Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes.

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.

Outcomes of Patients with Positive Interim Positron Emission Tomography (PET) Continuing ABVD in the Clinical Setting.

Recent prospective clinical trial data suggest that patients with Hodgkin's lymphoma who continue treatment with ABVD, despite failing to attain a complete metabolic response on interim PET (PET2+), may fare better than previously published. We describe the outcomes of PET2+ patients who continued ABVD and compare the performance of a quantitative measure based on the lesion-to-liver SUV ratio (LLS qPET2+) to that of the subjective Deauville criteria (dvPET2+). We analyzed all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at the Memorial Sloan Kettering Cancer Center between 2008 and 2017. Eligibility was set to correspond with the RATHL inclusion criteria. Images were reviewed by two nuclear medicine physicians and discordant cases were resolved with a third expert in consensus. qPET2+ was defined as LLS ≥ 1.3. We identified 227 patients of whom 25% (57) were qPET2+, but only 14% (31) were dvPET2+. Forty-eight patients (84%) continued ABVD with a 3-year PFS of 70% for qPET2+ and 64% for dvPET2+. In conclusion, interim PET interpretation in clinical practice may be associated with a higher rate of scans deemed positive. Irrespective of the criteria for PET2 positivity, a subset of patients may continue ABVD without a dismal outcome.

Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring.

PURPOSE: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. PATIENTS AND METHODS: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. RESULTS: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. CONCLUSIONS: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

Diagnostic and Prognostic Utility of 18F-FDG PET/CT in Recurrent Salivary Gland Cancers.

OBJECTIVE. The role of 18F-FDG PET/CT in the evaluation of recurrent salivary gland tumors remains poorly defined. We investigated the diagnostic and prognostic utility of PET in this setting. MATERIALS AND METHODS. A total of 146 patients with recurrent salivary gland cancer were treated at our institution between January 2002 and December 2015. Patients who underwent FDG PET/CT and conventional imaging (CT or MRI) within 3 months of recurrence (n = 78) were included in this retrospective analysis. On FDG PET/CT, we measured the SUVmax, total body metabolic tumor volume of all lesions, and total lesion glycolysis of all lesions to determine the intensity and extent of FDG-avid disease. We assessed the correlation of FDG PET/CT findings with clinicopathologic features, progression-free survival, and overall survival. RESULTS. FDG PET/CT was positive for recurrence in 74 of 78 patients (94.9%) and falsely negative in four patients (5.1%). In comparison with conventional imaging, FDG PET/CT performed for restaging detected additional recurrent lesions in 14 patients (17.9%). The median SUVmax was 7.4, the median total body metabolic tumor volume was 30.1 cm3, and median total lesion glycolysis was 97.3 g/mL × cm3. Sixty-six patients had progressive disease, and 54 died. Univariate and multivariate Cox hazards analysis identified pathologic risk group (p = .04), total body metabolic tumor volume (p < .001), and total lesion glycolysis (p < .001) as independent prognostic factors for progression-free survival and identified age (p = .05), total body metabolic tumor volume (p < .001), and total lesion glycolysis (p < .001) as independent prognostic factors for overall survival. CONCLUSION. In patients with recurrent salivary gland cancer, FDG PET/CT is useful as a single test for defining the extent of disease and providing prognostic information, which may help in selecting appropriate treatment strategies.

Safety and Feasibility of PARP1/2 Imaging with 18F-PARPi in Patients with Head and Neck Cancer.

PURPOSE: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer. PATIENTS AND METHODS: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration. RESULTS: 18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG-positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG-negative lymph nodes of 3 patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. The overall effective dose with 18F-PARPi PET was 3.9 mSv - 5.2 mSv, contrast was high [SUVmax(lesion)/SUVmax(trapezius muscle) = 4.5] and less variable than 18F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001). CONCLUSIONS: Imaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.

Baseline FDG-PET/CT detects bone marrow involvement in follicular lymphoma and provides relevant prognostic information.

In follicular lymphoma (FL), detection of bone marrow (BM) involvement (BMI) by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) improves the accuracy of staging vs BM biopsy (BMB) alone. Our objective was to determine the diagnostic utility of PET for BMI FL and the prognostic value of BMI by PET (positive PET result [PET+]). Records of patients (2002-2016) with PET and BMB at the time of initial treatment were reviewed. BMI was identified by positive BMB result (BMB+) and/or unifocal or multifocal BM FDG uptake on blindly reviewed PET scans with no corresponding CT abnormality (PET+). Among 261 patients, BMI was diagnosed in 78 patients (29.9%) by PET+, in 81 patients (31.0%) by BMB+, and in 113 patients (43.3%) by either PET+ or BMB+. PET+ upstaged 24 patients to stage IV, including 10 from stages I or II to stage IV. Median duration of follow-up was 6.0 years (range, 0-16.6 years). In univariate analysis, a high Follicular Lymphoma International Prognosis Index (FLIPI) score, PET+, and BMB+ correlated with shorter progression-free survival (PFS; all P ≤ .03), and high FLIPI, PET+, and combined PET+ and BMB+ with shorter overall survival (OS; all P ≤ .01). In multivariate analysis, PET+ was the only independent predictor of PFS, whereas high FLIPI score and PET+ predicted OS (P ≤ .03). Combined PET and BMB identify BMI more accurately than either BMB or PET alone, but BMB rarely adds critical information. For patients initiating treatment of FL, identification of BMI by PET is predictive of PFS and OS.

The geriatric syndrome of sarcopenia impacts allogeneic hematopoietic cell transplantation outcomes in older lymphoma patients.

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.

Rosai-Dorfman Disease-Utility of 18F-FDG PET/CT for Initial Evaluation and Follow-up.

BACKGROUND: The role of imaging in the management of Rosai-Dorfman disease (RDD), a rare non-Langerhans cell histiocytosis, is not clearly defined. We present an analysis of FDG PET/CT findings obtained for initial disease characterization, follow-up evaluation, and treatment planning for this disease. METHODS: From an institutional pathology database (2001-2018), we identified RDD patients who underwent FDG PET/CT scans either as part of clinical care or when done as part of clinical trials. For all scans, sites of abnormal FDG uptake were assessed, and SUVmax was measured. Comparison of PET/CT findings was made with anatomic (CT/MRI-based) imaging, where available. Instances of changing treatment based on PET/CT were recorded. RESULTS: We reviewed 109 FDG PET/CT scans in 27 patients with RDD. Five of 27 patients had only nodal/cutaneous disease, whereas 22 patients had extranodal disease, most commonly in bone (n = 9) and central nervous system (n = 7). PET/CT identified sites of active disease in 24 of 27 patients. All identified bone and extraskeletal lesions, except for a brain lesion in 1 patient, were FDG-avid. In 6 of 20 patients (30%) with available prior CT or MRI, PET/CT demonstrated additional RDD lesions (bones: n = 5, pleura: n = 1) that were not apparent on anatomic imaging; 3 of these lesions were outside the CT field of view, and 3 were not recognized on CT. Overall, 13 of 109 PET/CT scans led to a change in management, affecting 41% (11/27) of patients. CONCLUSION: FDG PET/CT was valuable in defining disease extent and optimizing treatment strategy in patients with RDD.

18F-FDG PET/CT for Monitoring of Ipilimumab Therapy in Patients with Metastatic Melanoma.

Immune checkpoint inhibitors (ICIs) are now commonly used to treat patients with metastatic malignant melanoma. Although concerns have been raised that the inflammatory response induced by ICIs may limit the ability of 18F-FDG PET/CT to assess tumor response, systematic analyses on the use of 18F-FDG PET/CT in this setting are mostly lacking. Thus, we set out to evaluate the association between tumor response on 18F-FDG PET/CT and prognosis in patients with metastatic malignant melanoma treated with ipilimumab. Methods: We analyzed 60 consecutive patients with metastatic melanoma who underwent 18F-FDG PET/CT scans both before and after treatment to evaluate treatment response after completion of ipilimumab therapy. Tumor response was assessed by the change in the sum of SULpeak (voxels with the highest average SUL [SUV normalized to lean body mass]) of up to 5 lesions according to PERCIST5. New lesions on PET that appeared suggestive of metastases were considered progressive metabolic disease (PMD). Because immunotherapy may cause new inflammatory lesions that are detectable on 18F-FDG PET/CT, we also evaluated an immunotherapy-modified response classification (imPERCIST5). In this classification, new lesions do not define PMD per se; rather, PMD requires an increase in the sum of SULpeak by 30%. The correlation between tumor response according to these 3 definitions and overall survival (OS) was evaluated and compared with known prognostic factors. Results: In responders and nonresponders, the 2-y OS was 66% versus 29% for imPERCIST5 (P = 0.003). After multivariate analysis, imPERCIST5 remained prognostic (hazard ratio, 3.853; 95% confidence interval, 1.498-9.911; P = 0.005). New sites of focal 18F-FDG uptake occurred more often in patients with PMD (n = 24) by imPERCIST5 than in those with stable metabolic disease (n = 7) or partial metabolic response (n = 4). In patients with partial metabolic response, 2 of 4 isolated new lesions regressed spontaneously during follow-up. Conclusion: In patients with metastatic melanoma treated with ipilimumab, tumor response according to PERCIST was associated with OS. Our data suggest that PMD should not be defined by the appearance of new lesions, but rather by an increase in the sum of SULpeak.

Modified fractal analysis of methionine positron emission tomography images for predicting prognosis in newly diagnosed patients with glioma.

OBJECTIVE: To assess intratumoural metabolic heterogeneity using modified fractal analysis and to determine its prognostic significance in patients with glioma. PATIENTS AND METHODS: A total of 57 patients with newly diagnosed glioma who underwent methionine PET-computed tomography between August 2012 and January 2017 were enrolled. The requirement for informed consent was waived for this retrospective study. Tumour-to-normal tissue ratio, metabolic tumour volume, total lesion methionine uptake and modified fractal dimension (m-FD) were calculated for each tumour using methionine PET-computed tomography. Associations between these indices and tumour grade and overall survival were analysed. RESULTS: Overall, eight patients had grade II, 20 had grade III and 29 had grade IV tumours. The tumour-to-normal tissue ratios of grade III and grade IV tumours were significantly greater than that of grade II tumours. The metabolic tumour volume and total lesion methionine uptake of grade III tumours were significantly greater than those of grade II and grade IV tumours. The m-FD of grade IV tumours was significantly greater than those of grade II and grade III tumours. A total of 47 patients were followed up, and their prognoses were evaluated. Only the m-FD was significantly associated with a poor prognosis (P<0.05). Multivariate analyses identified age (>58 years) (hazard ratio: 5.73; 95.0% confidence interval: 1.4-29.9; P=0.015) and the m-FD (>0.87) (hazard ratio: 4.80; 95.0% confidence interval: 1.12-32.9; P=0.033) as independent prognostic factors for overall survival. CONCLUSION: Intratumoural metabolic heterogeneity is a useful imaging biomarker in patients with glioma.