Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Baseline PET radiomics outperforms the IPI risk score for prediction of outcome in diffuse large B-cell lymphoma.

The objective of this study is to externally validate the clinical positron emission tomography (PET) model developed in the HOVON-84 trial and to compare the model performance of our clinical PET model using the international prognostic index (IPI). In total, 1195 patients with diffuse large B-cell lymphoma (DLBCL) were included in the study. Data of 887 patients from 6 studies were used as external validation data sets. The primary outcomes were 2-year progression-free survival (PFS) and 2-year time to progression (TTP). The metabolic tumor volume (MTV), maximum distance between the largest lesion and another lesion (Dmaxbulk), and peak standardized uptake value (SUVpeak) were extracted. The predictive values of the IPI and clinical PET model (MTV, Dmaxbulk, SUVpeak, performance status, and age) were tested. Model performance was assessed using the area under the curve (AUC), and diagnostic performance, using the positive predictive value (PPV). The IPI yielded an AUC of 0.62. The clinical PET model yielded a significantly higher AUC of 0.71 (P < .001). Patients with high-risk IPI had a 2-year PFS of 61.4% vs 51.9% for those with high-risk clinical PET, with an increase in PPV from 35.5% to 49.1%, respectively. A total of 66.4% of patients with high-risk IPI were free from progression or relapse vs 55.5% of patients with high-risk clinical PET scores, with an increased PPV from 33.7% to 44.6%, respectively. The clinical PET model remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI in all studies.

The frequency of change in five-point scale score with a Bayesian penalised likelihood PET reconstruction algorithm on interim FDG PET-CT and its potential implications for therapy decisions in Hodgkin's lymphoma.

AIM: To assess the effect of a Bayesian penalised likelihood (BPL) reconstruction algorithm on the five-point scale (5-PS) score, response categorisation, and potential implications for therapy decisions after interim 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-computed tomography (CT) (iPET-CT) to guide treatment in classical Hodgkin's lymphoma (HL). MATERIALS AND METHODS: The present study included new patients with HL undergoing iPET-CT from 2014-2019 after two cycles of doxorubicin (Adriamycin), bleomycin, vincristine, and dacarbazine (ABVD). Two reporters categorised response using the 5-PS and measured maximum standardised uptake values (SUVmax) of the most avid tumour residuum, mediastinal blood pool, and normal liver with ordered subset expected maximisation (OSEM) and BPL reconstructions. RESULTS: Eighty-one iPET-CT examinations were reviewed. Compared with OSEM, BPL increased the 5-PS score by a single score in 18/81 (22.2%) patients. The frequency of potential treatment intensification by changing a score of 3-4 was 13.6% (11/81) and represented 25% (11/44) of patients with a score of 3 on OSEM. All 11 patients remained in remission without a change in therapy (mean 63 months) except one who required second-line treatment for refractory disease. Median SUVmax of tumour residuum was significantly higher with BPL compared with OSEM (2.7 versus 2.4, p<<0.0001), whilst liver SUVmax was significantly lower for both reporters (up to 6.6%, p<0.0001). CONCLUSION: BPL PET reconstruction increased the 5-PS score on iPET-CT in 22% of HL patients and can potentially result in unnecessary treatment escalation in over half of these patients.

Cost-Effectiveness of Shortening Treatment Duration Based on Interim PET Outcome in Patients With Diffuse Large B-cell Lymphoma.

BACKGROUND: Guideline recommendations for diffuse large-B-cell lymphoma (DLBCL) treatment are shifting from long to short treatment duration, although it is still unclear whether shortening treatment duration does not cause any harm. As interim PET (I-PET) has high negative predictive value for progression, we evaluated the cost-effectiveness of shortening treatment duration dependent on I-PET result. MATERIALS AND METHODS: We developed a Markov cohort model using the PET Re-Analysis (PETRA) database to evaluate a long treatment duration (LTD) strategy, ie 8x R-CHOP or 6x R-CHOP plus 2 R, and a short treatment duration (STD) strategy, ie 6x R-CHOP. Strategies were evaluated separately in I-PET2 positive and I-PET2 negative patients. Outcomes included total costs and quality-adjusted life-years (QALYs) per patient (pp) from a societal perspective. Net monetary benefit (NMB) per strategy was calculated using a willingness-to-pay threshold of €50,000/QALY. Robustness of model predictions was assessed in sensitivity analyses. RESULTS: In I-PET2 positive patients, shortening treatment duration led to 50.4 additional deaths per 1000 patients. The STD strategy was less effective (-0.161 [95%CI: -0.343;0.028] QALYs pp) and less costly (-€2768 [95%CI: -€8420;€1105] pp). Shortening treatment duration was not cost-effective (incremental NMB -€5281). In I-PET2 negative patients, shortening treatment duration led to 5.0 additional deaths per 1000 patients and a minor difference in effectiveness (-0.007 [95%CI: -0.136;0.140] QALY pp). The STD strategy was less costly (-€5807 [95%CI: -€10,724;-€2685] pp) and led to an incremental NMB of €5449, indicating that it is cost-effective to shorten treatment duration. Robustness of these findings was underpinned by deterministic and probabilistic sensitivity analyses. CONCLUSION: Treatment duration should not be shortened in I-PET2 positive patients whereas it is cost-effective to shorten treatment duration in I-PET2 negative patients.

Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients.

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

18F-FDG PET-CT uptake is a feature of both normal diameter and aneurysmal aortic wall and is not related to aneurysm size.

PURPOSE: Aortic metabolic activity is suggested to correlate with presence and progression of aneurysmal disease, but has been inadequately studied. This study investigates the 2-[(18)F] fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in a population of infra-renal abdominal aortic aneurysms (AAA), compared to a matched non-aneurysmal control group. METHODS: The Positron Emission Tomography - Computed Tomography (PET/CT) database was searched for infra-renal AAA. Exclusion criteria were prior repair, vasculitis, and saccular/mycotic thoracic or thoraco-abdominal aneurysms. Matching of 159 non-aneurysmal (<3 cm diameter) controls from the same population was assessed. Infra-renal aortic wall FDG uptake was assessed using visual analysis; maximum standardized uptake value (SUVmax) and target to background mediastinal blood pool ratio (TBR) were documented. Predictors of FDG uptake (age, sex, aortic diameter, hypertension, statin use, and diabetes) were assessed using univariate analysis. Follow-up questionnaires were sent to referring clinicians. RESULTS: Aneurysms (n = 151) and controls (n = 159) were matched (p > 0.05) for age, sex, diabetes, hypertension, smoking status, statin use, and indication for PET/CT. Median aneurysm diameter was 5.0 cm (range 3.2-10.4). On visual analysis there was no significant difference in the overall numbers with increased visual uptake 24% (36/151) in the aneurysm group vs. 19% (30/159) in the controls, p = ns. SUVmax was slightly lower in the aneurysm group vs. controls (mean (2 SD) 1.75(0.79) vs. 1.84(0.58), p = 0.02). However there was no difference in TBR between the AAA group and controls (mean (2 SD) 1.03 (0.46) vs. 1.05(0.31), p = 0.36). During a median 18 (interquartile range 8-35) months' follow-up 20 were repaired and four were confirmed ruptured. CONCLUSIONS: The level of metabolic activity as assessed by (18)F-FDG PET/CT in infra-renal AAA does not correlate with aortic size and does not differ between aneurysms and matched controls.

Primary bone lymphoma.

Primary bone lymphoma is a distinct clinical entity that accounts for 5% of extra-nodal lymphoma. Most patients have diffuse large B-cell lymphoma and present with bone pain, a mass or both. The involvement could be in a single focus or disseminated. There are no prospective clinical studies in this disease. Patients have been treated with radiotherapy, chemotherapy or a combination. There is a trend towards improved outcome with combined modality treatment and further improvement with the addition of rituximab. Assessment of response may be difficult with current imaging techniques. The prognosis of primary bone lymphoma is generally good. Here, the current evidence for the optimal treatment of primary bone lymphoma is reviewed and questions for future investigation are addressed.

Establishment of a UK-wide network to facilitate the acquisition of quality assured FDG-PET data for clinical trials in lymphoma.

BACKGROUND: Multicentre trials are required to determine how [fluorine-18]-2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging can guide cancer treatment. Consistency in quality control (QC), scan acquisition and reporting is mandatory for high-quality results, which are comparable across sites. METHODS: A national positron emission tomography (PET) clinical trials network (CTN) has been set up with a 'core laboratory' to coordinate QC and interpret scans. The CTN is involved in trials in Hodgkin's lymphoma [Randomised Phase III trial to determine the role of FDG-PET Imaging in Clinical Stages IA/IIA Hodgkin's Disease (RAPID) and Randomised Phase III trial to assess response adapted therapy using FDG-PET imaging in patients with newly diagnosed, advanced Hodgkin lymphoma (RATHL)] and diffuse large B-cell lymphoma [Blinded evaluation of prognostic value of FDG-PET after 2 cycles of chemotherapy in diffuse large B-cell Non-Hodgkins Lymphoma, a sub-study of the R-CHOP-21 vs R-CHOP-14 trial (R-CHOP PET substudy)]. Approval to join requires scanner validation and agreement to follow a standard QC protocol. Scans are transferred to the core laboratory and reported centrally according to predetermined criteria. RESULTS: The qualification procedure was carried out on 15 scanners. All scanners were able to demonstrate the necessary quantitative accuracy, and following modification of image reconstruction where necessary, scanners demonstrated comparable recovery coefficients (RCs) indicating similar performance. The average RC (±1 standard deviation) was 0.56 ± 0.095 for the 13-mm sphere. Reports from 444 of 473 (94%) patients in RAPID and 67 of 73 (92%) patients in RATHL were available for randomisation of therapy. CONCLUSIONS: The CTN has enabled consistent quality assured PET results to be obtained from multiple centres in time for clinical decision making. The results of trials will be significantly strengthened by this system.

Thyroid lymphoma and airway obstruction - is there a rationale for surgical management?

BACKGROUND: The current management of thyroid lymphomas (TL) includes the combined use of chemotherapy and radiotherapy, with surgery mainly confined to diagnosis through an open biopsy following ultrasound-guided fine-needle aspiration cytology (US-FNAC). AIMS: To analyse the clinical presentation and methods of diagnosis of TL, its pitfalls and the management of these tumours presenting with compression symptoms and airway obstruction. METHODS: A retrospective review of nine patients diagnosed with TL at Guy's and St Thomas Hospital NHS Foundation Trust in London over the past 5 years. RESULTS: Nine consecutive patients were identified with the diagnosis of TL, and seven (78%) of them being women and with a mean age of 65 years. All patients presented with an anterior neck mass while four (44.4%) presented with stridor and vocal cord palsy. Two (22.2%) presented with a hoarse voice, dysphagia, and only one patient had a B symptom of weight loss. FNAC was diagnostic in three patients (33.3%) and a report of multi-nodular goitre in one patient. There was clinical suspicion of TL in three patients (33.3%). Of the three patients presenting with stridor, two had an open biopsy followed by the initiation of dexamethasone therapy and resolution of symptoms within 48 h. One patient had a partial thyroidectomy following a suspected diagnosis of multi-nodular goitre from US-FNAC. One patient required tracheostomy for airway management. CONCLUSION: Diagnosis of TL may be difficult. However, US-FNAC is useful in raising the suspicion of a TL. Open biopsy is still the definitive diagnostic tool of choice. In the emergency setting of airway obstruction, once definitive diagnosis is achieved, dexamethasone therapy and endotracheal intubation for airway management are all that is required for optimal management strategy. Surgical intervention has no role except for providing tissue for diagnosis.

FDG-PET after two to three cycles of chemotherapy predicts progression-free and overall survival in high-grade non-Hodgkin lymphoma.

BACKGROUND: Less than 50% of all high-grade non-Hodgkin lymphoma (NHL) patients experience lasting disease-free survival. Risk-adapted treatment strategies require better tools for prediction of outcome. This investigation aimed to assess the value of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) after two to three cycles of chemotherapy for prediction of progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: One hundred and twenty-one patients with high-grade NHL underwent FDG-PET. The therapy response on FDG-PET was correlated to PFS and OS using Kaplan-Meier survival analysis. Cox regression analyses were employed to test for independence of known pretreatment prognostic factors. RESULTS: Fifty FDG-PET scans were negative, 19 scans showed minimal residual uptake (MRU), and 52 scans were positive. The estimated 5 year PFS was 88.8% for the PET-negative group, 59.3% for the MRU group, and 16.2% for the PET-positive group. Kaplan-Meier analyses showed strong associations between FDG-PET results and PFS (P <0.0001) and OS (P <0.01). Early interim FDG-PET was independent of the other prognostic factors. CONCLUSIONS: Early interim FDG-PET is an accurate and independent predictor of PFS and OS. An early assessment of chemotherapy response with FDG-PET could provide the basis for selection of patients for alternative therapeutic strategies.

Prognostic value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin lymphoma.

BACKGROUND: Long-term survival from Hodgkin lymphoma (HL) is 80-90%, but the treatment has serious late adverse effects. Modern risk-adapted treatment requires accurate assessment of the patient's prognosis. This investigation assessed the value of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) after two or three cycles of chemotherapy for prediction of progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: A total of 85 patients with HL underwent FDG-PET after two or three cycles of chemotherapy. Median follow-up was 3.3 years. FDG-PET results were related to PFS and OS using Kaplan-Meier analysis. Regression analyses were employed to test for independence of established pretreatment prognostic factors. RESULTS: After two or three cycles of chemotherapy, 63 patients had negative FDG-PET scans, nine patients had minimal residual uptake (MRU) and 13 patients had positive scans. Three PET-negative patients and one patient from the MRU group relapsed. In the PET-positive group, nine patients progressed and two died. Survival analyses showed highly significant associations between early interim FDG-PET and PFS (P <0.0001) and OS (P <0.03). All advanced-stage patients with positive interim FDG-PET relapsed within 2 years. CONCLUSION: Early interim FDG-PET is an accurate and independent predictor of PFS and OS in HL. A positive interim FDG-PET is highly predictive of relapse in advanced-stage disease.

Positron emission tomography in the management of lymphomas.

Positron emission tomography is a functional imaging modality that capitalizes on biochemical changes within tumour cells to localize these changes within the body. As a functional imaging tool, unlike an anatomical imaging tool such as CT, it does not require enlargement of lymph nodes affected by disease but does require sufficient numbers of tumour cells to be present with altered biochemical function to visualize these disease sites. These changes are most commonly monitored using a glucose mimic fluorodeoxyglucose which is not only taken up into tumour cells but is trapped within these cells owing to alterations of the hexokinase and dephosphorylase enzymes. This review examines the current role of FDG PET imaging in patients with Hodgkins and Non-Hodgkins lymphoma and also speculates on future roles for this imaging modality.

Malignant pilomatrixoma with multiple local recurrences and distant metastases: a case report and review of the literature.

Malignant pilomatrixoma is a rare malignant tumour of the hair matrix, which was first described in 1980. Only five patients with distant metastases have been reported. We report a sixth case with metastatic disease in a 52-year-old male, who also developed multiple local recurrences. We also review the previous five cases.

18-FDG-PET for the assessment of residual masses on CT following treatment of lymphomas.

BACKGROUND: The problem of residual masses on post-treatment CT scans is a continuing dilemma for the oncologist treating malignant lymphomas. These masses may contain active disease or represent only necrotic tumour which continues to shrink without further treatment or post-treatment fibrosis which remains stable on continued follow-up. 18-FDG-PET offers a novel metabolic imaging modality, which can differentiate malignant from benign tissue on the basis of increased glycolytic activity. PATIENTS AND METHODS: Thirty-two patients (15 with Hodgkin's disease (HD) and 17 with aggressive histology non-Hodgkin's lymphoma (NHL)) who had residual masses on their post-treatment CT scans underwent 18-FDG-PET. The post-treatment CT and PET scans were compared and the accuracy of the 18-FDG-PET in assessing residual masses was evaluated using clinical and pathological follow-up data. RESULTS: Nine patients had positive post-treatment 18-FDG-PET, eight (89%) of whom have relapsed. Twenty-three patients had negative post-treatment PET with only two relapses in this group. The 2 patients who relapsed had aggressive NHL while none of the 11 HD patients with negative PET relapsed. The median follow-up of patients in continued complete remission is 38 months. CONCLUSIONS: 18-FDG-PET can differentiate between residual masses containing viable lymphoma where further treatment will be required to achieve cure and those representing ablated disease, where unnecessary treatment and additional morbidity may be avoided.

Nasal natural killer-cell lymphoma: a disease with very poor prognosis.

Nasal Natural Killer-Cell Lymphoma is an aggressive subtype of NHL even when it presents with localized disease. It is more common in Oriental than Western population. We report the case history of a white Caucasian male patient with this disease who died 5 months from diagnosis despite aggressive treatment with 2 different chemotherapy regimes and radiotherapy. We discuss the diagnosis, presentation, treatment and prognosis of this rare disease.

18-FDG-PET as a prognostic indicator in the treatment of aggressive Non-Hodgkin's Lymphoma-comparison with CT.

Less than 50% of newly diagnosed patients with aggressive histology Non-Hodgkin's Lymphoma (NHL) are cured with standard treatment. The ability to accurately monitor response to treatment is crucial in order to select out patients who need more intensive or salvage treatment. This study assesses the accuracy of FDG-PET as compared to CT in remission assessment following treatment of aggressive NHL, and its value in estimating relapse-free survival. It also evaluates the prognostic value of early interim PET scan in prediction of treatment outcome. Forty-nine adult patients with biopsy-proven aggressive NHL between September 1993 and December 1997 were included. All patients had pre-treatment FDG-PET demonstrating increased uptake in sites of disease. Forty-five patients had a post-treatment PET to assess remission status and 4 had an interim but not a post-treatment PET. Thirty-three of these patients also had a pre- and a post-treatment CT scan. Twenty-three of the 49 patients had an interim PET during chemotherapy to assess early response. PET and CT scan results were correlated with relapse data to examine their accuracy in remission assessment and prediction of prognosis. The median follow-up duration is 30 months. Overall the result of post-treatment PET scan appears to predict disease outcome, with relapse rates of 100% (9/9) and 17% (6/36) for positive and negative PET respectively [p<0.001]. In a subgroup of 33 patients, direct comparison of post-treatment PET and CT shows that PET was more accurate than CT in assessing remission status following treatment. Relapse rate was 100% for positive PET and only 18% for negative PET (p<0.001), compared to 41% and 25% for patients with positive and negative CT respectively (p>0.1). PET was particularly useful in assessment of residual masses seen on CT scan. The interim PET provided valuable information regarding early assessment of response and long-term prognosis, with no relapses in patients with no or minimal residual uptake compared to 87.5% relapse rate in patients with persistent PET activity (p<0.001). FDG-PET is an accurate method of assessing remission and estimating prognosis following treatment of aggressive NHL, with positive and negative predictive accuracies of 100% and 82% respectively. PET is more accurate than CT in assessing remission and prediction of relapse-free survival. An interim PET scan after 2-3 cycles of chemotherapy predicts the long-term outcome early-on and has a high negative predictive value (100%). This may assist to separate at an early stage good-prognosis patients who are likely to be cured with standard chemotherapy from those patients with poorer prognosis who require alternative treatment.