Controversies on the prognostic value of interim FDG‐PET in advanced‐stage Hodgkin lymphoma

Hodgkin lymphoma, even in advanced‐stage, is a highly curable malignancy, but treatment is associated with short‐term toxicity and long‐term side effects. Early predictive markers are required to identify those patients who do not require the full‐length standard therapy (and thus qualify for therapy de‐escalation) and those patients who will not be cured by standard therapy (and thus qualify for therapy escalation). Multiple trials have assessed the value of ¹⁸F‐fluoro‐2‐deoxy‐d ‐glucose positron emission tomography (FDG‐PET) after a few cycles of chemotherapy (also known as ‘interim FDG‐PET’) in predicting outcome in advanced‐stage Hodgkin lymphoma. Furthermore, multiple interim FDG‐PET‐adapted trials, in which patients with positive interim FDG‐PET scans are assigned to escalated therapies, and patients with negative interim FDG‐PET scans are assigned to de‐escalated therapies, have recently been published or are currently ongoing, with generally heterogeneous results. The present article reports the currently available evidence (and controversies) on the prognostic value of interim FDG‐PET in advanced‐stage Hodgkin lymphoma in patients with positive and negative interim FDG‐PET findings following continuation of standard chemotherapy or escalated/de‐escalated therapy.     

Minimal residual disease in non‐Hodgkin lymphoma – current applications and future directions

Non‐Hodgkin Lymphomas (NHLs) are a heterogeneous group of tumours with distinct treatment paradigms, but in all cases the goal of treatment is to maximize quality and duration of remission while minimizing therapy‐related toxicity. Identification of persistent disease or relapse is most often the trigger to intensify or re‐initiate anti‐neoplastic therapy, respectively. In the current era of NHL treatment, this determination is mostly based on imaging and clinical evaluations, tools with imperfect sensitivity and specificity. The availability of minimal residual disease (MRD) monitoring could transform treatment paradigms by allowing intensification of treatment in at‐risk patients or early intervention for impending relapse. Novel methods based on polymerase chain reaction and next‐generation sequencing are now being studied in NHL with promising results. This review outlines the current status of the field in the use of MRD techniques for diffuse large B‐cell lymphoma, mantle cell lymphoma and follicular lymphoma. Specifically, we address their demonstrated and potential clinical utility in risk stratification, monitoring of remission status, and guiding interim and post‐treatment escalation. Future applications of these techniques could identify novel markers of MRD, improve initial treatment selection, guide treatment escalation or de‐escalation, and allow for real‐time monitoring of patterns of clonal evolution, which together could redefine NHL treatment paradigms.     

Pretransplant FDG‐PET in aggressive non‐Hodgkin lymphoma: systematic review and meta‐analysis

This study aimed to systematically review and meta‐analyze the value of pretransplant FDG‐PET in predicting outcome after autologous stem cell transplantation in aggressive non‐Hodgkin lymphoma. MEDLINE was systematically searched; included studies were methodologically assessed and meta‐analyzed, when possible. Overall methodological quality of included studies (n = 11) was poor, with moderate risk of bias in the domains of study participation (n = 7) and prognostic factor measurement (n = 7), and high risk of bias in the domains of outcome measurement (n = 10), and study confounding (n = 11). In all aggressive non‐Hodgkin lymphomas, pooled sensitivity and specificity were 54.0% and 73.1% in predicting treatment failure, and 54.5% and 68.7% in predicting death. Because of interstudy heterogeneity, additional subgroup analyses were performed. In newly diagnosed aggressive non‐Hodgkin lymphoma, pooled sensitivity and specificity were 20.0% and 70.0% in predicting treatment failure, and 8.3% % and 30.5% in predicting death. In refractory/relapsed aggressive non‐Hodgkin lymphoma, pooled sensitivity and specificity were 68.1% and 72.1% in predicting treatment failure, and 77.3% and 69.6% in predicting death. At present, pretransplant FDG‐PET cannot be recommended in aggressive non‐Hodgkin lymphoma, because available studies suffer from major methodological flaws, and reported prognostic estimates are low (i.e., poor in newly diagnosed and moderate in refractory/relapsed aggressive non‐Hodgkin lymphoma).     

F‐18 FDG‐PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem‐cell transplantation for relapsed and refractory Hodgkin lymphoma

Total lymphoid irradiation (TLI) followed by high‐dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high‐dose chemotherapy and aHSCT. Pre‐transplant fludeoxyglucose positron emission tomography (FDG‐PET) studies were scored on the 5‐point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10‐year progression‐free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5‐year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long‐term survival rates for patients with relapsed/refractory HL, including those with high‐risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.     

Hodgkin lymphoma: a negative interim‐PET cannot circumvent the need for end‐of‐treatment‐PET evaluation

We examined the outcome of a cohort of patients with Hodgkin lymphoma (HL) in order to assess if fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) at the end of treatment (end‐PET) can be omitted when the interim PET (int‐PET) is negative. Seventy‐six ABVD(adriamycin, bleomycin, vinblastine, dacarbazine)‐treated patients were retrospectively included. No change in treatment was made on the basis of int‐PET results. Suspicious foci on end‐PET received biopsy confirmation whenever possible. Median follow‐up was 58·9 months. Uptake on int‐PET higher than liver (scores 4–5) was rated positive according to the Lugano classification, while a positive end‐PET corresponded to scores 3, 4 and 5. Fifteen patients had treatment failure. Sensitivity, specificity, positive predictive value (PPV), negative predictive value and accuracy of int‐PET were 46·7%, 85·2%, 43·8%, 86·7% and 77·6%, respectively. For end‐PET the figures were: 80%, 93·4%, 75%, 95% and 90·8%. Eight patients with negative int‐PET had treatment failure; six of them were identified as non‐responders with end‐PET. The 5‐year progression‐free survival (PFS) was 87% for patients with negative int‐PET versus 56% with positive int‐PET. The 5‐year PFS was 96% with negative end‐PET versus 23% with positive end‐PET. The prognostic information from int‐PET as regards PFS (log‐rank test P = 0·0048) was lower than that provided by end‐PET (P < 0·0001). Int‐PET predicted only half of the failures. When used in clinical routine, a negative int‐PET study cannot obviate the need for end‐PET examination.     

Modification of initial therapy in early and advanced Hodgkin lymphoma,based on interim PET/CT is beneficial: a prospective multicentre trial of 355 patients

This multicentre study evaluated 5‐year progression‐free (PFS) and overall survival (OS) in early and advanced Hodgkin lymphoma (HL), where therapy was individualized based on initial prognostic factors and positron emission tomography‐computed tomography performed after two cycles (PET‐2). Between September 2006 and August 2013, 359 patients aged 18–60 years, were recruited in nine Israeli centres. Early‐HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ×2. Depending on initial unfavourable prognostic features, PET‐2‐positive patients received additional ABVD followed by involved‐site radiotherapy (ISRT). Patients with negative PET‐2 and favourable disease received ISRT or ABVD ×2; those with unfavourable disease received ABVD ×2 with ISRT or, alternatively, ABVD ×4. Advanced‐HL patients initially received ABVD ×2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) ×2 based on their international prognostic score (≤2 or ≥3). PET‐2‐negative patients further received ABVD ×4; PET‐2‐positive patients received EB ×4 and ISRT to residual masses. With a median follow‐up of 55 (13–119) months, 5‐year PFS was 91% and 69% for PET‐2‐negative and positive early‐HL, respectively; 5‐year OS was 100% and 95%, respectively. For advanced‐HL, the PFS was 81% and 68%, respectively (P = 0·08); 5‐year OS was 98% and 91%, respectively. PET‐2 positivity is associated with inferior prognosis in early‐HL, even with additional ABVD and ISRT. Advanced‐HL patients benefit from therapy escalation following positive PET‐2. EB can be safely de‐escalated to ABVD in PET‐2‐negative patients.     

Decreasing mortality from non‐Hodgkin lymphoma in Australia

Based on the number of new cases (incidence), non‐Hodgkin lymphoma is an increasingly common cancer in Australia and many developed countries. Until recently, mortality trends have been stable or slightly increasing. However, since the year 2000, mortality has decreased every year by an average of 5.1% per year (95% confidence interval (CI) ?7.1 to ?3.1%), whereas incidence has continued to increase at 0.9% per year (95%CI 0.6 to 1.2%). It was not possible with the population‐based registry data available to us to untangle the causes of the decrease in mortality. The stable mortality rates during the 1990s (in the face of increasing incidence) might have been because of introduction of novel therapies such as autologous stem cell transplant for relapsed diffuse large cell lymphoma or the purine analogue‐based therapy for indolent lymphomas. A plausible explanation for the large decrease in mortality since 2000 is the introduction of the monoclonal antibody rituximab.     

FDG‐PET/CT in the management of lymphomas: current status and future directions

FDG‐PET/CT is the current state‐of‐the‐art imaging in lymphoma and plays a central role in treatment decisions. At diagnosis, accurate staging is crucial for appropriate therapy selection: FDG‐PET/CT can identify areas of lymphoma missed by CT alone and avoid under‐treatment of patients with advanced disease stage who would have been misclassified as having limited stage disease by CT. Particularly in Hodgkin lymphoma, positive interim FDG‐PET/CT scans are adversely prognostic for clinical outcomes and can inform PET‐adapted treatment strategies, but such data are less consistent in diffuse large B‐cell lymphoma. The use of quantitative FDG‐PET/CT metrics using metabolic tumour volume, possibly in combination with other biomarkers, may better define prognostic subgroups and thus facilitate better treatment selection. After chemotherapy, FDG‐PET/CT response is predictive of outcome and may identify a subgroup who benefit from consolidative radiotherapy. Novel therapies, in particular immunotherapies, exhibit different response patterns than conventional chemotherapy, which has led to modified response criteria that take into account the risk of transient pseudo‐progression. In relapsed lymphoma, FDG‐PET/CT after second‐line therapy and prior to high‐dose therapy is also strongly associated with outcome and may be used to guide intensity of salvage therapy in relapsed Hodgkin lymphoma. Currently, FDG‐PET/CT has no role in the routine follow‐up after complete metabolic response to therapy, but it remains a powerful tool for excluding relapse if patients develop clinical features suggestive of disease relapse. In conclusion, FDG‐PET/CT plays major roles in the various phases of management of lymphoma and constitutes a step towards the pursuit of personalized treatment.     

Phase IA/II,multicentre, open‐label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non‐Hodgkin or Hodgkin lymphoma

Despite advancements in the treatment of non‐Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8‐week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa‐associated lymphatic tissue (MZL/MALT) was 33·3% and 42·9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation.     

Classification of non‐Hodgkin lymphoma in South‐eastern Europe: review of 632 cases from the international non‐Hodgkin lymphoma classification project

The distribution of non‐Hodgkin lymphoma (NHL) subtypes varies around the world, but a systematic study of South‐eastern Europe (SEEU) has never been done. Therefore, we evaluated the relative frequencies of NHL subtypes in three SEEU countries – Croatia, Romania and Macedonia. Five expert haematopathologists reviewed 632 consecutive cases of newly diagnosed NHL from the three SEEU countries using the World Health Organization classification. The results were compared to 399 cases from North America (NA) and 580 cases from Western Europe (WEU). The proportions of B‐ and T‐cell NHL and the sex distribution in SEEU were similar to WEU and NA. However, the median ages of patients with low‐ and high‐grade B‐NHL in SEEU (60 and 59 years, respectively) were significantly lower than in NA (64 and 68 years, respectively; P < 0·05). SEEU had a significantly lower proportion of low‐grade B‐NHL (46·6%) and higher proportion of high‐grade B‐NHL (44·5%) compared to both WEU (54·5% and 36·4%, respectively) and NA (56·1% and 34·3%, respectively). There were no significant differences in the relative frequencies of T‐NHL subtypes. This study provides new insights into differences in the relative frequencies of NHL subtypes in different geographic regions. Epidemiological studies are needed to better characterize and explain these differences.     

Standardised uptake value of 18F‐FDG on staging PET/CT in newly diagnosed patients with different subtypes of non‐Hodgkin’s lymphoma

Objectives: Positron emission tomography using 2‐[fluorine‐18]‐fluoro‐2‐deoxy‐d ‐glucose (¹⁸F‐FDG) is considered to be the most beneficial imaging method for staging patients with non‐Hodgkin’s lymphoma (NHL). The intensity of ¹⁸F‐FDG accumulation may be determined by calculating the so‐called standardised uptake value (SUV). The study aimed at assessing the benefit of SUV_max determination in staging ¹⁸F‐FDG PET/CT in untreated patients with NHL. Methods: One hundred and forty‐nine initial staging ¹⁸F‐FDG PET/CT scans performed in patients with NHL between January 2007 and August 2009 were assessed, and the SUV_max was determined. Results: The highest mean and median values of SUV_max were observed in patients with diffuse large B‐cell lymphoma (DLBCL), the lowest mean and median values were found in small lymphocytic lymphoma. The overlap in SUV_max < 10 between DLBCL and the other subgroups of NHL was very significant. Statistically, no correlation was found between the lactate dehydrogenase and SUV_max values. On the other hand, a correlation of the Ki‐67 proliferative index of tumour cells and SUV_max was revealed (r = 0.409, P < 0.001). The geometric mean of SUV_max in patients with Ki‐67 ≤ 60 and those with Ki‐67 > 60 was 8.8 and 14.3, respectively (P < 0.001). Conclusions: The results confirm that SUV_max is not beneficial for making a more precise diagnosis in most patients with NHL. Correlation of SUV_max with the Ki‐67 values suggests that SUV_max might have a prognostic values in NHL.     

The prognostic value of interim positron emission tomography scan in patients with classical Hodgkin lymphoma

The prognostic value of interim positron emission tomography (PET) was evaluated after 2 cycles of doxorubicin, bleomycin, vinblastin and dacarbazine in classical Hodgkin lymphoma patients (n = 229), based on Deauville criteria. In early stage non‐bulky disease, bulky stage II disease, advanced stage low International Prognostic Score (IPS ≤2) and advanced stage (IPS ≥3), 3‐year progression‐free survival rates in PET2‐negative vs. PET2‐positive groups were 95·9% vs. 76·9% (P < 0·0018), 83·3% vs. 20·0% (P = 0·017), 77·0% vs. 30·0% (P < 0·001) and 71·0% vs. 44·4%(P = 0·155), respectively. The outcome after positive PET2 was better than previously reported. The results from non‐randomized studies of PET2‐guided therapy would be valuable with careful interpretation.     

Placental involvement by non‐Hodgkin lymphoma in a Crohn disease patient on long‐term thiopurine therapy

We report the first published case of aggressive diffuse large B‐cell (non‐Hodgkin) lymphoma in a 35‐year‐old pregnant woman who had Crohn disease and was taking long‐term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.     

18F‐FDG PET‐CT and trephine biopsy assessment of bone marrow involvement in lymphoma

The ability of positron emission tomography‐computerized tomography (PET‐CT) to accurately detect bone marrow involvement (BMI) has been suggested in Hodgkin lymphoma (HL) and diffuse large B‐cell lymphoma (DLBCL), but its abilities in other histologies is less established. The aim of this retrospective study was to confirm the role of PET‐CT in detecting BMI in DLBCL and HL, and to explore its usefulness in other subtypes. Of the 149 newly diagnosed patients, common subtypes included DLBCL, follicular lymphoma (FL) and HL. In DLBCL, the sensitivity and specificity of PET‐CT at diagnosis were 75% and 92%. In FL, the sensitivity and specificity of PET‐CT were 67% and 85% at diagnosis, and 73% and 89% at relapse. In HL, the sensitivity and specificity were 100% and 74%. PET‐CT was able to detect BMI in patients with negative biopsies. Most of the patients in which PET‐CT failed to identify BMI were already advanced stage by imaging. In this analysis, PET‐CT was highly accurate for detecting BMI at diagnosis in DLBCL and HL and highly specific in FL at diagnosis and relapse. Results also suggested the diagnostic advantage of PET‐CT over bone marrow biopsy in detecting BMI. Prospective evaluation is necessary and may eliminate biopsies in future patients.     

Hodgkin lymphoma patients in first remission: routine positron emission tomography/computerized tomography imaging is not superior to clinical follow‐up for patients with no residual mass

There is no consensus regarding optimal follow‐up mode for Hodgkin lymphoma (HL) patients that achieve complete remission following chemotherapy or combined chemo‐ and radiation therapy. Several studies demonstrated high sensitivity of positron emission tomography/computerized tomography (PET/CT) in detecting disease progression; however, these techniques are currently not recommended for routine follow‐up. This retrospective study conducted in two Israeli (N = 291) and one New Zealand academic centres (N = 77), compared a group of HL patients, followed‐up with routine imaging every 6 months during the first 2 years after achieving remission, once in the third year, with additional dedicated studies performed due to symptoms or physical findings (Group I) to a group of patients without residual masses who underwent clinically‐based surveillance with dedicated imaging upon relapse suspicion (Group II). Five‐year overall survival (OS) was 94% and median time to relapse was 8·6 months for both modes. Relapse rates in Groups I and II were 13% and 9%, respectively. During the first 3 years of follow‐up, 47·5 and 4·7 studies were performed per detected relapse in Groups I and II, respectively. The current study demonstrated no benefit in either progression‐free survival (PFS) or OS in HL patients followed by routine imaging versus clinical follow‐up. The cost was 10 times higher for routine imaging.     

Pre‐diagnosis cigarette smoking and overall survival in non‐Hodgkin lymphoma

We examined whether smoking prior to non‐Hodgkin lymphoma (NHL) diagnosis was associated with overall survival (OS) and conducted a meta‐analysis to assess the evidence relating pre‐diagnosis cigarette smoking with OS. Among 523 NHL patients, worse OS was suggested for greater pre‐diagnostic smoking habits when compared to never smokers. In the meta‐analysis (n = 5 patient populations), inferior OS was observed for greater number of cigarettes smoked per day, years of cigarette smoking, and pack‐years of cigarette smoking. The inferior survival was more pronounced for follicular than for diffuse large B cell lymphoma. Pre‐diagnosis cigarette smoking may adversely impact the survival of NHL patients.