The prevention of central nervous system relapse in diffuse large B‐cell lymphoma: a British Society for Haematology good practice paper

Abstract

This Good Practice Paper was compiled according to the BSH process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The British Society for Haematology (BSH) produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Ovid MEDLINE, Embase and Cochrane databases were searched for English language articles up to February 2020 using the keywords: diffuse large B-cell lymphoma, central nervous system prophylaxis, central nervous system (CNS) prophylaxis, central nervous system recurrence, CNS recurrence. The references from relevant publications were searched and published guidelines by the European Society for Medical Oncology were noted. Review of the manuscript was performed by the BSH Guidelines Committee Haematology Oncology Task Force, the BSH Guidelines Committee and the Haematology Oncology sounding board of BSH. It was also posted on the members section of the BSH website for comment. Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an uncommon event and often confers a poor prognosis. Estimates of incidence vary from 1·9% to 6·4% with discrepancy in the literature as to whether the introduction of rituximab has reduced this risk.1-4 Retrospective analyses of large-trial datasets have provided some insight into the pattern of CNS relapse in the rituximab era. The majority (70–80%) of relapses involve the brain parenchyma with isolated leptomeningeal relapses occurring in a minority of patients.5, 6 Concurrent CNS and systemic relapses occur in a significant proportion of cases (46–48%).2, 5 There is a lack of robust evidence to clearly recommend which patients should receive CNS prophylaxis and how this should be delivered. The data are largely retrospective with a wide variation in selection criteria for which patients received prophylaxis, primary treatment regimen used and type of CNS prophylaxis given. Although there is no clear answer as to what level of risk warrants CNS prophylaxis, a pragmatic approach would be to consider any patient with an estimated CNS relapse rate of >10% as a candidate for prophylactic therapy, whilst taking individual patient considerations and risk of toxicity into account. Even with this approach, a significant proportion of patients will receive CNS prophylaxis ‘unnecessarily’, and the priority should be to ensure delivery of optimal systemic treatment. Since the publication of British Society of Haematology (BSH) guidance on the prevention of CNS lymphoma relapse,7 there is increasing evidence to support the use of high-dose intravenous (IV) methotrexate and as such it was felt appropriate to update the guidance. Baseline positron emission tomography/computed tomography (PET/CT) should be performed in all patients who are being treated with curative intent as it has a higher sensitivity for detection of extranodal sites and thus influences the decision to give CNS prophylaxis. Contrast-enhanced brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination including flow cytometry may detect occult CNS disease in a small proportion of patients.8 This is recommended in the European Society for Medical Oncology (ESMO) guidelines9 as positive results would require consideration of a CNS-directed chemotherapy approach. This may be particularly relevant for patients who have disease sites in close proximity to the CNS. Several large studies demonstrated that both elevated lactate dehydrogenase (LDH) and advanced stage at diagnosis are associated with increased risk of CNS relapse.10-13 Van Besien et al.13 recommended raised LDH and ≥2 extranodal sites to define patients at high CNS risk and this approach was recommended in the 2013 BSH guideline7 for selecting patients to whom CNS prophylaxis should be offered. More recently, the German High-Grade Lymphoma Study Group (DSHNHL) has developed the ‘CNS-IPI (International Prognostic Index) score’ as a tool to estimate the risk of CNS relapse/progression in patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone).14 Univariable and multivariable analyses of potential risk factors for CNS relapse were performed on a training cohort of 2164 patients from prospective DSHNHL studies and the MabThera International Trial (MInT). The final model consists of the established IPI factors plus involvement of kidney and/or adrenal glands (Table I). The model was validated on a population-based cohort of 1597 patients from the British Columbia Cancer Agency (BCCA) with similar results, suggesting it can be applied to routine clinical practice. However, this approach still means approximately 90% of patients in the high CNS-IPI group potentially receive prophylaxis unnecessarily. Moreover, the model has suboptimal sensitivity with a significant proportion of CNS events occurring in the intermediate-risk group. In an attempt to improve on the sensitivity of this model, a further retrospective analysis evaluated the impact of the number of extranodal sites identified by PET/CT imaging on CNS relapse rates.15 From a cohort of 1 532 patients, a group of 144 patients (9%) who had ≥3 extranodal sites was identified which had a three-year cumulative incidence of CNS relapse of 15·2%. A pragmatic approach would be to offer CNS prophylaxis to patients with a high (4–6 points) CNS-IPI score and to any patient with involvement of three or more extranodal sites, irrespective of the CNS-IPI. Historically, several specific extranodal localisations have been associated with a high risk of CNS relapse; however, many reflect stage III/IV disease or the presence of ≥2 extranodal sites and, outside of the IPI parameters, few are independently predictive. Testicular involvement by DLBCL has the strongest evidence for a high risk of CNS relapse. Retrospective studies from the pre-rituximab era suggested a CNS relapse rate of 15–21% with the majority occurring in the brain parenchyma (64–85%).16, 17 In an attempt to reduce this risk, the IELSG-10 study protocol included four doses of intrathecal methotrexate, with a five-year cumulative incidence of CNS relapse of 6%.18 However, it should be noted that this was a small cohort (n = 53) and many patients had favourable IPI features. A subsequent trial (IELSG-30) involving intrathecal cytarabine intercalated with R-CHOP followed by two doses of IV methotrexate (1.5 g/m2) is primarily assessing the feasibility of intensified CNS prophylaxis, and the results with regard to CNS relapse rate are awaited. As a result of the IELSG-10 data, many centres include intrathecal chemotherapy during first-line therapy for testicular DLBCL, independent of decisions regarding systemically administered CNS prophylaxis. Renal parenchymal and/or adrenal involvement has been shown to be an independent risk factor for CNS relapse and is incorporated into the CNS-IPI model for this reason.14, 19 Breast involvement with DLBCL is rare. Retrospective data suggest it is often localised at presentation,20 largely based on CT imaging rather than PET. Such patients are likely to be underrepresented in clinical trials but retrospective studies have demonstrated high CNS relapse rates of 12–16%.21-23 Similarly, although uterine involvement in DLBCL is rare it does appear to carry a high risk of CNS relapse (41%, n = 17).15 Intravascular large B-cell lymphoma is rare but carries a very high risk of CNS involvement, both at initial presentation and at relapse.24 Epidural, orbital and craniofacial involvement have previously been considered as high risks of CNS disease but there is no robust confirmatory evidence in the rituximab era.25 In such cases, the key question is whether the dura has been breached, as there is no evidence to suggest that proximity to the CNS per se is an indication for CNS prophylaxis. There is insufficient evidence to suggest that bone or bone marrow involvement confers sufficiently increased risk in isolation to offer CNS prophylaxis. DLBCL with a MYC translocation occurring with a BCL2 and/or BCL6 translocation [so-called double-hit (DHL) and triple-hit lymphomas (THL)], have been associated with an aggressive clinical course and poor outcomes. Estimates of CNS involvement in such patients vary widely in the literature, with early data likely overestimating risk as fluorescence in situ hybridisation (FISH) was only performed on high-risk patients.26 More recent evidence suggests that the risk may not be as high as perceived – a retrospective analysis of a large dataset from the BCCA identified 24 patients with DHL/THL with a CNS relapse rate of 4·5%.27 Data from the phase III GOYA study showed a 5% risk of CNS relapse in 20 patients with DHL. The R-CHOP-14 versus -21 trial included 16 patients with DHL and a further 36 with isolated MYC rearrangement – no CNS relapses were reported in these patients.2 Although numbers of patients with DHL are small these were large, prospective trials with less bias than previous retrospective studies. The majority of patients with DHL/THL will meet other criteria for CNS prophylaxis and/or have primary intensified regimens but, for the uncommon situation where this is not the case, there does not appear to be sufficient evidence to recommend CNS prophylaxis due to DHL/THL status in isolation. Dual expression of MYC and BCL2 protein (DEL) is more common than DHL (~30% vs. 5% of DLBCL) but is also associated with poorer outcomes. Retrospective analysis of a BCCA dataset demonstrated that DEL is associated with an increased risk of CNS relapse (two-year risk 9·7%).27 Contrary to this, analysis of data from the GOYA study on CNS relapse confirmed CNS-IPI and activated B-cell (ABC) cell of origin (gene expression by NanoString (Nanostring Technologies, Seattle, WA, USA) as independent risk factors but not DEL.6 There is currently insufficient evidence to recommend CNS prophylaxis in patients with DEL and, until the data on cell of origin are validated on a separate cohort, CNS prophylaxis cannot currently be recommended for the ABC subtype per se. There are insufficient data to determine whether HIV infection is an independent risk factor for secondary CNS involvement in DLBCL. Therefore, we recommend that the criteria for non-HIV-associated DLBCL are applied to such patients, in line with current British HIV association guidelines.28 CNS involvement in DLBCL tends to occur early, either during systemic chemotherapy or shortly after its completion. The median times from diagnosis to CNS relapse in the recent NCRI R-CHOP-14 versus -21 and GOYA trials were 8·1 and 8·5 months respectively, with a wide range reported (e.g. 0·9–43·5 months in the GOYA trial).2, 6 Thus, it is logical to aim to deliver CNS-directed prophylaxis as early as possible for those at risk. This approach is being investigated by international study groups.29 It is also important to recognise that patients with high IPI DLBCL have a significant risk of systemic relapse, and some may receive regimens with more intensive protocols incorporating CNS-directed therapy, e.g. R-CODOX-M/R-IVAC. The additional value of intrathecal chemotherapy included in this protocol is uncertain when used for patients with DLBCL. Intrathecal (IT) chemotherapy has been widely used in high-risk patients with DLBCL for many years despite a lack of robust evidence demonstrating its efficacy. This has come under more scrutiny in the rituximab era given the predominance of parenchymal relapse. In the RICOVER-60 trial, lack of adherence to the CNS prophylaxis protocol allowed a comparison between patients who received IT prophylaxis versus those who did not, with no statistically significant influence on any type of CNS event demonstrated in patients who had received IT prophylaxis.1 Retrospective analyses of other large clinical trials have also demonstrated no reduction in CNS relapse rates with IT prophylaxis.30, 31 A recent systematic review of the efficacy of IT CNS prophylaxis included 14 studies and a total of 7357 patients treated with rituximab or obinutuzumab-based immunochemotherapy. IT prophylaxis was not found to be a univariable or multivariable factor associated with a reduction of CNS relapse in any study.32 In summary, the benefit of IT prophylaxis remains unclear with no strong evidence to support this as an effective means of reducing CNS relapse risk. Given that IT chemotherapy does not meaningfully penetrate the brain parenchyma (the commonest CNS compartment for relapse)33 it is reasonable to conclude that IT prophylaxis has a limited role in the prevention of CNS relapse. Reflecting the uncertainty around the efficacy of IT prophylaxis, systemically administered CNS prophylaxis in the form of high-dose intravenous methotrexate (HD-MTX) has been increasingly employed in recent years. However, there has been no randomised study demonstrating a benefit of HD-MTX CNS prophylaxis and there remains a lack of consensus regarding delivery (timing, dose and number of cycles). It has been demonstrated that a higher area under the curve of methotrexate is associated with superior outcome in primary CNS lymphoma, with the optimum way to achieve this being a short infusion (2–4 h) with doses of at least 3 g/m2 MTX.34 Given the predominantly renal excretion of methotrexate, patients should have a creatinine clearance of ≥50 ml/min. Furthermore, patients should be deemed to have sufficient cardiac function to cope with the intravascular fluid volume shifts of this regimen. A retrospective study investigated delivering HD-MTX at a dose of 3.5 g/m2 on day 15 of alternating cycles of R-CHOP.35 They demonstrated a low incidence of CNS relapse using this approach (3%), but there were issues with nephrotoxicity causing delay of chemotherapy in 8/65 (12%) patients and avoidance of further MTX in seven. A more recent multicentre retrospective analysis of 334 patients identified that intercalated HD-MTX significantly increased R-CHOP delays, mucositis and neutropenic fever compared to delivery after R-CHOP completion. Intercalated HD-MTX resulted in a delay of the subsequent R-CHOP cycle in 20% of instances (median seven days); however, delays were significantly reduced when HD-MTX was delivered before day 10 of the R-CHOP cycle (16% vs. 26%, P = 0·01). There was no difference in CNS relapse observed between the two approaches; however the event rate was low (19/334, 5·7%) and concurrent IT therapy in 60% of patients in the end of treatment group was a potential confounding factor.36 Given the increased incidence of febrile neutropenia, granulocyte-colony stimulating growth factor (G-CSF) may be considered as per institutional guidelines when HD-MTX is intercalated with R-CHOP. A Nordic Lymphoma Group study investigated an aggressive chemotherapy and systemic CNS prophylaxis regimen for younger (age 18–65) patients with high-risk DLBCL or grade III follicular lymphoma.37 Six cycles of R-CHOEP-14 were given followed by a course of high-dose cytarabine and a course of high-dose methotrexate (3 g/m2 as 24-h infusion). The CNS relapse rate of 4·5% was felt to be encouraging given the high-risk nature of the patient group (56% stage IV, 26·5% with ≥2 extranodal sites), but with all CNS relapses occurring within six months it was proposed that delivering CNS-directed therapy earlier might have improved outcomes. The same group is investigating this further in the NLG-LBC-05 trial, with initial results suggesting an improvement in CNS relapse risk by incorporation of HD-MTX at the beginning of therapy.29 Ferreri et al. reported a retrospective analysis of 107 patients with high-risk features for CNS relapse (involvement of specific extranodal sites or advanced stage with high LDH).38 In this study, 40/107 patients received CNS prophylaxis, the majority receiving HD-MTX +/− IT therapy. The CNS relapse rate in patients who received prophylaxis was 2·5% compared to 12% in those who did not, although the number of patients with high CNS-IPI was lower in the prophylaxis group. Although none of the above studies in isolation are definitive, taken together the data support consideration of HD-MTX as an effective strategy for CNS prophylaxis. Age >60 years is a factor in the CNS-IPI score and therefore a significant proportion of older patients with DLBCL will fall into the high-risk category for CNS relapse using this selection method. However, delivering sufficient relative dose intensity (RDI) of systemic therapy can be challenging in older patients, and when making decisions about CNS prophylaxis in this patient group one should carefully consider the potential impact on RDI and therefore risk of systemic relapse. The risk of renal toxicity with HD-MTX is particularly relevant in older patients and may be a limitation in delivering HD-MTX intercalated with R-CHOP. The need for CNS prophylaxis in this group of patients has recently been questioned. A retrospective analysis of 270 patients with DLBCL aged >80 years from two multicentre LYSA trials treated with mini-CHOP + rituximab or ofatumumab found that despite no patients receiving prophylaxis, CNS relapse rates were low at 3%.39 A retrospective analysis of 690 patients aged ≥70 treated with R-CHOP also found the CNS relapse rate to be low at 2·6%. 81·2% of patients received no CNS prophylaxis, with 14·3% receiving IT MTX alone.40 The BSH haematology oncology task force members at the time of writing this Good Practice Paper are Guy Pratt, Nilima Parry Jones, Oliver Miles, Elspeth Payne, Jonathan Lambert, Simon Stern, Alistair Whiteway and Pamela McKay. The authors would like to thank them, the BSH sounding board and the BSH guidelines committee for their support in preparing this Good Practice Paper. All authors were involved in the formulation and writing of the manuscript, as well as approval of its final version. No expenses were incurred during the writing of this Good Practice Paper. All authors have made a declaration of interests to the BSH and Task Force Chairs which may be viewed on request. Members of the writing group will inform the writing group Chair if any new pertinent evidence becomes available that would alter the strength of the recommendations made in this document or render it obsolete. The document will be archived and removed from the BSH current guidelines website if it becomes obsolete. If new recommendations are made an addendum will be published on the BSH guidelines website ( www.b-s-h.org.uk/guidelines/). While the advice and information in this guidance is believed to be true and accurate at the time of going to press, neither the authors, the BSH nor the publishers accept any legal responsibility for the content of this guidance.

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