Faculty Bibliography

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.

CONTEXT.—:The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery led to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings. OBJECTIVE.—:To develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma. DESIGN.—:The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, recommendations were derived based on the available evidence, strength of that evidence, and key judgements as defined in the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework. RESULTS.—:Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma. CONCLUSIONS.—:Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions on specimen suitability, diagnostic capabilities, and correct use of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.

OBJECTIVES:The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery lead to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings. THE AIM OF THIS REVIEW IS TO:develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma. METHODS:The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of the literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were derived based on the available evidence, the strength of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework. RESULTS:Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma. CONCLUSIONS:Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions about specimen suitability, diagnostic capabilities, and correct utilization of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.

Introduction: The advent of BTK inhibitors (BTKi; ibrutinib, acalabrutinib, zanubrutinib) has dramatically improved outcomes for many patients with B-cell malignancies including CLL/SLL, MCL, WM, and MZL. To ensure optimal patient outcomes with BTKi therapy, it is essential to maintain both ongoing therapy and patient quality of life. These dual goals require prompt recognition and management of the unique adverse events (AEs) associated with BTKi therapy. An online Interactive Decision Support Tool was developed to provide healthcare providers (HCPs) with case specific guidance on managing BTKi AEs (available at: https://urldefense.com/v3/__http://www.clinicaloptions.com/BTKiTool__;!!MXfaZl3l!Namm19tBWzwKg7-RIaURAO7q7OPuhWh5WaDfcuooLbzg4L7W0DN1VPAOXsKdkyfZ$ ). Here, we report HCP practice trend data for the management of various BTKi AEs collected with this online tool compared with recommendations from a panel of experts.
Method(s): The online tool was developed with input from 5 experts who provided BTKi AE management recommendations for specific patient scenarios. The online tool captured 164 unique clinical scenarios based on criteria including disease type, BTKi used, and the type and severity of the BTKi AE. To use the online tool, HCPs enter information about their patient case and their planned management strategy. The HCPs were then shown the management recommendation from the 5 experts for that specific BTKi AE scenario. After viewing the expert management recommendation, HCPs were asked if it had an impact on their intended management approach.
Result(s): Between September 2019 and July 2020, 754 unique case scenarios were entered into the BTKi AE tool, with 319 cases related to a specific BTKi AE, by 432 HCPs. Of HCPs who answered the optional demographics questions (n = 96), 65% of cases were entered by clinicians who treat <= 10 patients/year with BTKi and 51% of cases entered were for specific patients in their clinical practice. Most cases entered in the tool were for patients with CLL (69%) followed by MCL cases (15%). Cases involving ibrutinib treatment were most common in this analysis (82% of cases) with acalabrutinib treatment entered for the remaining 18% of cases. Zanubrutinib was not yet approved when this tool was created and therefore was not included as a BTKi option. The most common AEs selected by HCPs using the tool regardless of BTKi therapy were atrial fibrillation, bruising or bleeding, and diarrhea [Figure]. For patient scenarios treated with acalabrutinib, HCPs also frequently selected headache (24%) as an AE of interest [Figure]. Overall, the planned BTKi AE management strategy of HCPs for mild to moderate AEs matched the expert recommendations in 56% of cases with ibrutinib treatment and 79% with acalabrutinib treatment. There was lower concordance between HCPs and experts for the management of grade 3/4 events with either ibrutinib (42%; P <.0001) or acalabrutinib (36%; P <.0001). For example, for patient cases with grade 3/4 atrial fibrillation (n = 49), only 39% of HCPs would hold therapy whereas 41% indicated that they would continue therapy and 14% were unsure how to manage the AE. For HCPs who differed from expert recommendations, only 42% of respondents who entered mild to moderate AEs indicated that the expert recommendations provided by the tool changed their management plan, but 81% of respondents who entered grade 3/4 events would change their management plan.
Conclusion(s): These data suggest that management of BTKi AEs by HCPs often diverges from evidence-based expert recommendations, especially grade 3/4 AEs. Use of an online tool providing easy access to BTKi AE management recommendations may improve patient care and safety. A detailed analysis of the tool, including case entries and planned management vs expert recommendations will be presented. [Formula presented] Disclosures: Awan: Blueprint medicines: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Astrazeneca: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Genentech: Consultancy; Gilead Sciences: Consultancy; Kite Pharma: Consultancy; Dava Oncology: Consultancy. Leonard: MEI Pharma: Consultancy; Bayer: Consultancy; Gilead/Kite: Consultancy; Karyopharm: Consultancy; GenMab: Consultancy; BMS/Celgene: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Sutro: Consultancy; Miltenyi: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; ADC Therapeutics: Consultancy. Vose: AbbVie: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; Incyte: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Epizyme: Honoraria, Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Allogene: Honoraria; Bristol-Myers Squibb: Research Funding; Miltenyi Biotec: Honoraria; Wugen: Honoraria; Roche/Genetech: Consultancy, Honoraria, Other; Celgene: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Janssen: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding. Flowers: Denovo Biopharma: Consultancy; Kite: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; OptumRx: Consultancy; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Acerta: Research Funding; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy.
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The role of radiotherapy (RT) in the management of advanced Hodgkin Lymphoma (HL) is inadequately defined in this era of functional imaging with PET scan. SWOG-S0816 treated advanced stage Hodgkin lymphoma patients with ABVD+/- escBEACOPP and no RT. We queried whether RT might have benefited patients in S0816 who would have met the GHSG-HD15 criteria for RT by simulating RT use as per HD15 criteria of PET + residual disease ≥2.5 cm. Receiver-operating-characteristics analyses were performed by varying disease-control rates within radiation fields and size cutoffs for residual disease. Among the 49 PET3+ S0816 patients, RT would have raised the 2-year PFS from 30.6% to 50.2-58.1% using three residual disease cutoffs (1.5, 2.0 and 2.5 cm) and assuming 80 and 90% in-field control rates . Although there may be improvement in PFS as size cutoff point is lowered, consequential toxicities from RT require further definition to assess relative benefits.

PURPOSE:Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity. METHODS:Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy. RESULTS:Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes. CONCLUSION:To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.

New York City has been at the epicenter of the coronavirus disease 2019 (COVID-19) pandemic that has already infected over a million people and resulted in more than 70,000 deaths as of early May 2020 in the United States alone. This rapid and enormous influx of patients into the health care system has had profound effects on all aspects of health care, including the care of patients with cancer. In this report, the authors highlight the transformation they underwent within the Division of Hematology and Medical Oncology as they prepared for the COVID-19 crisis in New York City. Under stressful and uncertain conditions, some of the many changes they enacted within their division included developing a regular line of communication among division leaders to ensure the development and implementation of a restructuring strategy, completely reconfiguring the inpatient and outpatient units, rapidly developing the ability to perform telemedicine video visits, and creating new COVID-rule-out and COVID-positive clinics for their patients. These changes allowed them to manage the storm while minimizing the disruption of important continuity of care to their patients with cancer. The authors hope that their experiences will be helpful to other oncology practices about to experience their own individual COVID-19 crises.

As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

Lenalidomide is an immunomodulatory drug approved in the United States for use with rituximab in patients with relapsed/refractory follicular lymphoma. We reviewed data from trials addressing the safety and efficacy of lenalidomide alone and in combination with rituximab as a first-line therapy and as a treatment of patients with relapsed/refractory follicular lymphoma. Lenalidomide-rituximab has been demonstrated to be an effective chemotherapy-free therapy that improves upon single-agent rituximab and may become an alternative to chemoimmunotherapy.