Educational theme | PET as a prognostic tool in lymphoma

This month, the Lymphoma Hub will be concentrating on the value of positron emission tomography (PET) as a prognostic tool in lymphoma. The emergence of fluorodeoxyglucose-PET (FDG-PET) and PET-computed tomography (PET-CT) over the past few decades has heavily impacted the diagnosis, staging, and treatment of lymphoma.¹ This introductory article will touch on some of the studies that have led to the discovery of PET as a diverse prognostic tool in lymphoma.

Imaging in lymphoma

Nuclear imaging techniques have been used in the diagnosis of lymphoma since the late 20^th century. Unlike classic standalone CT scans, nuclear technology allows the differentiation between tumor tissue and fibrosis.² Gallium scans were the first to be implemented in lymphoma and are occasionally still used today. Gallium scans involve injection of radioactive gallium-67/68 (⁶⁷Ga/⁶⁸Ga), to diagnose, stage, and follow-up on malignant tumors, including lymphoma.² In contrast to the previously adopted gallium scans, PET technology can identify disease in normal-sized lymph nodes and is now used routinely along the treatment course of lymphoma.³ End-of-treatment assessment using FDG-PET and PET-CT became obligatory for Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) in 2005 and was subsequently recommended for disease staging assessment in 2014.⁴ More recently, interim FDG-PET-CT (iPET) has been explored as a predictive biomarker and there is hope that it will facilitate the shift to personalized treatment regimens, thereby improving patient outcomes.

iPET in DLBCL

Two abstracts presented at the 61st  American Society of Hematology (ASH) Annual Meeting & Exposition explored the potential use of PET in patients with DLBCL — read coverage by the Lymphoma Hub here.

Firstly, Corinne Eertink, Amsterdam University Medical Center (UMC), Amsterdam, NL, presented data from a retrospective meta-analysis of individual patient data from the PETRA database.⁵ The study aimed to determine whether iPET could be used as an early biomarker to predict response to treatment in patients with DLBCL. The study assessed patients with DLBCL who were treated with rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). iPET scans following 1–4 cycles of treatment and survival data were available. Results from this study demonstrate that iPET was prognostic for survival and could discriminate between responding and non-responding patients after therapy.

The second presentation was given by Daniel O. Persky, University of Arizona College of Medicine, Tuscon, US, who reported data from the largest study of limited DLBCL in the rituximab era (NCT01359592).⁶ The aim was to cure limited-stage DLBCL using the hypothesis that PET-directed therapy could guide the treatment intensity. Patients with previously untreated DLBCL underwent three cycles of R-CHOP treatment. iPET was performed on Day 15–18 of Cycle 3 and was centrally reviewed. Patients with a negative iPET score received an additional cycle of R-CHOP, whilst those who were iPET-positive received Gy involved-field radiation therapy (IFRT) followed by ibritumomab tiuxetan. iPET-guided treatment did not have a significant impact on 5-year progression-free survival (PFS) or 5-year overall survival (OS) and patients receiving IFRT followed by ibritumomab tiuxetan had similar outcomes to those that where iPET-negative.

The Lymphoma Hub was also pleased to talk to our scientific advisory board member, Sonali Smith, who discussed which patients with DLBCL may benefit from PET-directed induction therapy.

PET-CT in FL

GALLIUM

The initial results of the GALLIUM trial (NCT01332968) demonstrate that patients with follicular lymphoma (FL) had a longer PFS after first-line obinutuzumab-based immunochemotherapy than with rituximab-based therapy.⁷ A secondary analysis of the trial assessed the prognostic value of PET-CT following first-line immunochemotherapy in the same FL patients.⁸ The results of this analysis indicate that PET is more accurate than CT in evaluating responses. PET assessment may be a useful early prognostic marker of PFS and OS and guide response-adapted therapeutic approaches.

The Lymphoma Hub conducted two further interviews on the use of PET in FL. Stefano Luminari, University of Modena and Reggio Emilia, Modena, IT, at the 24th Congress of the European Hematology Association (EHA) discussed the effectiveness of using FDG-PET to guide the treatment of patients with FL. Stefano Luminari mentions the 2014 study by Judith Trotman, Concord Repatriation General Hospital, Sydney, AU, that demonstrated improved PFS and OS in PET-negative patients.⁹ Additionally, he gives reference to the aforementioned GALLIUM trial.

At the 2019 International Conference on Malignant Lymphoma (ICML), Massimo Federico, University of Modena and Reggio Emilia, Modena, IT, discussed response-oriented maintenance based on minimum residual disease and PET in patients with FL. He discusses the interim results of the FOLL12 prospective, randomized, phase III trial that showed maintenance therapy with rituximab for two years was superior to any kind of response-adapted approach. Unlike results from other studies, the data suggest that PET-based diagnosis and treatment guidance is unable to improve patient outcome to therapy.¹⁰

iPET in advanced-stage HL

AHL2011

In January 2019, results from the randomized, multicenter, phase III AHL2011 trial (NCT01358747) were published in The Lancet Oncology.¹¹ The study investigated the effectiveness of iPET at personalizing treatments for patients with newly diagnosed, advanced HL. It was of particular interest to determine whether PET monitoring could permit the shift from increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP_escalated) to oxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in early responders so as to minimize BEACOPP-associated toxicity, whilst maintaining treatment efficacy. The study demonstrated that, by following interim PET monitoring, chemotherapy intensity could be reduced in patients who achieved early metabolic response without losing disease control.

SWOG S0816

The phase II Southwest Oncology Group (SWOG) S0816 trial (NCT00822120) investigated the long-term outcomes in patients who received PET-adapted therapy.¹² Patients were treated with two cycles of the front-line standard of care ABVD regimen and then a PET scan (PET2) was performed to evaluate the efficacy of the treatment. Patients achieving complete response on PET2 continued ABVD treatment for four additional cycles, while those who didn’t switched to eBEACOPP_escalated for six cycles.  After a median follow-up of 5.9 years (n = 331 eligible patients), PET2 was negative in 82% of patients and positive in 18%. Nearly one-quarter of the PET2-negative patients experienced relapse, demonstrating that the ABVD regimen has limitations and that a negative PET2 has a predictive value. Although PET2-positive patients who received eBEACOPP had a favorable PFS, the treatment was associated with a high rate of secondary malignancies.

Conclusion

Data from previous and ongoing studies suggest that using PET as an indicative biomarker in lymphoma may be an effective prognostic tool in many lymphoma subtypes. If routine iPET is implemented in treatment planning, it holds the possibility to increase survival rates, improve patient quality of life, and have a positive economic impact.