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The management of Castleman disease

2021; Wiley; Volume: 195; Issue: 3 Linguagem: Inglês

10.1111/bjh.17688

1365-2141

Oliver Lomas, Matthew Streetly, Guy Pratt, Jim Cavet, Daniel Royston, Stephen Schey, Karthik Ramasamy,

Parvovirus B19 Infection Studies

This 'Good Practice Paper' was compiled according to the British Society for Haematology (BSH) process at (http://www.b-s-h.org.uk/guidelines). The 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. The PubMed database was searched for English language articles up to June 2021 using the keywords: Castleman, POEMS, HHV8, HIV, lymphoma, lymphadenopathy, investigation, imaging, histology. The references from relevant publications were searched as well. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-oncology Task Force, the BSH Guidelines Committee and the Haemato-oncology of sounding board of BSH. It was also on the members section of the BSH website for comment. Castleman disease (CD) describes a rare group of lymphoproliferative disorders with characteristic histopathological appearances.1 Unicentric CD (UCD) presents with isolated lymphadenopathy, usually accompanied by mild or localised symptoms. In contrast, multicentric CD (MCD), presents with lymphadenopathy across multiple sites, usually accompanied by mild to life-threatening constitutional symptoms. MCD represents a constellation of different clinicopathological subtypes that vary in their aetiology, presentation and management. The incidence of all forms of CD is estimated at 21–25 per million person-years, based on insurance registries in the USA.2 Application of this rate to the UK adult population provides an estimated incidence of CD in the UK of 1100–1300 patients per year.3 There is an approximately even distribution of CD between men and women. UCD is most commonly diagnosed in the fourth decade of life, whereas MCD usually presents later in the fifth and sixth decades.4, 5 The introduction of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code D47.Z2 in 2016 should facilitate the understanding of the epidemiology of the disease.6 Lymphadenopathy is found most in the chest and neck and less commonly in abdominal nodes or as a retroperitoneal mass.5, 7, 8 The clinical presentation of UCD often relates to the localised mass effect on organ function. Systemic symptoms are uncommon with fever in 2]; signs of end-organ damage or haemophagocytic syndrome. In a case series, the risk-stratified use of etoposide appeared to be well tolerated and was not associated with excess death compared to rituximab alone.38 All patients responded to therapy, although only 2% achieved a complete response (CR). It is, therefore, reasonable to consider etoposide in higher risk cases. Rituximab ± etoposide therapy also appears to be effective in patients with HIV-negative HHV8-MCD.16 Around a quarter to a third of patients relapsed in the year after therapy, with a median time to first relapse being 30 months in one study.40, 41 The use of rituximab in this cohort has been associated with a lower risk of HHV8 lymphoma42 but with an increased risk of exacerbating of co-existent Kaposi sarcoma.38, 41, 43 Rituximab in combination with at least three cycles of anthracycline chemotherapy (provided cardiac function is satisfactory) has been used successfully in a cohort of patients with HIV-associated HHV8-MCD who predominantly had undergone some treatment previously. Particularly, this approach has shown efficacy in treating concomitant Kaposi sarcoma.38, 43 Therapeutic intervention should be guided by the presence of constitutional symptoms and organ function, irrespective of HIV status. Patients with MCD may present with some features of POEMS, which are often milder than in classical POEMS. Conversely, patients with POEMS may be found to exhibit some histological features of CD.21 Given the pathophysiological overlap between POEMS and MCD, patients with simultaneous presentations may require therapy tailored to both conditions depending on the clinical presentation.44 The high prevalence of sensorimotor neuropathy in POEMS-MCD should warrant caution with bortezomib or thalidomide therapy at induction, but this can be well-tolerated.45 Given their efficacy and low neurotoxicity compared to thalidomide and bortezomib, lenalidomide-based myeloma regimens may be considered. The role of ASCT in MCD is less clearly defined than for POEMS. Therefore, it may be considered in the experimental setting in a specialist centre. The cases of MCD that lack an associated driver such as HHV8 or POEMS, are described as being idiopathic. TAFRO represents a subset of clinically aggressive disease, compared to the remainder of cases having a milder inflammatory presentation of iMCD, which is referred to as iMCD-NOS (Figure 1). Several therapeutic options have been described in case reports and small cohort studies. These include systemic corticosteroids, monoclonal antibodies and systemic combination chemotherapy. Given the limited evidence underlying many of the therapeutic options, clinical trials should be considered depending on availability as part of a regional MDT discussion. Consensus guidelines for the treatment of iMCD have been published by the CDCN.46 The choice of treatment is driven primarily by the urgency for a symptomatic response, rather than histopathological characteristics.47, 48 The burden of symptoms in severe cases may be defined as those with at least two of the following: ECOG PS score of ≥2; severe renal impairment (glomerular filtration rate <30 ml/min/1.73 m2); widespread serous effusions; haemoglobin <80 g/l and pulmonary involvement including pneumonitis.46 Similar to the approach used in the 2018 consensus guidelines, the iMCD International Prognostic Index (iMCD-IPI) has recently sought to stratify patients according to performance status and organ dysfunction to predict response to therapy.48 In iMCD, CRP concentration remains closely correlated with IL-6 and may be used to track activity and treatment response.49 A suggested treatment algorithm for iMCD-NOS is shown in Figure 2. The primary role of corticosteroids is for the rapid control of systemic inflammation or associated phenomena such as autoimmune haemolytic anaemia. Responses to corticosteroids are observed across the spectrum of MCD, but they are not durable. A recommended starting regimen would be a dose of 1 mg/kg prednisolone for 2 weeks followed by a taper.28 The control of inflammatory symptoms in a patient requiring critical care will likely require a more intense dosage of steroid than for the management of paraneoplastic autoimmune phenomena. Therefore, the dose of steroid should be commensurate with the nature and severity of the primary or concomitant clinical condition. Interleukin-6 has been identified as an important mediator of the inflammatory state that promotes lymphadenopathy in MCD.11 However, elevated serum concentrations of IL-6 are not found in all cases of active iMCD. Furthermore, circulating concentrations of the cytokine do not predict clinical efficacy from anti-IL-6 therapy.50 Despite these caveats, IL-6 signalling has been made a therapeutic target in iMCD. Siltuximab is a chimeric human-murine IgG monoclonal antibody that binds human IL-6 (but not virally derived, vIL-6 as found in HHV8-MCD) to block signal transduction. It is the only drug licensed in the UK for the treatment of iMCD. Siltuximab [11 mg/kg intravenously (IV) every 3 weeks] may be reserved for prompt use on signs of relapse, with the aim to avoid re-induction with high-dose chemotherapy. Siltuximab has a half-life of 17–20 days, necessitating initial dosing every 3 weeks, although extending to 6-weekly maintenance makes treatment more acceptable. A phase I, open-label study demonstrated the safety of siltuximab in several lymphoproliferative disorders including iMCD.51 The most common side-effects were cytopenias (10–25%) and hyperlipidaemia (15–20%). The cytopenias were generally Grade 1–2, and rarely prompted delay or discontinuation of therapy. CNTO238MCD003, the only blinded randomised controlled trial (RCT) of any therapy in iMCD, compared siltuximab with placebo.50 Approximately one-third of symptomatic patients with iMCD achieved partial remission, compared to none on placebo (no steroid escalation was permitted). Siltuximab therapy improved symptoms (median time to response 33 days) more rapidly than a reduction in volume of lymphadenopathy (155 days for significant nodal regression). The response was durable whilst on treatment. Importantly, iMCD symptoms of fatigue improve significantly in the siltuximab-treated cohort (68%), compared to placebo or best-supportive care (35%) and the multi-point iMCD symptomatic score improved overall.52 Patient-reported outcome showed benefit, even though iMCD patients were relatively mildly affected but, due to the screening period, delays for central review of eligibility and placebo-controlled design, the most severe, fulminant cases had been excluded. However, secondary analysis within phase II clinical trial data suggests that patients exhibiting signs of a more moderately increased inflammatory state may benefit the most from siltuximab therapy.53 The evidence for siltuximab currently supports its use in non-severe cases in need of long-term control. Long-term safety and efficacy have been examined in a follow-on study, whereby 70% of responders sustained a response over a median follow-up of 6 years.54 The response rates to siltuximab have recently been analysed for those patients who had previously received non-IL-6-targeted therapies. Both newly diagnosed and previously treated patients showed similar levels of response to siltuximab. Very few patients achieved a CR and the majority showed partial response or stable disease.55 Siltuximab has received regulatory approval in the UK for use in iMCD, but as of November 2020, requires an individual funding request (IFR), which may hamper access. In the absence of a prospective direct comparison with anti-IL-6-targeted therapy, retrospective series of the use of rituximab in MCD show poorer depth and overall rate of remission compared to siltuximab.56 However, rituximab is very well tolerated and readily available and, therefore, may be considered as first-line therapy in mild disease or in the presence of immune-mediated cytopenias. Despite the success of IL-6-signalling blockade, there remains a significant unmet clinical need not only for patients who are intolerant of anti-IL-6 therapy, but also for a reliable disease-modifying therapy.50 Tocilizumab is a monoclonal antibody that antagonises the IL-6 receptor (IL-6R) to block signal transduction.57 Tocilizumab is licensed in Japan, but not in the UK, for the treatment of iMCD-TAFRO. iMCD-TAFRO is a relatively recently described condition, which is even rarer than other forms of CD. Only anecdotal reports of response to calcineurin blockade and anti-IL-6 therapies have been reported.58, 59 Although tocilizumab has not been subjected to a RCT, patients have been reported to exhibit significant reductions in lymphadenopathy and resolution of constitutional symptoms and signs.60 In a small, dose-finding study, humanised anti IL-6R antibody was administered at 50 or 100 mg IV weekly and was associated with a persistent improvement in symptoms and reduction in lymphadenopathy over 1 year.25 A retrospective study comprising nine cases of TAFRO appeared to suggest that more durable remissions were associated with steroids and anti-IL-6 therapy compared to combination chemotherapy.7 Nevertheless, tocilizumab is approved in the UK for use in highly inflammatory cytokine release syndromes. Therefore, in the event of a severely unwell patient requiring intensive care support, the authors envisage that tocilizumab may be used on an unlicensed basis given that is more readily available than siltuximab, which usually requires an IFR. Standard cytotoxic lymphoma regimens, such as cyclophosphamide, vincristine, prednisone (CVP)/cyclophosphamide, hydroxydoxorubcin, vincristine (Oncovin) and prednisolone (CHOP), with or without rituximab have been described in multiple cases studies but no randomised prospective data exist to guide their routine use.61 A retrospective cohort study of MCD revealed that a CR was achieved in just under half of patients but the median time to relapse was 6 months.12 Despite significant myelo-, neuro- and cardio-toxicity, combination chemotherapy may achieve rapid control of severe cases refractory to anti-inflammatory therapy. Thalidomide has been shown to exert its anti-inflammatory effects partly via suppression of IL-6 signalling.62 The long-term continuation of thalidomide has been reported to be associated with prolonged disease control in MCD.63, 64 Rituximab (4 weeks) and thalidomide (1–3 months) in combination have been observed in a retrospective mixed cohort of MCD to show complete regression of lymph nodes and symptoms in 91% of patients, which was maintained after discontinuation of treatment with a 2-year progression-free survival of 60%.65 The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice weekly for 1 year) has undergone a phase II study in a cohort of 25 patients with newly diagnosed iMCD. The primary end-point was durable tumour and symptomatic response for at least 24 weeks and was achieved in 48% of patients but failed in 40% of patients. The remainder (12%) exhibited stable disease. There were three deaths in total, two of which were after disease progression. OS at 1 year was 88% but a control arm was not recruited. Therefore, thalidomide therapy for at least 3 months and up to 2 years based on current long-term follow-up data in combination with weekly rituximab for 4 weeks, and steroids as required at induction, is suggested when siltuximab is neither available nor tolerated. Castleman disease remains a diagnostic and therapeutic challenge. It is now clear that UCD and the subtypes of MCD have different presentations and pursue different clinical courses, which should guide the choice of therapy offered to the patient. Despite the success of surgery for UCD, rituximab for HHV8-MCD and IL-6-antagonism in iMCD, there remains a significant unmet clinical need for definitive therapy, particularly in the cases of iMCD. All patients with CD should be encouraged to self-enrol in the ACCELERATE natural history registry of the CDCN (#NCT02817997, http://www.cdcn.org/accelerate). Thanks to such collaborative efforts, the field has advanced more in the last 15 years than in the preceding half-century and the authors, therefore, look forward to further advances in our knowledge and in therapy for this heterogeneous disease. The BSH Haemato-oncology Task Force members at the time of writing this good practice paper were Oliver C. Lomas, Daniel Royston, Jim Cavet, Guy Pratt, Matthew Streetly, Stephen Schey and Karthik Ramasamy. The authors thank them, the BSH sounding board, and the BSH guidelines committee for their support in preparing this good practice paper. The BSH paid the expenses incurred during the writing of this good practice paper. All authors have made a declaration of interests to the BSH and Task Force Chairs that may be viewed on request. The following authors have conflict of interest to declare: Karthik Ramasamy: EUSA Pharmaceutical Advisory Board. The following members of the writing group: Oliver C. Lomas, Daniel Royston, Jim Cavet, Guy Pratt, Matthew Streetly and Stephen Schey have no conflict of interest to declare. 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 (http://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.