Tarec Christoffer El-Galaly

Routine Bone Marrow Biopsy Has Little or No Therapeutic Consequence for Positron Emission Tomography/Computed Tomography–Staged Treatment-Naive Patients With Hodgkin Lymphoma

PURPOSE To investigate whether bone marrow biopsy (BMB) adds useful information to [(18)F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) staging in patients with Hodgkin lymphoma (HL). PATIENTS AND METHODS Newly diagnosed patients with HL undergoing a pretherapeutic staging that encompasses both PET/CT and BMB were included in this retrospective study. The pattern of skeletal FDG uptake was categorized as uni-, bi-, or multifocal (≥ three lesions). Clinical stage, risk assessment, and treatment plan were determined with and without the contribution of BMB results according to the Ann Arbor classification and the guidelines from the German Hodgkin Study Group. RESULTS A total of 454 patients with HL were included of whom 82 (18%) had focal skeletal PET/CT lesions and 27 (6%) had positive BMB. No patients with positive BMB were assessed as having stage I to II disease by PET/CT staging. BMB upstaged five patients, assessed as being stage III before BMB; none of the 454 patients would have been allocated to another treatment on the basis of BMB results. Focal skeletal PET/CT lesions identified positive and negative BMBs with a sensitivity and specificity of 85% and 86%, respectively. The positive and negative predictive values of focal skeletal PET/CT lesions for BMB results were 28% and 99%, respectively. CONCLUSION A consistent finding of this study was the absence of positive BMBs in PET/CT-assessed stage I to II disease. The omission of staging BMB would not have changed the risk assessment or treatment strategy in this cohort of 454 newly diagnosed patients with HL.

Positron emission tomography/computed tomography surveillance in patients with Hodgkin lymphoma in first remission has a low positive predictive value and high costs

Background The value of performing post-therapy routine surveillance imaging in patients with Hodgkin lymphoma is controversial. This study evaluates the utility of positron emission tomography/computed tomography using 2-[18F]fluoro-2-deoxyglucose for this purpose and in situations with suspected lymphoma relapse. Design and Methods We conducted a multicenter retrospective study. Patients with newly diagnosed Hodgkin lymphoma achieving at least a partial remission on first-line therapy were eligible if they received positron emission tomography/computed tomography surveillance during follow-up. Two types of imaging surveillance were analyzed: “routine” when patients showed no signs of relapse at referral to positron emission tomography/computed tomography, and “clinically indicated” when recurrence was suspected. Results A total of 211 routine and 88 clinically indicated positron emission tomography/computed tomography studies were performed in 161 patients. In ten of 22 patients with recurrence of Hodgkin lymphoma, routine imaging surveillance was the primary tool for the diagnosis of the relapse. Extranodal disease, interim positron emission tomography-positive lesions and positron emission tomography activity at response evaluation were all associated with a positron emission tomography/computed tomography-diagnosed preclinical relapse. The true positive rates of routine and clinically indicated imaging were 5% and 13%, respectively (P=0.02). The overall positive predictive value and negative predictive value of positron emission tomography/computed tomography were 28% and 100%, respectively. The estimated cost per routine imaging diagnosed relapse was US

Efficacy of routine surveillance with positron emission tomography/computed tomography in aggressive non-Hodgkin lymphoma in complete remission: status in a single center

50,778. Conclusions Negative positron emission tomography/computed tomography reliably rules out a relapse. The high false positive rate is, however, an important limitation and a confirmatory biopsy is mandatory for the diagnosis of a relapse. With no proven survival benefit for patients with a pre-clinically diagnosed relapse, the high costs and low positive predictive value make positron emission tomography/computed tomography unsuitable for routine surveillance of patients with Hodgkin lymphoma.

Routine Imaging for Diffuse Large B-Cell Lymphoma in First Complete Remission Does Not Improve Post-Treatment Survival: A Danish–Swedish Population-Based Study

Post-therapy surveillance imaging in patients with lymphoma remains controversial. We report our experience with positron emission tomography/computed tomography (PET/CT) surveillance in patients with aggressive non-Hodgkin lymphoma in first complete remission (CR). The 138 PET/CTs performed in 52 patients revealed four unsuspected relapses. In one patient, relapse was visualized by fluorodeoxyglucose (FDG) accumulation without any significant CT pathology. The specificity and sensitivity of surveillance PET/CT were 89% and 100%, respectively. The predictive values of positive and negative PET/CTs were 21% and 100%, respectively. The cost of half-yearly routine PET/CT surveillance during the first 2 years in CR was

Role of routine imaging in detecting recurrent lymphoma; a review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma

US8552 per patient and accounted for 81% of the total follow-up costs. PET/CT was effective in detecting unexpected relapse and normal PET/CT supported continuous CR. However, the impact of PET/CT was limited by the high number of false-positive results and PET/CT surveillance was costly compared to CT surveillance.

Diffuse Large B-Cell Lymphoma Classification System That Associates Normal B-Cell Subset Phenotypes With Prognosis

PURPOSE Routine imaging for diffuse large B-cell lymphoma (DLBCL) in first complete remission (CR) is controversial and plays a limited role in detecting relapse. This population-based study compared the survival of Danish and Swedish patients with DLBCL for whom traditions for routine imaging have been different. PATIENTS AND METHODS Patients from the Danish and Swedish lymphoma registries were included according to the following criteria: newly diagnosed DLBCL from 2007 to 2012, age 18 to 65 years, and CR after R-CHOP/CHOEP. Follow-up for Swedish patients included symptom assessment, clinical examinations, and blood tests at 3- to 4-month intervals for 2 years, with longer intervals later in follow-up. Imaging was only recommended when relapse was clinically suspected. Follow-up for Danish patients was similar but included routine imaging (usually computed tomography every 6 months for 2 years). RESULTS Danish (n = 525) and Swedish (n = 696) patients with DLBCL had comparable baseline characteristics. Cumulative 2-year progression rate after CR was 6% (95% CI, 4 to 9) for International Prognostic Index (IPI) ≤ 2 versus 21% (95% CI, 13 to 28) for IPI > 2. Age > 60 years (hazard ratio [HR], 2.3; 95% CI, 1.6 to 3.4), elevated lactate dehydrogenase (HR, 2.3; 95% CI, 1.4 to 3.8), B symptoms (HR, 1.7; 95% CI, 1.1 to 2.5), and Eastern Cooperative Oncology Group performance status ≥ 2 (HR, 1.8; 95% CI, 1.0 to 3.0) were associated with worse post-CR survival. Imaging-based follow-up strategy had no impact on survival, neither for all patients nor for IPI-specific subgroups. CONCLUSION DLBCL relapse after first CR is infrequent, and the widespread use of routine imaging in Denmark did not translate into better survival. This favors follow-up without routine imaging and, more generally, a shift of focus from relapse detection to improved survivorship.

Impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography staging in newly diagnosed classical Hodgkin lymphoma: fewer cases with stage I disease and more with skeletal involvement

After first‐line therapy, patients with Hodgkin lymphoma (HL) and aggressive non‐HL are followed up closely for early signs of relapse. The current follow‐up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore, a retrospective multicenter study of relapsed HL and aggressive non‐HL (nodal T‐cell and diffuse large B‐cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002–2011 and relapsed after achieving complete remission on first‐line therapy. Characteristics and outcome of imaging‐detected relapses were compared with other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient‐reported symptoms alone or in combination with abnormal blood tests or physical examination in 64% of the patients. Routine imaging prompted relapse investigations in 27% of the patients. The estimated number of routine scans per relapse was 91–255 depending on the lymphoma subtype. Patients with imaging‐detected relapse had lower disease burden (P = 0.045) and reduced risk of death following relapse (hazard ratio = 0.62, P = 0.02 in multivariate analysis). Patient‐reported symptoms are still the most common factor for detecting lymphoma relapse and the high number of scans per relapse calls for improved criteria for use of surveillance imaging. However, imaging‐detected relapse was associated with lower disease burden and a possible survival advantage. The future role of routine surveillance imaging should be defined in a randomized trial. Am. J. Hematol. 89:575–580, 2014.

Outcome prediction by extranodal involvement, IPI, R-IPI, and NCCN-IPI in the PET/CT and rituximab era: A Danish–Canadian study of 443 patients with diffuse-large B-cell lymphoma

PURPOSE Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell-associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. PATIENTS AND METHODS We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. RESULTS Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP-treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell-like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1-signature and major histocompatibility complex class II-signature genes, which are known to have a positive impact on prognosis. CONCLUSION Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.

Predicting response to multidrug regimens in cancer patients using cell line experiments and regularised regression models

Abstract 18F-Fluorodeoxyglucose positron emission tomography/ computed tomography (PET/CT) is a highly accurate staging method in classical Hodgkin lymphoma (cHL). We retrospectively compared the staging results obtained in two large cohorts of patients with cHL diagnosed before (n = 324) and after (n = 406) the introduction of PET/CT staging in a retrospective study. In PET/CT staged patients, stage I disease was less frequent (16% vs. 27%, p < 0.001) while stage IV disease was more frequent (17% vs. 10%, p = 0.02). Imaging-detected skeletal involvement was recognized more often in PET/CT staged patients (17% vs. 2%, p < 0.001), and the presence of focal skeletal PET/CT lesions was associated with higher risk of progression (hazard ratio [HR] 1.96, 95% confidence interval [CI]: 1.14–3.36). The German Hodgkin Study Group (GHSG) risk classification (early, intermediate, advanced disease) predicted outcome in PET/CT staged patients. In conclusion, PET/CT led to higher disease stages, and the more frequently diagnosed skeletal lesions may be an adverse prognostic factor.

Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma

18F‐fluorodeoxyglucose PET/CT (PET/CT) is the current state‐of‐the‐art in the staging of diffuse large B‐cell lymphoma (DLBCL) and has a high sensitivity for extranodal involvement. Therefore, reassessment of extranodal involvement and the current prognostic indices in the PET/CT era is warranted. We screened patients with newly diagnosed DLBCL seen at the academic centers of Aalborg, Copenhagen, and British Columbia for eligibility. Patients that had been staged with PET/CT and treated with R‐CHOP(‐like) 1st line treatment were retrospectively included. In total 443 patients met the inclusion criteria. With a median follow‐up of 2.4 years, the 3‐year overall (OS) and progression‐free survival (PFS) were 73% and 69%, respectively. The Ann Arbor classification had no prognostic impact in itself with the exception of stage IV disease (HR 2.14 for PFS, P<0.01). Extranodal involvement was associated with a worse outcome in general, and in particular for patients with involvement of >2 extranodal sites, including HR 7.81 (P < 0.001) for PFS for >3 sites. Bone/bone marrow involvement was the most commonly involved extranodal site identified by PET/CT (29%) and was associated with an inferior PFS and OS. The IPI, R‐IPI, and NCCN‐IPI were predictive of PFS and OS, and the two latter could identify a very good prognostic subgroup with 3‐year PFS and OS of 100%. PET/CT‐ascertained extranodal involvement in DLBCL is common and involvement of >2 extranodal sites is associated with a dismal outcome. The IPI, R‐IPI, and NCCN‐IPI predict outcome with high accuracy. Am. J. Hematol. 90:1041–1046, 2015.