioactivity dose of 1.5 MBq (2 or 10 mg antibody), and the radioactivity dose escalated in ∼1.5 MBq increments (10 mg antibody) until the maximum tolerated dose (MTD) was reported. The primary objective was to determine the safety, tolerability, and MTD. Results: Twenty-one patients received BAY 1862864. Two dose-limiting toxicities (grade 3 febrile neutropenia and grade 4 thrombocytopenia) were reported in one patient in the 4.6 MBq (10 mg antibody) cohort. The MTD was not reached. Ten (48%) patients reported grade ≥3 treatment-emergent adverse events, with the most common being neutropenia, thrombocytopenia, and leukopenia, each occurring in 3 (14%) patients. Pharmacokinetics demonstrated the dose proportionality and stability of BAY 1862864 in the blood. The objective response rate (ORR) was 25% (5/21 patients) according to the LUGANO 2014 criteria, including 1 complete and 4 partial responses. The ORR was 11% (1/9) and 30% (3/10) in patients with relapsed high- and low-grade lymphomas, respectively. Conclusions: BAY 1862864 was safe and tolerated in patients with R/R-NHL. Clinical Trial Registration numbers: NCT02581878 and EudraCT 2014-004140-36.

Feasibility of Thorium-227/Radium-223 Gamma-Camera Imaging During Radionuclide Therapy.

Thorium-227 (227Th) is a long-lived (T1/2 = 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 (223Ra) have photon emissions in the same energy range as 227Th. The long half-life of 223Ra (T1/2 = 11.4 d) and the possibility of redistribution motivates efforts to separate 227Th and 223Ra. The aim of this study was to investigate the feasibility of imaging of patients treated with 227Th-labeled-monoclonal antibody (mAb) and to determine acquisition and image processing parameters to enable discrimination between 227Th and 223Ra. 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 227Th or 223Ra. 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 227Th-labeled-mAb were imaged. Imaging of vials showed that 223Ra can be distinguished from 227Th 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 227Th and 223Ra. γ-Camera imaging of patients treated with 227Th-mAb is feasible and 223Ra can be distinguished from 227Th. 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 (227Th and 223Ra); (2) 215-260 keV (227Th); (3) 260-290 keV (223Ra); (4) 350-420 keV (223Ra).

Targeted Alpha Therapy, an Emerging Class of Cancer Agents: A Review.

Importance: Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types. Observations: Theoretically, the high-energy emission of short-range alpha particles causes complex double-stranded DNA breaks, eliciting cell death. No known resistance mechanism to alpha particles has been reported or scientifically established. The short-range emission of alpha particle radiation confines its cytotoxic effect to cancerous lesions and the surrounding tumor microenvironment while limiting toxic effects to noncancerous tissues. The high level of radiobiological effectiveness of alpha particles, in comparison with beta emissions, requires fewer particle tracks to induce cell death. Clinically effective alpha particle-emitting isotopes for cancer therapy should have a short half-life, which will limit long-term radiation exposure and allow for the production, preparation, and administration of these isotopes for clinical use and application. Radium 223 dichloride is the first-in-class, commercially available targeted alpha therapy approved for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases. Given the established overall survival benefit conferred by radium 223 for patients with metastatic castration-resistant prostate cancer, several other targeted alpha therapies are being investigated in clinical trials across many tumor types. Conclusions and Relevance: Targeted alpha therapy represents an emerging treatment approach and provides for the possibility to bypass mechanisms of acquired resistance in selected tumors. In addition, developing novel radionuclide conjugation strategies may overcome targeting limitations. So far, the clinical success of radium 223 has demonstrated the proof of concept for targeted alpha therapy, and future studies may lead to additional treatment options for many cancer types.

Season of diagnosis is associated with overall survival in patients with diffuse large B-cell lymphoma but not with Hodgkin's lymphoma - A population-based Swedish Lymphoma Register study.

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.

Long-term remission in idiopathic Castleman's disease with tocilizumab followed by consolidation with high-dose melphalan--two case studies.

Multicentric Castleman's disease (MCD) is an uncommon lymphoproliferative disorder, often associated with a clinically aggressive behavior. No standard treatment has been established, but patients are usually treated with lymphoma-type regimens such as rituximab or combination chemotherapy. Recently, immunotherapies targeting IL-6 have proven effective and have been approved for this indication. However, these agents require long-term administration. Here, we describe the clinical course of two patients, refractory to rituximab and chemotherapy, showing long-term remission (18 and 24 months), following an induction phase with tocilizumab (an anti-IL-6 receptor antibody) and a consolidative phase with high-dose melphalan accompanied by autologous stem cell support. This may prove to be an effective option for this group of patients with an orphan disorder.

Case-report: EBV driven lymphoproliferative disorder associated with Ruxolitinib.

BACKGROUND: Ruxolitinib, a novel inhibitor of Janus kinases 1 and 2, was recently approved for the treatment of myelofibrosis but, recently, attention has been drawn to potential side effects and especially opportunistic infections and virus reactivations. EBV reactivation has not previously been reported to occur in association with Ruxolitinib. CASE PRESENTATION: We report a case of a 57 year old female with post-polycythemic myelofibrosis who was treated with Ruxolitinib. Approximately 9 weeks later she presented with a rapidly fatal, suspected EBV driven lymphoproliferative disorder in the CNS. CONCLUSIONS: Our report further underlines that patients treated with Ruxolitinib should be monitored closely for reactivations of opportunistic pathogens and viral infections.

Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas.

Patients with advanced CD20 + indolent lymphoma, requiring therapy, were randomized to rituximab (four weekly infusions of 375 mg/m(2)) or to rituximab combined with 5 weeks of interferon-α2a (IFN-α2a) (3-4.5 MIU daily) as priming. Responding patients were eligible for a second cycle with the same allocated treatment. In total, 156 patients were randomized to rituximab and 157 to rituximab + IFN-α2a. In the intention-to treat (ITT) population, 244 patients (78%) responded to cycle 1. After a second cycle the complete remission/complete remission unconfirmed (CR/CRu) rate was 41% with the combination versus 24% with monotherapy (p = 0.005). The median time to treatment failure (primary endpoint) in ITT patients was 28 vs. 21.5 months, respectively (p = 0.302). After a long median follow-up (61 months), 33% (42% of patients responding to cycle 1) were still failure-free with an overall survival rate of 88% and with no difference between the treatment groups. The trial was registered at ClinicalTrials.gov Identifier: NCT01609010.

(90)Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial.

PURPOSE: 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). PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: (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.

T cells in tumors and blood predict outcome in follicular lymphoma treated with rituximab.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.

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.

90Y Bremsstrahlung imaging for absorbed-dose assessment in high-dose radioimmunotherapy.

UNLABELLED: This feasibility study demonstrates (90)Y quantitative bremsstrahlung imaging of patients undergoing high-dose myeloablative (90)Y-ibritumomab treatment. METHODS: 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. RESULTS: 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. CONCLUSION: Quantitative bremsstrahlung imaging to estimate organ activities and absorbed doses is feasible.

Diversity in antibody-based approaches to non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) remains one of the most common cancers in the US, with survival dependent on the type and stage of disease. B-cell lymphomas account for approximately 85% of all cases of NHL, and are commonly treated with chemotherapy, or monoclonal antibodies (mAbs) that target CD20 antigens on the surface of malignant tumors. The use of mAbs, either as single agents or in combination with chemotherapy, has made a huge impact on NHL survival rates. Rituximab remains the most commonly used and established mAb, and is used in a wide range of NHLs, but does not produce an effective therapeutic response in all patients. Novel therapeutics with enhanced binding affinity or alternative antigen targets are currently in development and in some cases have demonstrated improved efficacy over currently available treatments. Radioimmunotherapy has been included in transplant conditioning regimens to improve long-term disease control while limiting toxicity. These regimens have been safe, effective, and feasible, and are therefore promising for patients who cannot tolerate high-dose chemotherapy and/or total body irradiation.

EANM Dosimetry Committee guidelines for bone marrow and whole-body dosimetry.

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.

Development and evaluation of a pharmacokinetic model for prediction of radioimmunotherapy based on pretherapy data.

The aim of this work was to develop a pharmacokinetic model for the analysis of the pharmacokinetics of (111)Inlabeled monoclonal antibodies (mAbs) in B-cell lymphoma patients and to evaluate the model's ability to predict a subsequent radioimmunotherapy by (90)Y-labeled mAbs. Data from quantified scintillation camera images and blood samples were used to fit a compartment model. The modeling included two steps: 1) a two-compartment model describing the total-body kinetics for the estimation of a set of global parameters and 2) a multicompartment model for estimating the model parameters for organs. In both steps, a correction for radiochemical impurity in the form of (111)In-DTPA (diethylene triamine pentaacetic acid) was included. The model was found to describe all patient data with good accuracy. From the model, the time-activity data of all organs could be separated into extravascular and vascular components, where the estimates of the regional vascular volumes were found to be in close agreement with literature data. A significant improvement of the model fit to total-body activity data was obtained by correcting for radiochemical impurity. The therapy kinetics area under the curves (AUCs) predicted from pretherapy data were in good agreement with the measured therapy AUCs. The good correlation between the model estimates and measured data, the accurate prediction of the therapy kinetics, and the good estimates of regional vascular volumes demonstrates the reliability of the model. These findings also indicate that the model can be useful for individual optimization of the amount of activity to be administered with respect to patient dosimetry.

Chemorefractory rhabdomyosarcoma treated with radiotherapy, bevacizumab, statins and surgery and maintenance with bevacizumab and chemotherapy.

BACKGROUND: Rhabdomyosarcoma is a rare disease in children and young adults, usually responsive to chemotherapy. Here we report on a patient with chemorefractory disease, treated in an unconventional approach. CASE REPORT: A young woman presented with an embryonal rhabdomyosarcoma of the retromaxillary space. She exhibited progressive disease to two chemotherapy regimens. The patient started hyperfractionated radiotherapy that due to lack of response was changed to 3 Gy fractions once daily to a total absorbed dose of 53 Gy. The therapeutic predicament led us to add bevacizumab and hydroxymethylglutaryl-CoA reductase inhibitors (statins), for which some experimental support could be found. RESULTS: The tumour responded clearly, and a radical R0 resection followed. The patient was treated postoperatively with bevacizumab and chemotherapy. The combined treatment was accompanied by side effects such as mucositis grade IV, impaired healing of the mandibulotomy as well as a prominent cystitis. Side effects subsided following treatment with hyperbaric oxygen. CONCLUSION: Rhabdomyosarcoma refractory to chemotherapy may respond to radiotherapy and the addition of bevacizumab and statins. Although the contribution of the adjuncts is unclear, the unexpected tumour control in this case may help in decision-making in similar cases and may encourage the investigation of these adjuncts in protocols.

Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: a randomized phase II study from the Nordic Lymphoma Group.

The purpose of this phase II randomized trial was to evaluate the effect and safety of interferon-alpha2a (IFN) in combination with extended dosing rituximab in patients with symptomatic, advanced indolent lymphoma responding to a standard single course of rituximab. Totally 123 patients were treated with rituximab 375 mg/m2 once weekly for 4 weeks leading to 14 complete response (CR; 11%), 56 partial response (PR; 46%), and 13 minor responses (MR; 11%). Patients achieving either PR or MR were randomized to four more infusions of rituximab alone (n = 36) or in combination with five weeks of IFN (n = 33), with an overall response rate (CR + PR) of 78% and 94%, respectively. Significantly more patients in the combination arm improved their response from PR/MR to CR (P < 0.05) and more maintained their responses for > or = 24 months (72% versus 50%), respectively. Overall, 26 out of the 52 patients who achieved CR underwent minimal residual disease (MRD) evaluation. Totally 17 of these (65%) achieved MRD negativity, 14 of whom remain in CR after 4.8 years' follow-up. The addition of IFN to rituximab was generally safe, but reversible thrombocytopenia and neutropenia were noted in one and six patients, respectively, requiring a reduction in the IFN dose. Extended rituximab is effective and well tolerated and combination with IFN seems to improve both the quality and duration of the responses, providing the opportunity to achieve long-term molecular CRs and prolonged failure-free survival without chemotherapy.

Parametric images of antibody pharmacokinetics based on serial quantitative whole-body imaging and blood sampling.

UNLABELLED: We present a method for pharmacokinetic modeling of distributions of (111)In-labeled monoclonal antibodies (mAbs) on individual pixels of planar scintillation-camera images. METHODS: The method is applied to 2 sets of clinical whole-body images, each consisting of 6 consecutive images acquired over a week. Quantification is performed on a pixel basis, yielding images in units of Bq/pixel. The images acquired on the different occasions are registered using a nonrigid method, and for each pixel location a time-activity curve is obtained for which kinetic modeling is performed. The (111)In-mAb is assumed to be located in either the vascular or the extravascular space. The vascular content is assumed to follow the global blood kinetics as determined from blood samples, together with a model parameter alpha that describes the fraction of the whole-body blood volume present in the particular pixel. The rate of change of the extravascular compartment is described by a linear 1-tissue-compartment model with 2 rate constants, K'1 and k2, reflecting extravasation and washout, respectively. The model is optimized for each pixel position with regard to the values of the 3 parameters (alpha, K'1, and k2), resulting in 3 parametric images. From these, images of the cumulated activity in vascular and extravascular spaces are calculated, as is an image of the rate-constants ratio, which is closely related to the volume of distribution. RESULTS: The resulting parametric images are analyzed in terms of the appearance of the time-activity curves at various locations. Results also include interpretation of the parametric images in their clinical context, and the location of regions that exhibit high extravasation and a low washout rate is compared with confirmed malignant sites. CONCLUSION: Parametric imaging allows the study and analysis of the spatial and temporal distributions of mAbs simultaneously. Parametric imaging enhances regions where the pharmacokinetics differ from the surrounding tissue and provides a tool to detect and locate unexpected kinetic behavior, which is sometimes characteristic of malignant tissue. For dosimetry in radionuclide therapy, parametric imaging offers a less biased means of analyzing serial mAb images than traditional region-of-interest-based analysis.