Follicular lymphoma (FL) is the most common indolent lymphoma where a majority of patients have a favourable outlook with the median survival approaching 20 years. However, for a small subset of patients with early progression or refractory disease, the 5-year overall survival (OS) is remarkably poor. The limbic spoke with Professor John Seymour, Director of the Department of Haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital about the latest developments for patients with early progression of disease from the GALLIUM study.

“It’s certainly one of the most underappreciated lymphomas, probably because for many patients there is little impact on OS compared with age-matched controls. The exception has always been those with early progression. Those who show progression of disease at 24 months (POD24) have a particularly poor outcome, around a 50% risk of death within 5 years compared with an OS of 90% to 94% for patients without POD24,” notes Prof. Seymour.¹

Australia made headlines in FL for all the wrong reasons

FL is a B-cell lymphoma that makes up 20% to 30% of all non-Hodgkin lymphomas.² Within the last few decades, rates of all types of lymphoma in Australia have steadily increased. In 1982 there were 1,916 new cases diagnosed and in 2014 this jumpted to 5,882.³ Over the same period, the age-standardised incidence rate increased from 15 cases per 100,000 to 23 cases per 100,000. In 2018 the rate is predicted to remain at 22 cases per 100,000.³ Most patients are diagnosed in their late 60s or early 70s, and historically around 20% of these will have a POD24 event.⁴

“We don’t really know why there was an increase in the incidence of FL in Australia.⁵ That’s something we haven’t figured out yet. But with more patients and a consistent proportion having a POD24 event has meant here in Australia we’re seeing quite a few patients with an unacceptable prognosis,” notes Prof. Seymour.

Chemotherapy has worked for many, but not those with a POD24 event

The combination of rituximab with chemotherapy followed by rituximab has been a standard treatment for FL.⁶ The choice of chemotherapy backbones are dependant on patient and clinician preference, but include bendamustine, or cyclophosphamide, vincristine, doxyrubicin and prednisolone (CHOP) or cyclophosphamide, vincristine and prednisolone (CVP).⁶ Maintenance treatment with a monoclonal antibody is used for up to 2 years to prolong remission, although it is unlikely to be curative.⁶ Yet, around 20% will progress while on maintenance treatment within 2 years.⁴

“What is also unfortunate is that not only have we not been able to change the outcome for these patients experiencing an early event,we have also not ben able to identify them propsectively. POD24 is a retrospective treatment outcome that is of limited clinical utility because it cannot be used to guide our up-front treatment decisions,” points out Prof. Seymour.

Turning the tide with a new treatment

However, things might be starting to change for those currently at risk of a POD24 event – even if we don’t accurately know who these patients are from the outset. This is due to results from the GALLIUM study which looked at the anti-CD20 monoclonal antibody obinutuzumab compared with rituximab (each combined with a chemotherapy backbone) in patients with previously untreated FL.^7,8

“What we found in GALLIUM is that as expected, around a fifth (16%) of patients had a POD24 event in the rituximab arm. But in the obinutuzumab arm, only 9% of patients had a POD24 event. Now that’s very exciting as that’s a 46% relative risk reduction in a POD24 event, and it’s the first time we’ve been able to change the odds for patients with FL,” notes Prof. Seymour.⁸

What’s even more promising is that reducing the incidence of POD24 events appears to have an enduring impact.⁸ In patients who did not experience a POD24 event, the OS was similar between the treatment groups.⁸ “That’s good news, because it means the effect we see on POD24 is truly meaningful, we’re not just delaying the inevitable. Treatment appears to be making an enduring difference,” explains Prof. Seymour.⁸ “Plus, for the first time we have identified stratification of risk within the POD24 subjects. We’re now able to study those who progress at 6 months compared to those at 12 months and 18 months and look for markers we might be able to use to develop some prognostic markers and treatment targets in the future. This study has really opened the gates to understand the fundamental biology behind early relapse in FL – its an exciting phase to witness.”⁸

Obinutuzumab has recently been listed on the PBS as an induction treatment for follicular lymphoma in Stage II bulky or Stage III/IV FL in combination with chemotherapy followed by obinutuzumab maintenance.⁹ The ideal choice of backbone is something Prof. Seymour thinks will take some time yet to define. “Treatment for FL now is really about better tailoring the combination and intensity of therapy to match the biology of the patient’s disease and the patient’s physiologic status. Until now, we haven’t been able to preselect based on biology, therefore we’re probably over-treating some patients and under-treating others. For now, we need to understand as much as we can about the underlying biology, especially for those who are at risk of a POD24 event.”

Prof. Seymour has received honoraria from Roche and Genentech.

This article was sponsored by Roche, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Roche.

References:

1. Casulo C, et al. J Clin Oncol 2015;33(23):2516-2522.
2. Leukaemia Foundation. Follicular lymphoma. Available at: https://www.leukaemia.org.au/disease-information/lymphomas/non-hodgkin-lymphoma/other-non-hodgkin-lymphomas/follicular-lymphoma/ (accessed 18 October 2018).
3. Australian Government. Australian Institute of Health and Welfare. Cancer compendium: information and trends by cancer type. Available at: https://www.aihw.gov.au/reports/cancer/cancer-compendium-information-trends-by-cancer/report-contents/lymphoma (accessed 18 October 2018).
4. Jurinovic V, et al. Blood 2016;128(8):1112-1120.
5. Vajdic C. What’s causing the spike in non-Hodgkin lymphoma? 21 Nov 2012. Available at: https://newsroom.unsw.edu.au/news/health/whats-causing-spike-non-hodgkin-lymphoma (accessed 18 October 2018).
6. Lymphoma Austarlia. Follicular lymphoma fact sheet. Available at: https://engonetlymaus.blob.core.windows.net/assets/uploads/files/Fact%20Sheets/LYA084_FL_FactSheet_FA(web).pdf (accessed 18 October 2018).
7. Marcus R, et al. N Engl J Med 2017;377:1331-44.
8. Launonen A, et al. Early disease progression predicts poorer survival in patients with follicular lymphoma (FL) in the GALLIUM study. Poster presented at the 59^th ASH Annual Meeting & Exposition, December 9-12 2017, Atlanta Georgia, USA.
9. Australian Government. Department of Health. Pharmaceutical Benefits Scheme. Available at: pbs.gov.au (accessed 18 October 2018).