Relevance of Bone Marrow Biopsies for Response Assessment in US National Cancer Institute National Clinical Trials Network Follicular Lymphoma Clinical Trials.

PURPOSE: Bone marrow biopsies (BMB) are performed before/after therapy to confirm complete response (CR) in patients with lymphoma on clinical trials. We sought to establish whether BMB add value in assessing response or predict progression-free survival (PFS) or overall survival (OS) outcomes in follicular lymphoma (FL) subjects in a large, multicenter, multitrial cohort. METHODS: Data were pooled from seven trials of 580 subjects with previously untreated FL through Alliance for Clinical Trials in Oncology (Alliance) and SWOG Cancer Research Network (SWOG) completing enrollment from 2008 to 2016. RESULTS: Only 5/580 (0.9%) had positive baseline BMB, CR on imaging, and subsequent positive BMB (P < .0001). Therefore, BMB were irrelevant to response in 99% of subjects. A sensitivity analysis of 385 FL subjects treated on an Eastern Cooperative Oncology Group study was included. In the Eastern Cooperative Oncology Group cohort, 5/385 (1.3%) had BMB that affected response assessment. Since some subjects do not undergo confirmatory BMB, we performed a landmark survival analysis from first radiologic CR with data from 580 subjects from Alliance and SWOG. Of subjects with CR on imaging (n = 187), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 47) versus those without repeat BMB (n = 140; PFS: adjusted hazard ratio, 1.10, 95% CI, 0.62 to 1.94, log-rank P = .686; OS: hazard ratio, 0.59, 95% CI, 0.23 to 1.53, log-rank P = .276). CONCLUSION: We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment.

The evolving use of minimal residual disease (MRD) assessment in chronic lymphocytic leukemia.

The treatment of chronic lymphocytic leukemia (CLL) has changed remarkably throughout the past decade, with patients achieving deeper and more durable responses. Importantly, this clinical activity has been found to translate to prolonged survival. With some treatments, these responses are now allowing patients to stop therapy after 1 or 2 years, a concept referred to as "fixed duration." However, not all patients experience these outcomes. How to determine which patients can safely stop treatment remains unclear. Minimal residual disease (MRD) is emerging as a prognostic biomarker. In CLL, undetectable MRD has been shown to correlate with prolonged progression-free survival and, in some cases, overall survival. The incorporation of MRD status into clinical decision-making is not yet widely done, primarily based on the lack of prospective clinical trial data. As the endpoint of MRD status becomes more common in clinical trials of CLL, the role in the clinical setting will become more clear. Furthermore, prognostic models will help to determine the utility of MRD as a surrogate endpoint in clinical studies. This monograph examines clinical trial data regarding the role of MRD in CLL, and provides recommendations on how to incorporate MRD assessment into clinical management.

iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.

The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.

Pros and cons of rituximab maintenance in follicular lymphoma.

Follicular lymphoma (FL) is the most prevalent indolent non-Hodgkin lymphoma. Most patients present with advanced disease and are incurable with current therapy. The approval of rituximab has revolutionized the treatment of follicular lymphoma when administered in the induction setting for high-tumor burden disease, but the use of rituximab as a maintenance therapy (MR) continues to be a point of controversy. In this article, we review the main data and arguments in favor and against MR in FL. In summary, most studies have demonstrated a significant benefit in progression-free or event-free survival in this notoriously recurrent disease; however, long-term outcomes could not consistently demonstrate to be improved with this intervention. In a meta-analysis of randomized trials overall survival (OS) showed a tendency to improvement when given to patients in relapse, but no single study reached a significant OS advantage. The risk of high-grade transformation does not seem to be reduced in prospective trials. On the other hand, MR clearly increases toxicity without an improvement in quality of life. Finally, MR is expensive, and it is not proven that the delayed relapse time can compensate for these costs. In conclusion, despite the proven increase in progression-free survival, MR can't be recommended as a standard for the treatment of FL.

FDG-PET for Early Response Assessment in Lymphomas: Part 1-Hodgkin Lymphoma.

Interim positron emission tomography (PET)/CT has shown encouraging results when used as a prognostic tool early in the course of treatment of advanced Hodgkin lymphoma, allowing for a reduction in treatment for patients with favorable characteristics, while suggesting a benefit from changing therapy for those with a positive scan. For patients with limited disease, a negative scan allows for a decrease in treatment; however, the benefits for those patients whose scans are positive are less certain. Here we critically analyze the role of PET/CT in the early assessment of Hodgkin lymphoma. In Part 2, we will review the role of interim PET/CT in diffuse large B-cell lymphoma (DLBCL), and also explore the question of whether new approaches to quantitative assessment improve the prognostic value of interim PET scans in both Hodgkin lymphoma and DLBCL.

FDG-PET for Early Response Assessment in Lymphomas: Part 2-Diffuse Large B-Cell Lymphoma, Use of Quantitative PET Evaluation.

In Part 1, we reviewed the role of interim positron emission tomography (PET)/CT scans in Hodgkin lymphoma. In advanced Hodgkin lymphoma, interim PET is a useful prognostic tool that can be used to implement risk-adapted therapy with potential benefits for both patients who have negative interim scans and those whose scans are positive. Interim PET/CT has not shown as encouraging results in diffuse large B-cell lymphoma (DLBCL), with the exception of germinal center B-cell DLBCL. Thus, quantitative methods of interpreting interim PET scans have been pursued in an effort to improve their predictive value. Early results using the change in maximal standardized uptake value between baseline and interim PET (ΔSUVmax) to quantitatively interpret interim PET scans in DLBCL patients showed promise, but later results were contradictory. Thus, there is not firm evidence of a prognostic value for interim PET interpreted using either visual or ΔSUVmax-based analysis in patients with DLBCL. Nor are there data to support altering treatment in DLBCL on the basis of an interim PET scan. More sophisticated methods of quantitative interpretation of interim PET, using metabolic tumor volume and tumor lesion glycolysis measurements, have been investigated in both Hodgkin lymphoma and DLBCL. Although to date studies of these approaches have been small and heterogeneous, they do provide some support for the potential of a PET-derived volumetric approach to discriminate between risk groups better than ΔSUVmax; this remains to be proven in well-designed large-scale studies.

Investigator and independent review committee exploratory assessment and verification of tumor response in a non-Hodgkin lymphoma study.

Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accurate and reliable measurement and identification of tumors. Regulatory agencies recommend blinded reviews of imaging data by independent review committees (IRCs). Differences in response outcomes that arise between IRCs and site investigators raise regulatory/sponsor concerns. Here, we evaluate discrepant tumor response assessments by the IRC and unblinded investigators (complete versus partial response, respectively) occurring in 52 (13% of 393 IRC-assessed responders) of 447 enrolled patients with treatment-naïve non-Hodgkin lymphoma from a randomized study. The IRC and investigators were 'likely correct' in 73% and 25% of cases, respectively (p < .001). Investigators were more likely to make errors by misinterpreting lymph node data and not utilizing PET results. This post hoc finding suggests a possible role for post-training site evaluation/audit, with retraining as needed, and a specialized consensus committee for concurrent blinded review of site/central data.

(18) F-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.

Rethinking clinical response and outcome assessment in a biologic age.

Standardized response criteria for lymphoma are critical for the evaluation of new therapies. Widely adopted recommendations, most recently the Lugano classification, have been developed primarily for assessment of conventional chemotherapeutic regimens. More recently, several classes of drugs, including immunomodulatory agents, B cell receptor pathway targeting kinases, and checkpoint (PD-1, PDL-1) inhibitors have demonstrated impressive activity in a broad range of histologies. However, they may be associated with features during treatment suggestive of progressive disease despite clinical benefit. Immune response criteria have been proposed for solid tumors, and a modification is needed to be more applicable to lymphomas. Following treatment, conservative use of imaging is recommended based on clinical indications. As newer targeted agents with unique mechanisms of action are developed, current response and follow-up criteria must be made sufficiently flexible for optimal evaluation.

Staging and response assessment in lymphomas: the new Lugano classification.

Staging and response criteria were initially developed for Hodgkin lymphoma (HL) over 60 years ago, but not until 1999 were response criteria published for non-HL (NHL). Revisions to these criteria for both NHL and HL were published in 2007 by an international working group, incorporating PET for response assessment, and were widely adopted. After years of experience with these criteria, a workshop including representatives of most major international lymphoma cooperative groups and cancer centers was held at the 11(th) International Conference on Malignant Lymphoma (ICML) in June, 2011 to determine what changes were needed. An Imaging Task Force was created to update the relevance of existing imaging for staging, reassess the role of interim PET-CT, standardize PET-CT reporting, and to evaluate the potential prognostic value of quantitative analyses using PET and CT. A clinical task force was charged with assessing the potential of PET-CT to modify initial staging. A subsequent workshop was help at ICML-12, June 2013. Conclusions included: PET-CT should now be used to stage FDG-avid lymphomas; for others, CT will define stage. Whereas Ann Arbor classification will still be used for disease localization, patients should be treated as limited disease [I (E), II (E)], or extensive disease [III-IV (E)], directed by prognostic and risk factors. Since symptom designation A and B are frequently neither recorded nor accurate, and are not prognostic in most widely used prognostic indices for HL or the various types of NHL, these designations need only be applied to the limited clinical situations where they impact treatment decisions (e.g., stage II HL). PET-CT can replace the bone marrow biopsy (BMBx) for HL. A positive PET of bone or bone marrow is adequate to designate advanced stage in DLBCL. However, BMBx can be considered in DLBCL with no PET evidence of BM involvement, if identification of discordant histology is relevant for patient management, or if the results would alter treatment. BMBx remains recommended for staging of other histologies, primarily if it will impact therapy. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale, and included in new PET-based response criteria, but CT should be used in non-avid histologies. The definition of PD can be based on a single node, but must consider the potential for flare reactions seen early in treatment with newer targeted agents which can mimic disease progression. Routine surveillance scans are strongly discouraged, and the number of scans should be minimized in practice and in clinical trials, when not a direct study question. Hopefully, these recommendations will improve the conduct of clinical trials and patient management.

Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.

The purpose of this work was to modernize recommendations for evaluation, staging, and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshop was held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, representing major international lymphoma clinical trials groups and cancer centers. Clinical and imaging subcommittees presented their conclusions at a subsequent workshop at the 12th International Conference on Malignant Lymphoma, leading to revised criteria for staging and of the International Working Group Guidelines of 2007 for response. As a result, fluorodeoxyglucose (FDG) positron emission tomography (PET)­computed tomography (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modification of the Ann Arbor descriptive terminology will be used for anatomic distribution of disease extent, but the suffixes A or B for symptoms will only be included for HL. A bone marrow biopsy is no longer indicated for the routine staging of HL and most diffuse large B-cell lymphomas. However, regardless of stage, general practice is to treat patients based on limited (stages I and II, nonbulky) or advanced (stage III or IV) disease, with stage II bulky disease considered as limited or advanced disease based on histology and a number of prognostic factors. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale. The product of the perpendicular diameters of a single node can be used to identify progressive disease. Routine surveillance scans are discouraged. These recommendations should improve evaluation of patients with lymphoma and enhance the ability to compare outcomes of clinical trials.

Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group.

PURPOSE: Recent advances in imaging, use of prognostic indices, and molecular profiling techniques have the potential to improve disease characterization and outcomes in lymphoma. International trials are under way to test image-based response­adapted treatment guided by early interim positron emission tomography (PET)­computed tomography (CT). Progress in imaging is influencing trial design and affecting clinical practice. In particular, a five-point scale to grade response using PET-CT, which can be adapted to suit requirements for early- and late-response assessment with good interobserver agreement, is becoming widely used both in practice- and response-adapted trials. A workshop held at the 11th International Conference on Malignant Lymphomas (ICML) in 2011 concluded that revision to current staging and response criteria was timely. METHODS: An imaging working group composed of representatives from major international cooperative groups was asked to review the literature, share knowledge about research in progress, and identify key areas for research pertaining to imaging and lymphoma. RESULTS: A working paper was circulated for comment and presented at the Fourth International Workshop on PET in Lymphoma in Menton, France, and the 12th ICML in Lugano, Switzerland, to update the International Harmonisation Project guidance regarding PET. Recommendations were made to optimize the use of PET-CT in staging and response assessment of lymphoma, including qualitative and quantitative methods. CONCLUSION: This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for [18F]fluorodeoxyglucose-avid lymphomas in clinical practice and late-phase trials.