Novel Therapy Approaches to Follicular Lymphoma

Michael Northend1,2 · William Townsend1

Published online: 22 February 2021
© Springer Nature Switzerland AG 2021

Abstract
Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma. It is a disease characterised by a long median overall survival and high response rates to currently available chemotherapy and anti-CD20 monoclonal antibody therapy combinations. However, for a sub-group of patients the disease behaves aggressively, fails to respond adequately to initial therapy or relapses early. For others, the disease becomes resistant following multiple lines of therapy, and despite recent advances the main cause of death for patients with FL remains their lymphoma. A wide landscape of novel therapies is emerging and the role of individual agents in the FL treatment paradigm is still being established. Some agents, including the cereblon modulator lenalidomide, the phosphatidylinositol 3-kinase inhibitors idelalisib, copanlisib and duvelisib, and the EZH2 inhibitor tazemetostat have received regulatory approval in the USA or European Union and have entered clinical practice for relapsed FL. Other developments, such as the emergence of immunotherapies including CAR-T cell therapy and bispecific antibodies, are expected to fundamentally change the approach to FL treatment in the future.

⦁ Overview
Follicular lymphoma (FL) is the second most commonly diagnosed lymphoma in Europe and North America after diffuse large B-cell lymphoma (DLBCL) and is the most common form of indolent lymphoma. Although incurable for most patients with standard treatments, for many, the disease follows an indolent, slowly progressing course with excellent response rates to currently available immuno-chemotherapy, long periods of disease control and prolonged survival. However, a sub-group of patients presents with clinically aggressive disease, while some are refractory to or relapse early following initial therapy, and others develop refrac- tory disease following multiple lines of treatment. Accurate risk assessment at the time of diagnosis is challenging, and for a majority of patients with refractory disease or early progression, outcomes remain poor. For such patients there is an unmet need for effective early risk-stratification, with risk-adapted approaches to treatment, and novel therapeutic

 Michael Northend [email protected]
1 Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
2 Cancer Research UK and UCL Cancer Trials Centre, London, UK

strategies in both the first line and relapse settings in order to improve survival.

⦁ Epidemiology
The annual incidence rate of FL in the USA is 2.7 cases per 100,000 persons while in the UK, FL accounts for 16
% of all lymphoma diagnoses. Cases are roughly balanced between males and females. Incidence increases with age, and the median age at diagnosis is 65 years, although cases are seen in all adult age groups [1, 2].

⦁ Prognosis
Median overall survival (OS) is estimated to be around 25 years for FL. In an analysis of 1446 patients diagnosed between 1998 and 2009, 15-year OS was 65 % and median OS was not reached [3]. However for a sub-group of patients with refractory disease or early relapse, median OS is much shorter at around 5 years, and despite recent advances, the leading cause of death for patients with FL remains their lymphoma [4, 5]. A recent driver of improved OS is the widespread incorporation of the anti-CD20 monoclonal anti- body rituximab into treatment, as demonstrated in a Swedish registry study where sequential improvements in OS were

Key Points
While the median overall survival for follicular lym- phoma (FL) is in the region of 25 years, there remains an unmet need for novel treatment approaches for patients with refractory disease and early progression where outcomes are poor.
A number of agents have received regulatory approval and are entering routine clinical practice in the relapse setting. These include the cereblon modulator lenalido- mide, PI3K inhibitors, and the EZH2 inhibitor tazem- etostat, which represents the first approved targeted
biomarker-driven treatment in FL.
Treatments in development include immunotherapy such as CAR-T cell therapy and bispecific antibodies. These treatments have potential to dramatically change the treatment paradigm for patients who respond poorly to established immuno-chemotherapy approaches.
Improved characterisation of the genetic drivers of dis- ease and better risk assessment at diagnosis could lead to tailored treatment approaches for individual patients.

associated with increased rituximab use over a 10-year period [6]. When a complete response (CR) to initial immuno-chem- otherapy is maintained for 30 months (CR30) survival may be equivalent to that of the sex- and age-matched general population. In a retrospective analysis, 10-year OS was 87 % for CR30 patients (relative survival 100 %) and 53 % for non- CR30 patients showing that depth and duration of response are important predictors of survival [7].
Several prognostic scoring systems have been validated in FL. The Follicular Lymphoma International Prognostic Index (FLIPI) score incorporates five variables (age, num- ber of nodal sites, serum lactate dehydrogenase (LDH), haemoglobin, and disease stage). Low-, intermediate-, and high-risk groups had 10-year OS rates of 70%, 50%, and 35%, respectively in the original 1985–1992 data set and the score has also been validated in the rituximab era [8, 9]. The FLIPI2 score is predictive of progression-free sur- vival (PFS). Low-, intermediate-, and high-risk groups are demarcated according to serum beta-2 microglobulin, the presence of bone marrow lymphoma infiltration, maximum nodal diameter, haemoglobin, and age, with 3-year PFS rates of 91%, 69%, and 51%, respectively [10, 11]. Although the FLIPI remains widely used in practice, the surrogate meas- ure of PFS, predicted by the FLIPI2 score, may have particu- lar utility in a disease with such long median OS. However, neither score is sufficiently specific to accurately identify the most high-risk patients who fail treatment or progress early.
The simplified PRIMA Prognostic Index, designed for patients with high tumour-burden FL (HTBFL), uses two parameters: elevated beta-2 microglobulin (B2M) and the presence of bone marrow lymphoma infiltration. In the original cohort, 5-year PFS rates were 69%, 55%, and 37%, respectively for low-, intermediate-, and high-risk groups and for the whole cohort event-free survival (EFS) at 24 months was predictive of OS [12]. The clinico-genetic m7-FLIPI score combines mutations in seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11),
which carry varying prognostic significance, with the FLIPI score and the Eastern Cooperative Oncology Group perfor- mance score (ECOG PS). It produces low- and high-risk groups with 5-year failure-free survival (FFS) rates of 72% and 32%, respectively, and performs well for the identifica- tion of high-risk patients, but is no better than the FLIPI alone at identifying patients with a good prognosis. In one cohort, it was a sensitive predictor of progression of disease within 24 months of treatment (POD-24) in patients treated with rituximab with cyclophosphamide, doxorubicin, vin- cristine, and prednisolone (R-CHOP) or cyclophosphamide, vincristine, and prednisolone (R-CVP) and when tested in the GALLIUM cohort it was predictive of PFS in those treated with R-CHOP/R-CVP but not bendamustine [13–15]. Further significant genetic aberrations were identified in a SWOG S0016 sub-study where increased genomic complex- ity was associated with poor outcomes, VRK2 and FANCL mutations were associated with POD-24, CDKN2A/B muta- tions with inferior PFS, and CREBBP and TP53 deletions with inferior OS [16].
Around 20% of patients with FL experience POD-24,
which correlates with inferior OS. In the observational National LymphoCare study five-year OS was 50% for patients with POD-24 and 90% for those without early pro- gression, confirming its prognostic significance [17]. A ret- rospective analysis of POD-24 in 296 patients treated with bendamustine and rituximab (BR) again demonstrated poor OS (38% at 2 years) and also showed a majority of patients (76%) had histological high-grade transformation, suggest- ing that occult early transformation may be a driver of early progression in FL [18]. While POD-24 is clearly a reliable predictor of OS and may have a role in determining optimal treatment at progression, it does not allow for up-front risk stratification or tailoring of first-line treatment and therefore earlier risk-assessment at diagnosis is desirable.
FL is almost always 18F-fluorodeoxyglucose–positron
emission tomography (PET)-avid. In a retrospective analysis, a high total metabolic tumour volume (TMTV, > 510cm3) assessed by PET was predictive of inferior PFS in previously untreated FL and correlated with the presence of circulating tumour cells and cell-free DNA (both independently asso- ciated with inferior outcomes) [19]. Achieving a complete metabolic response (CMR) by PET following treatment

is predictive of superior survival and of note around 15% of patients with a CR by conventional computed tomogra- phy (CT) have a partial metabolic response (PMR) by PET [20]. In one trial achieving CMR after the fourth cycle of R-CHOP predicted superior PFS, while 2-year PFS and OS rates were both higher with CMR at the end of treatment. In the GALLIUM study, 2.5-year PFS was 87.4% for those with CMR post-induction versus 54.9% for non-CMR patients [21, 22].
The detection and persistence of the IGH/BCL2 translo- cation in peripheral blood as measurable residual disease following treatment can predict PFS in FL [23]. This was demonstrated in both treatment arms for patients treated in the GALLIUM study, but rates of MRD negativity were found to be higher in those treated with obinutuzumab as opposed to rituximab (92.6% vs 85.2%, p = 0.0034) [24]. Circulating cell-free DNA may become a valuable tool in predicting prognosis and monitoring response to treatment in FL, but further data are required to define its utility [19]. Finally, the tumour microenvironment composition may influence prognosis. In one study, using gene-expression profiling survival was superior for those with an increased expression of T-cell–associated genes and inferior when the microenvironment was composed of macrophages and den- dritic cells, although there is as yet no reliable, reproducible signal that can be applied in practice [25, 26].

⦁ Pathobiology
The 2016 World Health Organization classification recog- nises 4 entities – FL, in situ follicular neoplasia, duodenal- type FL, and paediatric-type FL (the latter 3 are beyond the scope of this review). FL is a neoplasm of germinal centre (GC) B-lymphocytes and cut sections of affected lymph nodes demonstrate a follicular pattern with a mixture of cen- trocytes and centroblasts, their ratio determining the tumour grading from 1 to 3b with a higher grade corresponding to a higher proportion of centroblasts. The typical immunophe- notype shows the pan B-cell markers CD19, CD20, CD22, and CD79a and usually B-cell lymphoma (BCL)2, BCL6, CD10, and surface immunoglobulin [27].
The t(14;18)(q32;q21) IGH/BCL2 translocation is present in 85% of cases. It causes overexpression of the BCL2 onco- gene promoted by the immunoglobulin heavy chain (IGH) regulatory regions. However, circulating cells harbouring the t(14;18) translocation have been identified at low levels in a high proportion (perhaps > 70%) of healthy individuals, most of whom never develop FL, in keeping with a multi-hit model where accumulation of further genetic aberrations is required for the development of the disease [28–30]. It has, though, been demonstrated in a registry study of pre- diagnostic blood samples that there is an increased incidence
of peripheral blood t(14;18) positive cells in those who later develop FL when compared to those who do not [31]. Other frequent recurrent mutations are observed in FL including in JAK-STAT, BCR-NFκB, and mTOR signalling pathway genes and the chromatin regulator genes CREBBP, EZH2, and KMT2D (MLL2), some of which have been utilised as therapeutic targets [32].
The tumour microenvironment within the neoplastic fol- licles is composed of T-cells and follicular dendritic cells (FDCs). In normal GCs CD4+ follicular helper (FH) T-cells are crucial for the survival and proliferation of GC B-cells and they also support malignant B-cell growth in FL, where the number of TFH cells within neoplastic follicles has been shown to correlate with the cell proliferation rate and tumour grade [33]. This may have prognostic significance or repre- sent a potential therapeutic target.

⦁ Treatment—Current Standard of Care
⦁ Early Stage I‑IIA, Amenable to Radiotherapy

FL is highly radiosensitive and radiotherapy (RT) is cura- tive in up to 50% of patients with early-stage disease [34]. Most relapses occur outside the radiation field and thorough assessment for occult sites of disease with bone marrow biopsy and PET is highly recommended [35]. PET upstages 10–60% of patients compared to CT and favourable out- comes (5-year PFS 68.9% and OS 96%) were reported from one cohort where PET was used for staging before RT [36]. In a randomised trial there was no loss of efficacy with 24Gy versus 40–45Gy, while in another study an increase in relapses within the radiation field was observed with 4Gy [37, 38]. Thus, 24Gy is established as the standard of care for this group.
A combined approach with radiotherapy and rituximab has also been investigated for early stage FL. In one single arm study, the 5-year PFS was 78% for the combination, while another study has shown that MRD monitoring after radiotherapy can predict prognosis and guide therapy with rituximab [39, 40].
⦁ Advanced‑stage Asymptomatic/Low Tumour Burden FL

Low tumour burden FL (LTBFL) is defined in the Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria as nodal or extra-nodal tumour mass with a diameter less than 7 cm; involvement of fewer than three nodal sites with a diameter greater than 3 cm; absence of systemic symptoms; no substantial splenic enlargement; no serous effusion; absence of local risk of compression; and no leukaemia or blood cytopenia [41]. Asymptomatic patients not meeting

these criteria may initially be managed expectantly or with single-agent rituximab.
The question of whether to start immediate treatment or follow a ‘watch and wait’ strategy was addressed in the pre-rituximab era in a randomised comparison between con- tinuous daily oral chlorambucil and no treatment where no difference in cause-specific or OS was found. In fact, 19 of 151 patients in the observation arm were alive and had not required treatment at 10 years [42]. In the Phase III ‘Watch- and-Wait’ study, patients with advanced-stage asymptomatic LTBFL were randomised to observation, 4 doses of rituxi- mab induction, or rituximab induction followed by mainte- nance (MR, 8 weekly for 2 years). At 3 years, 88% and 78% of the patients in the maintenance group and induction-only group, respectively, did not require treatment versus 46% in the observation group, with the differences between each rituximab treatment group and the observation group reach- ing statistical significance [43].
When LTBFL is treated with rituximab induction, re- treatment at each disease progression until treatment-failure, has been shown to be as effective as MR and reduces treat- ment exposure [44]. In an assessment of brief immunochem- otherapy with 2 cycles of BR followed by MR for those aged
≥ 60 with LTBFL, the overall response rate (ORR) and CR rate were 94% and 54%, respectively, and 2-year PFS was 85.4%, although 3 treatment-related deaths occurred during maintenance and hence the regimen was not recommended [45].
⦁ Advanced‑stage Symptomatic FL

The addition of rituximab to a CVP or CHOP backbone is the only intervention to date to have demonstrated an OS benefit for previously untreated HTBFL [46, 47]. In a three- way comparison between R-CHOP, R-CVP, and rituximab, fludarabine and mitoxantrone (R-FM), PFS and TTF were superior for R-CHOP compared to R-CVP, but increased toxicity was associated with R-FM [48]. However, many cli- nicians opt to reserve anthracycline for those with proven or suspected high-grade transformation. BR had a better PFS and favourable toxicity profile when compared to R-CHOP or R-CVP for the treatment of indolent non-Hodgkin lym- phoma (iNHL) in the BRIGHT and STiL studies, and hence BR is now frequently used for first-line treatment of HTBFL [49, 50]. Autologous stem cell transplantation (ASCT) fol- lowing first-line therapy has no proven OS benefit and is not recommended [51].
MR every 8 weeks for 2 years following R-CHOP, R-CVP, or rituximab, fludarabine, cyclophosphamide and mitoxantrone (R-FCM) improved PFS, but not OS, when compared to observation in advanced-stage HTBFL, and the benefit was sustained at a median follow-up of 9 years in the
Phase III PRIMA study [52, 53]. Longer-term MR following rituximab induction, for a maximum of 5 years or until pro- gression, did not increase EFS, but did increase toxicity in a comparison with short MR 2 monthly for 4 doses [54]. There has been no prospective randomised trial assessing MR after BR; however, in one retrospective analysis, patients in par- tial response (PR) following BR had increased duration of response (DOR) with MR, but those in CR did not and the possibility of omitting MR for FL in CMR by PET is the subject of ongoing prospective trials [55, 56]. Subcutaneous rituximab is as efficacious and safe as intravenous and may be preferable in some settings [57].
Obinutuzumab, a glycoengineered humanised type-2 anti- CD20 monoclonal antibody, is associated with increased antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, and less complement-dependent cytotoxicity (CDC), when compared to type 1 antibodies, thus avoid- ing some proposed mechanisms of rituximab-resistance [58]. It was assessed in first line treatment in the Phase III GALLIUM trial where patients received R-chemotherapy (CHOP, CVP, or bendamustine) or obinutuzumab (O)- chemotherapy induction then maintenance with the same antibody 8 weekly for 2 years. The obinutuzumab group had superior 3-year PFS (80% vs 73.3%, HR 0.66 (0.51–0.85, p = 0.0012)), with a benefit across all chemotherapy back- bones as reported separately, and 5-year PFS remained sig- nificantly higher for obinutuzumab in a subsequent analysis [59–61]. At latest follow-up there were numerically more grade 3–5 adverse events (AEs) in the O arm (472 vs 425) with more episodes of grade 3–5 febrile neutropenia (45 vs 28) and infusion reactions (74 vs 45) in the O arm than the R-arm but an identical number of fatal AEs in each arm (n
= 25 in each arm, 4.2%) [62].
⦁ Grade 3B and Transformed FL (tFL)

FL grade 3B presents as a clinically more aggressive entity akin to DLBCL and is typically treated as such. A retro- spective review demonstrated improved outcomes when anthracycline was used in first line therapy and observed no relapses beyond 5 years implying that the disease may be curable with high-grade lymphoma-directed therapy [63].
In a review of patients treated for tFL, the 5-year OS rate was 64.3%, comparable to reported outcomes for de novo DLBCL [64]. Outcomes are inferior for sequential transfor- mation in previously diagnosed FL as opposed to composite/ discordant transformation at the time of initial diagnosis and the benefit of consolidation ASCT seems to be limited to the former [65, 66].

⦁ Relapsed FL

There is no standard of care for relapsed FL, and the choice of therapy should take into account patient- and disease- related factors including tumour burden, symptoms, prior treatments, duration of response, and PS.
For iNHL, previously responsive to a rituximab-contain- ing regimen, re-induction with obinutuzumab monotherapy followed by 2 years of maintenance had a superior ORR, but not PFS, when compared to rituximab in a randomised trial [67]. For FL refractory to rituximab (failure to respond to, or progression during or within 6 months of, any rituximab- containing regimen) obinutuzumab with bendamustine (OB, 90 mg/m2 for 2 days per cycle) improved PFS and OS when compared to bendamustine monotherapy (120 mg/m2 for 2 days). Median PFS was 25.8 months versus 14.1 months in favour of OB. At 31.8 months median follow-up OS events occurred in 25.5% of patients in the OB arm and 34.9% of patients in the bendamustine arm (HR for OS 0.67; 95 % CI 0.47–0.96; p = 0.0269) [68, 69]. OB is thus an option for rituximab-refractory FL, but benefit has not been demon- strated in rituximab-responsive disease.
At relapse, options include treatment with an alterna- tive first line regimen (such as BR, R-CVP, or R-CHOP in anthracycline-naïve patients), or platinum-based salvage combinations, after which ASCT consolidation can be considered [70–73]. A review of 70 patients undergoing ASCT for FL reported 7-year OS and PFS of 76% and 60%, respectively, and found no relapses beyond 6.4 years sug- gesting that durable remissions may be achieved for some patients [74]. ASCT may be of particular benefit after early progression—in one cohort OS was improved for patients undergoing ASCT within 1 year of early progression but not in patients undergoing ASCT later [75]. In a comparison of ASCT with matched sibling donor (MSD) and matched unrelated donor (MUD), allogeneic haematopoietic stem cell transplantation (allo-HSCT) for patients with POD-24 OS was comparable for ASCT and MSD patients, and inferior for MUD, but non-relapse mortality (NRM) was higher for both allo-HSCT subtypes, confirming ASCT as the most appropriate consolidation for most patients with POD-24 [76]. No survival benefit has been found for rituximab purg- ing pre-ASCT; however, improved PFS was observed with MR 2 monthly for 4 doses following transplant, although this is not routinely used [77].
Allo-HSCT provides a potentially curative option for
sufficiently fit patients with relapsed FL [78]. Myeloabla- tive allo-HSCT is associated with high NRM, but good outcomes were reported from a prospective UK study of 82 FL patients undergoing T-cell–depleted allo-HSCT with reduced-intensity conditioning (RIC). Four-year PFS was 76%, NRM was 15%, and the incidence of chronic extensive graft-versus-host disease was 18%, with better outcomes for
MSD compared to MUD [79]. RIC allo-HSCT can therefore be considered for some younger patients with relapsed FL.

⦁ Recent and Emerging Therapeutic Approaches to FL
The range of new treatment approaches in FL is summarised in Table 1. Some have received regulatory approval for the treatment of relapsed or refractory (R/R) FL in the USA (lenalidomide, idelalisib, copanlisib, duvelisib, and tazem- etostat) and the European Union (EU) (lenalidomide and idelalisib) and have entered routine clinical practice. Pivotal trials for agents that have received FDA approval are sum- marised in Table 2.
⦁ Cereblon Modulators

Lenalidomide is an orally administered immunomodulatory agent with direct and indirect anti-neoplastic activities. It targets cereblon in tumour cells with downstream effects reducing interferon regulatory factor 4 and inhibiting pro- liferative activity. It increases NK cell–mediated cytotox- icity and ADCC, enhances cytotoxic T-cell and dendritic cell activity, improves T-cell to malignant B cell synapse formation, reduces pro-inflammatory cytokines, and inhibits angiogenesis via interactions with the microenvironment, endothelial cells, and vascular endothelial growth factor. It has a synergistic effect in combination with anti-CD20 monoclonal antibodies [80–82].
Off-target effects include reduced granulopoiesis caus- ing neutropenia—in one study grade 3–4 neutropenia and thrombocytopenia were seen in 46% and 19% of patients, respectively. Significant non-haematological toxicities include increased risk of venous thromboembolism (man- dating prophylaxis with low molecular weight heparin or aspirin), skin reactions, and diarrhoea [81, 83].
Single-agent lenalidomide for the treatment of R/R iNHL given for a maximum of 52 weeks was assessed in a single- arm Phase II study. For FL patients, the ORR was 27% and for all patients the CR/unconfirmed CR (CRu) rate was 7% with median PFS of 4.4 months [83]. In contrast, when used in combination with rituximab (R2) in R/R iNHL, the ORR was 77% for FL patients with a median PFS for all patients of 12.4 months. In those patients with low affinity Fc pol- ymorphisms, the ORR was 61.5% demonstrating that the addition of lenalidomide may overcome this mechanism of rituximab-resistance [84]. Improved ORR (76% vs 52%) and CR rates (39% vs 20%) were seen in a Phase II randomised trial comparing single-agent lenalidomide to R2 and a high CR rate was seen in a single-centre Phase II study from the MD Anderson Cancer Centre [85, 86]. A Phase III study has assessed R2 for R/R iNHL, where patients received

Table 1 Summary of recently approved and emerging therapies in follicular lymphoma

Treatment class Agent
Immunomodulatory agents Small molecule inhibitors Lenalidomide, R2
PI3K inhibitors
Idelalisib
Copanlisib
Duvelisib
HDAC inhibitors

BCL2 inhibitor Vorinostat Abexinostat
Venetoclax

Immunotherapy

Antibody-drug conjugates

Proteasome inhibitor BTK inhibitor EZH2 inhibitor
Anti-CD19 CAR-T cell therapy Bispecific antibodies (CD20-CD3)

BiTE (CD19-CD3)
Checkpoint (PD1) inhibitor Anti-CD47 mAb
Anti-CD79b Anti-CD19 Anti-CD22
Bortezomib Ibrutinib Tazemetostat Tisagenlecleucel
Axicabtagene ciloleucel Mosunetuzumab Odronextamab Epcoritamab Glofitamab Blinatumomab Nivolumab
Hu5F9-G4
Polatuzumab vedotin Loncastuximab tesirine Inotuzumab ozogamicin
Agents with FDA marketing approval in italics

lenalidomide or placebo for a maximum of 12 cycles, with rituximab in cycles 1 through 5. Median PFS was 39.4 ver- sus 14.1 months in favour of the R2 group, and although the combination was overall well tolerated, increased rates of infection, cutaneous reactions, and neutropenia were seen when compared to rituximab alone [87].
In the first line setting, R2 was used in the large Phase III RELEVANCE study. Patients with previously untreated FL grade 1-3a, requiring treatment according to the GELF criteria, were randomly assigned to receive R2 consisting of lenalidomide for a maximum of 18 cycles and rituximab during induction and as maintenance, or to R-chemotherapy (R-CHOP, BR or R-CVP) for 6 cycles then MR. The study was designed to demonstrate superiority, but no differences in the rates of CR at 120 weeks or 3-year PFS were observed between the groups [88]. R2 was also compared to single- agent rituximab as first line treatment in a Phase II study which demonstrated superior CR rates and PFS with the combination. Lenalidomide with R-CHOP was evaluated in a single-arm Phase II trial where CR and CR30 rates were 74% and 69% [89, 90].
The evidence is compelling that R2 has more activity than either agent alone, and the regimen is attractive for patients with contraindications to chemotherapy in the first line set- ting, and also at relapse including in rituximab-refractory
patients. It is licensed for use in previously treated FL in both the USA and the EU and is thus, now an option in rou- tine clinical practice (Table 2). Lenalidomide in combina- tion with obinutuzumab has also shown activity in a Phase II study including first line and R/R patients and warrants further evaluation [91].
In addition, another cereblon modulator—avadomide (CC-122)—has been assessed in a Phase I dose escalation study in combination with obinutuzumab for R/R B-NHL with a median of 3 prior lines of therapy. Fifty-three of 73 patients in the study had FL and for all patients the ORR and CR rates were 68% and 34%, respectively, with 55.5% 12-month PFS [92].
⦁ Phosphatidylinositol 3‑kinase (PI3K) Inhibitors

The PI3K/Akt/mTOR pathway is constitutively activated in many B-cell malignancies. In both normal and malig- nant B-cells the PI3K enzymes lie downstream of the B-cell receptor and lead to cell proliferation via the nuclear fac- tor kappa-B (NFkB) pathway. Type IA PI3Ks, associated with signalling via receptor tyrosine kinases, are most often implicated in B-cell malignancies and are associ- ated with the tissue-specific isoforms α, β, and δ. Idelalisib and umbralisib have activity against PI3Kδ only, whereas

Drug Name Trial Name and Identifier Reference Patient Population Intervention Efficacy Safety
Lenalidomide RELEVANCE Morschhauser F et al. n=1030 Multicentre, interna- Median follow-up 37.9 R2: 65 % Gd 3-4 AE

Table 2 Summary of new agents which have received marketing authorisation from the United States Food & Drug Administration for the treatment of follicular lymphoma Indication

(Revlimid®) with rituxi- mab
Previously untreated and previously treated FL following 1 prior systemic therapy

Idelalisib (Zydelig®) FL following 2 prior systemic therapies
NCT01650701 NCT01476787

AUGMENT NCT01938001

DELTA NCT01282424
N Engl J Med 2018; 379:934-947

Leonard JP et al. J Clin Oncol 2019; 37:1188-
1199

Gopal AK et al. N Eng J Med 2014; 370:1008-
1018
Previously untreated FL grade 1-3a requiring treat- ment as per GELF criteria

n=358 (295 FL)
MZL or FL grade 1-3a
≥1 prior line of therapy Prior rituximab and not R-refractory

n=125 (72 FL)
Indolent B-cell NHL
≥2 prior lines of therapy Refractory to rituximab & alkylating agents
tional, randomised, open-label Phase III
1:1 randomisation: R2: Lenalidomide for
18 cycles. Rituxi- mab cycles 1-6. MR in patients with a response.
R-Chemotherapy (investigator’s choice – R-CHOP, BR, R-CVP)
followed by MR

Multicentre, interna- tional, randomised, placebo-controlled Phase III
1:1 randomisation:
R2: Lenalidomide for 12 cycles, rituximab cycles 1-5
Placebo plus rituximab

International single group, open label, Phase II
Oral idelalisib twice daily until progression, unacceptable toxicity or death
months
Co-primary end-points: CR/CRu at 120 weeks: R2 48 % (95 % CI 44-53)
R-Chemo 53 % (95 % CI
49-57) P=0.13
3-year PFS:
R2 77 % (95 % CI 72-80)
R-Chemo 78 % (95 % CI
74-82)
HR 1.10 (95 % CI 0.85-
1.43; P=0.48)
Median follow-up 28.3 months
Primary end point – PFS, median:
R2 39.4 months (95 % CI 22.9-not reached)
R-Placebo 14.1 months
(95 % CI 11.4-16.7)
HR 0.46 (95 % CI 0.34- 0.62;P=0.0001)
Primary end-point – ORR 57 % (95 % CI 48-66),
CR 6 %
Median DOR 12.5
months (range 0.03-
14.8)
Median PFS 11 months (range 0.03-16.6)
Median OS 20.3 months (range 0.7-22)
R-Chemo: 68 % Gd 3-4 AE
Fatal AEs 1 % in both groups
Cutaneous reactions grade 3-4 more common in R2 group
Grade 4 neutropenia more common in R-Chemo group
Second malignancy – 7 % R2 and 10 % R-Chemo
R2: 69 % Gd 3-4 AE
R-Placebo: 32 % Gd 3-4 AE
Gd 3-4 neutropenia
50 % R2 versus 13 % R-Placebo

AE Gd 3-4 in 54 %
Diarrhoea 13 %
Pneumonia 7 %
Neutropenia 27 % Raised ALT 13 %
Treatment discontinuation in 25 patients
3 deaths due to pneumonia during treatment

Novel Therapy Approaches to Follicular Lymphoma
459

Table 2 (continued)
Drug Name Indication

Trial Name and Identifier Reference Patient Population Intervention Efficacy Safety

Copanlisib (AliquopaTM)
FL following 2 prior systemic therapies

Duvelisib (Copiktra®) FL following 2 prior systemic therapies
CHRONOS-1 (indolent cohort)
NCT01660451

DYNAMO NCT01882803
Dreyling M et al. Ann Oncol 2017; 28:2169-
2178

Flinn IW et al. J Clin Oncol 2019; 37:912-
922
n=33 (16 FL)
Indolent NHL Relapsed or refractory after ≥2 prior lines of therapy

n=129 (83 FL) FL, MZL or SLL
≥1 prior line of therapy Refractory to rituximab & chemo/RIT
Prior alkylating agent or purine analogue
Open label, single arm Phase II
Intravenous copanlisib on day 1, 8 and 15 of a 28-day cycle until disease progression, worsening ECOG per- formance score to ≥3
or unacceptable toxicity
Open label, single arm, Phase II
Continuous twice daily oral duvelisib in 28-day cycles until disease pro- gression, unacceptable toxicity or death
Primary endpoint – ORR 43.8 % (90 % CI 28.7-
59.7), CR 6.3 %
Median DOR 390 days (range 0-825)
Median PFS 294 days (range 0-874)
Median OS 657 days (range 0-958)
Primary end-point – ORR 47 % (95 % CI
38-56), CR 1.6 %
Median DOR 10 months (95 % CI 6.5-10.5)
Median PFS 9.5 months (95 % CI 8.1-11.8)
Median OS 28.9 months (95 % CI 21.4-not
reached)
AE Gd 3-4 79.8 %
Hypertension 40.5 %
Hyperglycaemia 25 %
Neutropenia 29.8 % Lung infection 14.3 %
25 % treatment discontinu- ation due to AEs
⦁ treatment related deaths

AE Gd 3-4 88.4 %
Neutropenia 24.8 %
Diarrhoea 14.7 %
Thrombocytopenia 11.6 % Febrile neutropenia 9.3 % 31 % treatment discontinu-
ation due to AEs
⦁ treatment related deaths

Tazemetostat
(TazverikTM)
EZH2MT FL following 2 systemic therapies, or R/R FL with no treat- ment alternatives
NCT01897571 Morschhauser F et al. Lancet Oncol 2020;
21:1433-1442
n=99 (45 EZH2MUT and 54 EZH2WT)
FL grade 1-3b
≥2 prior lines of therapy
Open label, single arm, Phase II
Continuous twice daily oral tazemetostat in 28-day cycles until disease progression, unacceptable toxicity,
withdrawal of consent, or for up to 2 years of treatment
Primary end-point – ORR
EZH2MUT 69 % (95 % CI
53-82), CR 13 %
EZH2WT 35 % (95 % CI
23-49), CR 4 %
Median DOR 10.9
months (EZH2MUT), 13 months (EZH2WT)
Median PFS 13.8 months (EZH2MUT), 11.1
months (EZH2WT)
Median OS not reached for either group
AE Gd 3-4
Neutropenia 3 %
Thrombocytopenia 3 % 8 % discontinued due to
AEs
No treatment-related deaths

460
M. Northend, W. Townsend

AE adverse event, CR complete response, Cru unconfirmed complete response, DOR duration of response, FL follicular lymphoma, HR hazard ratio, MR maintenance rituximab, MZL marginal zone lymphoma, NHL non-Hodgkin lymphoma, ORR objective response rate, OS overall survival, PFS progression-free survival, R2 lenalidomide with rituximab, SLL small lymphocytic lym- phoma

copanlisib has most activity against α and δ, and duvelisib targets δ and γ [93].
Whilst efficacious in B-cell malignancies, significant toxicity has been associated with PI3K inhibitors, which has led safety warnings regarding infections including cyto- megalovirus (CMV) reactivation and Pneumocystis jirovecii pneumonia (PJP) in patients taking idelalisib [94–96]. A PJP rate of 2.5% was found in one retrospective analysis and CMV end-organ disease and invasive fungal infections have been reported [97–99]. In addition, immune-mediated toxicities including pneumonitis, hepatitis, and colitis are seen, possibly related to the effect of PI3K δ on regulatory T-cells (Tregs) [93, 100]. Careful attention should therefore be paid to antimicrobial prophylaxis and monitoring during treatment.
Daily idelalisib was given until disease progression or patient withdrawal in a Phase II study of 125 iNHL patients refractory to rituximab and alkylating agents. The ORR and CR rates were 57% and 6%, respectively, with a median DOR and PFS of 12.5 and 11 months, and grade ≥ 3 diar- rhoea, aminotransferase increase, or pneumonia occurred in 41% of patients [101]. In a study of its use via the UK compassionate access programme, also in double refractory patients, the ORR was 57% and the CR/CRu rate 15%. In those with a response, the median PFS was 14.1 months (for all patients it was 7.1 months) and a number of patients were bridged to allo-HSCT. Although idelalisib was well tolerated in most patients, 1 patient died due to CMV pneumonitis and treatment was discontinued in 7, mainly due to immune- related toxicities [102].
Copanlisib was assessed in patients with R/R indolent or aggressive lymphoma in a Phase II study where 16 of 32 patients in the indolent cohort had FL refractory to at least 2 prior lines of therapy. Patients received intravenous copanlisib on days 1, 8 and 15 of a 28-day cycle continued until progression or withdrawal. The ORR was 43.8% with CR/CRu in 9.4% and the median PFS and DOR were 294 days and 390 days, respectively. Pneumonitis of grade ≥ 3 occurred in 2 patients in the study [103]. Randomised Phase III studies of copanlisib in combination with rituximab or R-chemotherapy for R/R iNHL are ongoing [104].
Duvelisib was evaluated in 129 patients with iNHL refractory to rituximab and either chemotherapy or radio- immunotherapy in the Phase II DYNAMO study. The study included 83 patients with FL and treatment comprised daily oral duvelisib given until progression or withdrawal. The ORR was 47% and median DOR, PFS, and OS were 10, 9.5, and 28.9 months, respectively. Rates of toxicity includ- ing haematological AEs, diarrhoea, colitis, pneumonia, and aminotransferase increase were comparable to other trials of PI3K inhibitors, with serious opportunistic infection seen in less than 5% [105].
Overall, these studies demonstrate moderate activity for the PI3K inhibitors in R/R FL; however, treatment comes with a risk of toxicity, and larger-scale studies are required in order to fully define their position in the FL treatment paradigm. All three agents are licensed in the USA for use in relapsed FL following 2 or more prior lines of therapy, and idelalisib has received approval in the EU, and so these agents may now be used in routine practice (Table 2).
⦁ EZH2 Inhibitor—Tazemetostat

Tazemetostat is a first-in-class oral selective inhibitor of mutant or wildtype EZH2, an epigenetic regulator of gene expression and cell fate. It is highly expressed on GC B-cells, is essential for the formation of the GC, and is down-regulated on exit. Oncogenic mutations in EZH2 keep cells in the GC and are frequently found in FL. In an open-label Phase II study of tazemetostat 45 EZH2 mutated (EZH2MT) and 54 wildtype (EZH2WT) R/R FL patients were treated for 2 years, or until disease progression, unacceptable toxicity, or withdrawal. Forty-nine percent of EZH2MT and 59% of EZH2WT patients were refractory to a rituximab-con- taining regimen. The ORRs for the 2 groups, respectively, were 69% and 35% (CR rate 13% and 4%), the median PFS
13.8 months and 11.1 months, and overall the treatment was well tolerated [134]. The agent represents the first approved biomarker-directed therapy in FL and has received acceler- ated FDA marketing authorisation in the USA for use in R/R FL—it may be used following 2 prior lines of therapy in EZH2MT FL, and in EZH2WT patients where there are no other treatment options (Table 2).
6.4 Histone Deacetylase (HDAC) Inhibitors

Gene expression is regulated through opposing actions of HDACs and histone acetyltransferases (HATs). HATs pro- mote gene transcription, while HDACs cause transcriptional repression. HDAC inhibitors (HDACis) alter the balance between pro- and anti-apoptotic proteins, and cause cell cycle arrest, immune modulation, and impairment of angio- genesis. Two pan-HDACis with activity against class I, II and IV HDACs have been clinically tested in FL [106–108]. Vorinostat is an orally administered HDACi. In a Phase II study in R/R iNHL, 17 of 37 patients had FL. Treatment was given for 14 days of 21 and those with a response continued until progression. Those with a CR stopped treatment after a further 2 cycles but could restart in the event of relapse within 6 months. The ORR was 29% for all patients, but 47% for those with FL (CR 10.8%), and the median PFS was
15.4 months. Most grade 3–4 toxicities were haematological [109]. In another Phase II trial, vorinostat was given until disease progression or withdrawal for patients with iNHL following at least 1 prior line of therapy. For FL patients, the

ORR was 49% and the median PFS was 20 months and again most grade 3–4 AEs were haematological [110]. It has also been tested in combination with rituximab, continued until progression, in newly diagnosed or previously treated iNHL (22 of 28 had FL). For FL patients, the ORR was 41%, the CR rate was 27% and the 2-year PFS was 61%. Patients with CR were allowed to discontinue treatment and restart in the event of progression and 2 of 4 achieved a second CR [111]. Abexinostat, also an oral pan-HDACi taken twice daily, has been evaluated in two Phase II studies. The first study included patients with R/R FL and mantle cell lymphoma where 16% were refractory to their most recent treatment. For FL patients the ORR was 56.3%, 1 patient had a CR, and the median PFS was 20.5 months [112]. In the second study, patients with R/R NHL or chronic lymphocytic leu- kaemia received treatment until progression or withdrawal for another reason. Eighteen of 100 patients had FL and for these the ORR was 56% and the median DOR was 16 months [92]. The majority of grade 3–4 toxicities were haematological in both of these studies and, while there is concern about cardiac toxicity with HDACis including QT interval prolongation, this was seen in just 1 patient in each
study [112, 113].
Activity has therefore been demonstrated for the HDAC inhibitors in R/R FL, although larger scale studies will be required in order to define their place in the FL treatment paradigm.
⦁ BCL2 and BTK Inhibitors

Agents that disrupt the B-cell receptor signalling pathway, including the BTK-inhibitor ibrutinib and the BCL2 inhib- itor venetoclax, have shown activity in a range of B-cell malignancies including in FL. Ibrutinib was assessed in 2 single-arm Phase II studies in patients with R/R FL—the first reported an ORR of 20.9% and median PFS of 4.6 months, while in the second these were 20.5% and 14 months—a difference which may be explained by the higher propor- tion of rituximab and alkylating agent refractory patients in the former [135, 136]. Ibrutinib is also being assessed in combination with BR or R-CHOP in a Phase II, randomised, double-blind trial for patients with previously treated FL or marginal zone lymphoma [137].
Venetoclax has been assessed in Phase I studies in com- bination with R- or O-CHOP for patients with B-cell NHL including 24 FL patients with 0–1 prior line of therapy and in combination with bendamustine and rituximab for NHL patients with at least 1 prior line. A high CR rate (70% with venetoclax+R-CHOP and 80% with venetoclax+O-CHOP) was reported from the former study and the ORR was 75% for FL patients in the latter (median PFS for all patients 10.7 months) [138, 139]. Despite the clear biological rationale for BCL2 inhibition in FL, further studies are required to
determine whether the agent will bring about meaningful improvements in survival or whether other approaches to targeting BCL2 will be beneficial in this disease.
⦁ Antibody‑drug Conjugates

Polatuzumab vedotin comprises a monoclonal antibody targeting CD79b conjugated to the microtubule inhibitor monomethyl auristatin E. The drug is being taken forward for development in DLBCL, but had demonstrated activity in R/R FL grade 1-3a in a Phase II study. For FL patients treated with R-polatuzumab the ORR was 70%, with a CR rate of 45%, including a CR rate of 29% in those refractory to the most recent line of therapy, and median PFS was 15.3 months. The principle toxicities were neuropathy and cyto- penias [114].
Loncastuximab tesirine (ADCT-402) is a humanised monoclonal antibody directed against CD19 conjugated to a pyrrolobenzodiazepine dimer toxin, which binds the minor groove of DNA causing DNA damage that evades normal repair mechanisms. In a Phase I study, the drug was tested in 15 patients with R/R FL and 15 with R/R MCL who had no other available treatments. For patients with FL, the ORR and CR rates were high at 80% and 53.3%, respectively, and the median PFS and DOR were not reached after median follow-up of 7.56 months. Important toxicities include liver function test derangement, effusions, cytopenias and skin reactions [115]. Further studies of the agent in FL are expected.
Inotuzumab ozogamicin (IO), an anti-CD22 monoclonal antibody conjugated to the cytotoxic calicheamicin, was tested in combination with rituximab in a Phase II cohort including 34 patients with relapsed, but not refractory, FL and an ORR of 87% and a 2-year PFS of 68% were reported [116].
⦁ Immunotherapy—Chimeric Antigen Receptor (CAR)‑T Cells, Bispecific Antibodies and Checkpoint Inhibitors

Therapies harnessing the patient’s immune system to treat FL show significant promise. Autologous CAR-T cells typically target CD19 on the lymphoma cell surface, while bispecific antibodies bind both a tumour B-cell antigen (CD19 or CD20) and T-cells via CD3 in order to bring about an immune response.
High rates of CR with apparently durable responses have been demonstrated with the two approved CAR-T cell products in high-grade B-cell lymphoma (including tFL) in single arm Phase II commercial trials and promising out- comes have also been reported in FL [117, 118]. A Phase I/II study of CD19 directed CAR-T cells in FL included 8 patients with R/R FL and 13 with tFL. The CR rates were

88% and 46% for FL and tFL, respectively, and all patients with FL who achieved CR remained in remission after a median follow-up of 24 months post-treatment. Cytokine release syndrome (CRS) and neurotoxicity both occurred in 50% of FL patients and were more common in FL than tFL [119]. In another study from the University of Pennsylvania, 14 patients with FL were treated with CD19 CAR-T cells of which 8 were refractory to both rituximab and alkylating agents. The ORR was 79% and at 6 months the CR rate was 71%, the median PFS was not reached and at the median follow-up duration of 28.6 months, 70% remained progres- sion free [120]. Interim analysis the ZUMA-5 study of axi- cabtagene ciloleucel reported an ORR of 95% and CR rate of 80% for 80 FL patients. Grade ≥ 3 CRS and neurological events occurred in 19% and 11% of patients, respectively, for the whole iNHL cohort. Given such promising results, CAR-T cell therapy is expected to play an important role in the future management of FL and clinical trials of commer- cial products are ongoing [121–123].
The CD19-CD3 bi-specific T-cell engager (BiTE) blino-
tumumab was investigated for the treatment of R/R NHL in a Phase I dose escalation study including 28 FL patients. Of 15 patients treated at the target dose, 12 achieved an objec- tive response and 6 achieved CR/CRu [124]. Full-length CD3-CD20 bi-specific antibodies are now in develop- ment. Advantages over BiTEs include short infusion time, long half-life, and apparently lower rates of neurotoxicity. There are at least 4 agents in development (namely mosu- netuzumab, odronextamab, epcoritamab, and glofitamab) and provisional data published in abstract form indicate high remission rates in heavily pre-treated patients with B-cell NHL, including patients with FL. The largest cohort included 69 patients with iNHL treated with mosenutu- zumab where the ORR and CR rates were 64.1% and 42.2%, respectively, for response evaluable patients and the median number of prior systemic therapies was 3 [125]. In another study with 14 patients with R/R FL grade 1-3a treated with odronextamab at ≥ 5 mg, the ORR and CR rates were 93% and 71.4%, respectively [126]. The principle toxicity is CRS, which appears to be dose dependent and determined in part by disease burden, it is manageable with appropriate step- up dosing and treatment. These highly effective drugs are likely to change the FL treatment landscape in the years to come and well-designed randomised controlled trials will be required to fully understand their place in the treatment paradigm [127–130].
Programmed cell death-1 (PD1)-axis inhibitors, which
have shown so much promise in other malignancies includ- ing in classical Hodgkin lymphoma, have limited sin- gle-agent activity in B-cell NHL but may be effective in combination with other drugs. There is limited published experience in FL; however, the PD-1 inhibitor nivolumab was assessed in combination with the Bruton’s tyrosine
kinase (BTK) inhibitor ibrutinib, given until disease progres- sion, in a Phase I/II study including 40 R/R FL patients. The ORR was 33% and the CR rate 10% [131]. In another study, patients with FL were treated with single agent nivolumab after at least 2 prior lines of therapy—after a minimum fol- low-up of 12 months the ORR was only 4 % with a median PFS of 2.2 months [132].
Cell surface CD47 is an antiphagocytic “don’t eat me” signal over-expressed by almost all cancers. The Hu5F9-G4 monoclonal antibody blocks CD47, thus enabling phago- cytosis of malignant cells and its effect is enhanced by co-administration with rituximab. In a Phase Ib study of Hu5F9-G4+R the cohort of 22 patients included 7 with FL, all of whom were refractory to rituximab—3 achieved a CR and 5 had an objective response [133].
⦁ Other Agents

The proteasome inhibitor bortezomib has been assessed in combination with rituximab for patients with relapsed FL in a randomised Phase III study where no improvement in PFS was observed with the combination, although a benefit was reported separately for a high-risk sub-group with FLIPI score ≥ 3 and high tumour burden [140, 141].
The combination of interleukin-2 (IL2) with rituximab, with the aim of depleting Tregs, has been investigated in FL but has not been shown to improve response rates or survival [142, 143]. Agonists to toll-like receptor-9 (TLR-9) have been trialled in combination with rituximab with the aim of stimulating innate and adaptive immune responses and have demonstrated clinical activity in small R/R FL cohorts [144]. Intratumoural investigations of TLR-9 agonists have also been made.
Autologous tumour-derived immunoglobulin idiotype vaccines, given to patients who achieve CR following first line immunochemotherapy, have been tested. In one Phase III trial no difference in disease-free survival (DFS) was found in the intention-to treat-analysis, but for those who received the vaccine (n = 117) median PFS was 44.2 months versus 30.6 months for those who did not and the difference reached statistical significance. However in a trial of another vaccine no benefit was observed [145, 146].
The only commercially available radioimmunotherapy (RIT) agent remains 90Y-ibritumomab, which comprises an anti-CD20 monoclonal antibody conjugated to a radio- isotope. It was tested in combination with CHOP as first line induction therapy and compared to R-CHOP—while 10-year PFS was superior in the CHOP-RIT group, there was no difference in OS [147]. It was also tested in patients who achieved CR or PR following induction where PFS was superior in the RIT arm but again there was no difference in OS [148]. Given the lack of OS benefit, the challenge of administering the treatment, and concerns about a possible

increase in myeloid malignancies, it has not been widely adopted.

7 Conclusions
For many patients with FL, immuno-chemotherapy as per the current standard of care is associated with excellent out- comes and survival is often measured in decades. However, it is clear that a different approach is required for a subset of patients with early progression or relapsed/refractory dis- ease. Understanding of the genetic drivers of the disease is improving and will facilitate better early risk-stratification and potentially risk-adapted treatment approaches.
The approval of lenalidomide for previously treated FL, the PI3K inhibitors for FL after at least 2 prior lines of ther- apy, and tazemetostat according to the EZH2 mutational status, mean that novel targeted therapies are already being incorporated into the FL treatment algorithm and repre- sent valid alternatives to traditional immuno-chemotherapy approaches. The therapeutic landscape is broad and the posi- tions of many agents are not yet clear—R2, although not without side-effects, is an attractive option in the older age group affected by FL and its use in the first-line setting is likely to become more widespread, while the use of some agents such as the PI3K inhibitors needs to be balanced against their toxicity. Further trial data, including from care- fully conducted RCTs, will be required in order to deter- mine the place of the emerging therapies in the sequence of FL treatments. Given the near-normal life expectancy for many patients with FL, and the consequent challenge of demonstrating an OS benefit (especially in the frontline setting), novel trial endpoints are required but these need to be clinically meaningful and well-validated. In the future, immunotherapies including CAR-T cells and bispecific anti- bodies will undoubtedly have a significant role to play for those patients with the poorest outcomes who fail standard treatment approaches or indeed as front-line therapy if early risk stratification becomes more precise. However, the health economic impact of their increased use will need to be con- sidered given the considerable associated cost.
Declarations

Funding No external funding was used in the preparation of this manu- script.

Conflict of interest William Townsend has received consultancy fees and honoraria from Roche, Gilead, Celgene and Janssen. Michael Northend declares that he has no conflicts of interest that might be relevant to the contents of this manuscript.
Author contributions Concept and design: WT and ML. Literature search and manuscript writing: MN. Review of the manuscript, editing and final approval: WT.

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