Front‐line management of post‐transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline

Abstract

This document is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT). Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT. Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.1 In adult SOT recipients, PTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality.1 The reported incidence varies according to patient age, transplant type and the degree of immunosuppression. Historically, PTLD has been reported to occur most frequently in the first year following transplantation.2-4 However, these studies also report a similar incidence of PTLD beyond one year, suggesting the late occurrence is as prevalent post SOT.2-5 The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.6, 7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%) followed by lung transplants (3·0–10%), heart transplants (2·0–8·0%), liver transplants (1·0–5·5%), pancreatic transplants (0·5–5·0%) and renal transplant recipients having the lowest incidence of PTLD (0·8–2·5%).8, 9 PTLDs are sub-classified into four histopathological categories as shown10 in Table I. Establishing a tissue diagnosis of PTLD can be challenging and all diagnostic material should be accompanied by relevant clinical information including the date of transplant, immune suppression regimen and organ type. Where possible, excision biopsy samples are recommended to enable accurate PTLD sub-classification and to provide sufficient material for subsequent ancillary investigations. Patients with PTLD require a comprehensive pre-treatment evaluation as shown in Table II. Accurate staging and response assessments are crucial for patient management. Staging should be recorded using the Ann Arbor classification or the Lugano classification13 which is the recommended classification for staging following Positron Emission Tomography–Computed Tomography (PET-CT) in 18F-fluorodeoxyglucose -avid (FDG-avid) nodal lymphomas. Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH) Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres Bone marrow biopsy is indicated and some selected patients it may not be clinically needed or appropriate14 All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response Where available, PET-CT scan should be utilised for staging over CT scan Fertility-preserving treatments, such as sperm cryopreservation for male and referral to a fertility specialist in female patients, should be considered for eligible patients Details should include; date of transplant, organ type and immunosuppresion regimen All patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician The role of PET-CT in the staging of PTLD is less well defined when compared to lymphoma in the immunocompetent. A recent systematic review and meta-analysis where the majority of the cases (215/269) were of the monomorphic subtype of PTLD has confirmed the utility of PET-CT for staging. PET-CT detected additional sites of disease in 28% of cases, resulting in upstaging in 15% when compared to CT alone. End-of-treatment PET-CT appears to have moderate sensitivity (71%) and specificity (73%) for predicting relapse but a higher negative predictive value of 92%.15 In addition, PET-CT may also have a role in the diagnostic work-up as demonstrated in a retrospective study published by Montes de Jesus et al. They reported a sensitivity of 85% and specificity of 90% with a positive predictive value of 83% and a negative predictive value of 92% in PTLD.16 Despite the limitations of these PTLD data, a staging PET-CT, where available, should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients.17, 18 Magnetic resonance imaging (MRI) or CT imaging of the brain, orbits and sinuses is recommended for patients with suspected central nervous system (CNS) or craniofacial disease. Diagnostic lumbar puncture for cerebrospinal fluid (CSF) analysis, including cytology and flow cytometry, is recommended for patients with suspected CNS involvement. Patients with PTLD present a multifaceted clinical challenge. It is essential to consider not only the patient’s general health, but also the histological subtypes and clinical stage of the lymphoproliferative disorder, the SOT function, the degree of immunosuppression, and the modalities of therapy available. A management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.19 The MDT process should be in line with the 2016 NICE guideline (NG47), ‘Haematological cancers: improving outcomes’. It is recommended that the lead MDT should be the lymphoma MDT and where possible, a representative of the transplant team should attend. There is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treatments and often being retrospective or single-institution series. However, a number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia.2, 6, 20-22 The Ghobrial prognostic score allocated one point for ECOG (Eastern Cooperative Oncology Group) > 2, monomorphic disease and graft involvement to demonstrated significant for overall survival (OS) but its utility was limited due to a majority of patient having monomorphic disease (96%) and only 16% having graft involvement.22, 23 Another prognostic scoring system utilised in PTLD is the International Prognostic Index (IPI) for non-Hodgkin lymphoma. Although, it was not specifically developed for PTLD,24 it has validity in this setting.25-28 IPI is based on the baseline parameters age, stage of disease, EGOG performance status, extra-nodal site involvement and LDH. IPI in relation to PTLD is separated into two groups: low (0, 1, 2 points) and high (3, 4, 5 points) which has a significant effect on OS (P = 0·006) and treatment-related mortality, but did not have an effect on progression-free survival (PFS).28 In addition, another prognostic score, the PTLD Prognostic Index, is a variation of the IPI with baseline factors of age, ECOG performance status and LDH. Similar to the IPI is had a significant effect on the OS (P = 0·032) but not the PFS and a large bias towards one risk group.27, 28 More recently, real-world analysis of CD20-positive B-cell PTLDs incorporated the IPI to demonstrate its utility. The IPI was statistically significant, with low IPI risk (0–2 points) exhibiting a superior OS compared to high IPI risk (≥3 points) at three years (OS 78% vs 54%, respectively, P = 0·0003).27 Thus, the IPI is a pragmatic choice of up-front score to use.26-28 Given the rarity of the diagnosis and the histological heterogeneity together with the medical complexity of the patients, there are no data available from randomised trials to inform management. For the rarer subtypes and in the relapsed/refractory setting, treatment decisions are informed by small case series and case reports. However, for the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms.23, 24 Where safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team. RIS aims to partially restore T-cell function. This may be the only treatment required for a select group of patients with low-risk patients which have early lesions, low-stage disease and non-bulky disease.21, 27, 29 Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond. If a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors.29-31 Close monitoring for rejection of the SOT by the relevant transplant team is crucial in these patients who are in CR and maintained at RIS.29, 31, 32 Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment may be considered as described in the section Rituximab +/− chemotherapy.29-31 The most recent SOT guidelines support the recommendation for RIS33-35 but none give specific guidance on how this should be achieved. The European Renal Guidelines have been outlined in Table III; however, there have been no recent updates.36 Reduction of CNIs by 50% Consider stopping azathioprine/MMF Maintain prednisolone 7·5/10 mg/day Stop azathioprine/methotrexate/cyclophosphamide Initial reduction of CNIs by 75% Prednisolone to 7·5 mg/day (glucocorticoid to physiological maintenance dose) Stop azathioprine and methotrexate Reduction of CNIs by 50% and further reduction by 50% if not in complete remission by day 14 Reduce glucocorticoids by 50%, with a lower limit of prednisone of 7·5 mg/day Stop azathioprine and cyclophosphamide Reduce CNIs by 50% and maintain steriods Or withdrawal of all immunosuppressant drugs except for corticosteroids The American guidelines recommend an alternative approach according to the clinical picture and the extent of the disease.37, 38 A prospective study of sequential RIS according to the clinical picture conducted by the Southwest Oncology Group (SWOG) on Protocol S9239 had a similar approach, which was then considered best practice32 as shown in Table III. Historically, some guidelines suggest stopping all immune suppression in certain clinical scenarios. However, this should only be done with guidance from the transplant team and only if absolutely necessary. A more pragmatic approach that should be adopted for RIS is to follow the criteria used for entry into the prospective phase II PTLD-1 trial. PTLD-1 trial inclusion criteria included failure of up-front RIS, where the recommendation was to stop antimetabolites [azathioprine and mycophenolate mofetil (MMF)] and reduce calcineurin inhibitors (CNIs) by 30–50% while maintaining corticosteroids, if feasible. The response to RIS was assessed early between two and four weeks and failure of RIS was followed by sequential treatment with rituximab and subsequently by CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy in adult B-cell PTLD.39 RIS should be considered in conjunction with other therapies, in patients who have risk factors which include clinically aggressive PTLD Ann Arbor stage ≥III, elevated LDH and more than one extra-nodal site or a high-risk IPI.27, 39, 40 Significant reduction or even interruption of immunosuppression is more realistic following a renal SOT than a lung or heart transplant, where alternative support strategies for acute rejection are not available.41, 42 Therefore, in patients where RIS is not possible, alternative therapies are indicated. The commonest form of PTLD has a CD20-positive, B-cell monomorphic histology similar to DLBCL (see later sections for management of other subtypes; Fig 1). Rituximab is a monoclonal anti-CD20 antibody that has become a standard of care in patients with polymorphic PTLD, or monomorphic DLBCL-like PTLD, who are unresponsive to initial RIS. The international phase II PTLD-1 trial39 established sequential therapy of four cycles of weekly intravenous rituximab at standard dose (375 mg/m2) followed by four cycles of chemotherapy vincristine, prednisolone) This approach in a OS of years and a on the PFS it is to these compared with those of patients with rituximab where the OS was approximately was to compared to retrospective case series with front-line CHOP therapy which of to (see Table for a of 85% monomorphic DLBCL 15% polymorphic polymorphic monomorphic DLBCL monomorphic polymorphic OS OS years polymorphic monomorphic DLBCL In of the in PTLD-1 and the of rituximab the of the PTLD-1 study a treatment in an to limit the of patients to response and In the trial patients with CD20-positive PTLD who had RIS four weekly rituximab followed by CT day Patients a CR were considered and a further four of rituximab and then Patients to CR by CT criteria or who the initial rituximab were considered and were to four cycles of was chemotherapy and was of patients CR at CT with rituximab and with rituximab therapy alone. In the the to was not and the was OS was was to analysis, initial response to four of rituximab and a baseline IPI were significant prognostic on the data available from PTLD-1 and the low-risk group was further in the study into account the initial response to rituximab and the IPI at Patients with a low risk of disease are defined as those who achieve a CR after the first four of rituximab and those with an IPI of who achieve a remission at staging. This the number of PTLD patients who only require rituximab and is to reduce and subsequently the but a similar This is not an approach to in selected patients and et al. demonstrated in a prospective phase II trial where of patients that PR after rituximab to CR with treatment with rituximab all patients be for chemotherapy as described treatment or alternative less treatment as corticosteroids, and can be considered in selected should be to transplant patients with patients often heart failure with on standard Therefore, a not function in this group of with the transplant team to an assessment of the and function is In patients where there is an clinical to with rituximab therapy is recommended with RIS as the treatment used in DLBCL for the immunocompetent this should be done with as there is a significant risk of with this approach as outlined the of the PTLD-1 In case of clinical of disease at rituximab or should be performed and should be considered to if disease is to treatment can be assessed by however, even the role of PET-CT is not established it can be considered a more for response assessment and should be utilised where on the management of polymorphic CD20-positive B-cell PTLD are limited and these cases have been included in the PTLD-1 trial. Therefore, are with the as monomorphic CD20-positive B-cell PTLD as described polymorphic PTLD can have an with PTLD and the management be as described in the PTLD The role of as a of treatment for PTLD is heterogeneous case series include patients with RIS with of cases having included in initial A retrospective analysis that with disease, of the histological subtype, can after or usually with monomorphic type DLBCL and lymphoma PTLD be considered for treatment with RIS and treatment in line with standard the of or in with RIS +/− rituximab in DLBCL if the patient is not eligible for may be considered for some extra-nodal such as the CNS and is an therapy in extra-nodal lymphomas of the lymphoid tissue In of PTLD, to be incorporated with the chemotherapy such as in The dose and regimen to follow lymphoma There a of data or further to demonstrate response of established lymphoproliferative disorders to or either as or in with The of and there are no to recommend its of clinical There are no prospective data to the treatment of patients with or PTLD. The is limited to case various histological In patients who are unresponsive to using is a and A sequential approach as in front-line therapy can be considered if relapse post rituximab Patients with PTLD post have a poor survival with OS as with transplantation are challenging to in SOT treatments from DLBCL in immunocompetent patients is but this approach has in PTLD. should be to the of chemotherapy in relation to the SOT and patient Patients should be in a clinical trial where available. another approach in the treatment of PTLD the risk of graft either the to or a of partially to a T-cell response to these B If available, or should be considered in patients with PTLD. overall response of has been described in patients who had initial and remission at years of 14 patients who an initial A recent updated report from the group using has shown of 75% and a OS of in patients with PTLD following This is similar to the demonstrated by et al. where a in PTLD patients who were to rituximab was using specifically for PTLD are but the and the recent of reported for B-cell that this have a role in the treatment of PTLD. PTLD has in common with but some can be A with EBV is with an with in patients with histopathological but a The series of patients with monomorphic PTLD demonstrated that rituximab was at remission = of patients an regimen = doxorubicin, vincristine, prednisone and = CHOP = with RIS a which was similar to with more chemotherapy and RIS = = regimen = 83% are by a small of patients from the PTLD-1 trial and a PTLD In of these small with RIS be considered a for PTLD as in diffuse large B-cell lymphoma in the immunocompetent However, with CNS may also a clinically in selected patients to achieve data for and the PTLD The CNS should be assessed for or involvement at baseline and CNS should be There is a of data on these subtypes to recommend a approach and it is to as for the disease in the immunocompetent. RIS should be incorporated in the management T-cell lymphomas are a form of PTLD. They occur later after SOT and are often associated with poor The published is limited to case reports. A approach in patients with function is to RIS with used in immunocompetent patients with T-cell lymphoma can be adopted on T-cell lymphoma PTLD There are no published cases the of in first remission in the of PTLD. PTLD is and data on therapy are Patients with PTLD are from clinical trials with data from cases data suggest that at a of post had a OS of compared to for patients the SOT patients particularly demonstrated a superior standard chemotherapy with with or may a safe and RIS in patients with and doxorubicin, vincristine, or for should only be considered and used with in patients with particularly high-risk disease the associated and with these SOT is to the risk of extra-nodal lymphoma by to The site of involvement of lymphoma is cases of and involvement are are heterogeneous and lymphoma in the skin and may well to RIS in the first Rituximab has been shown to be and can be a treatment is an treatment in this as in the section may be adopted as the treatment used in immunocompetent patients with extra-nodal the risk of CNS lymphoma is elevated in SOT recipients, it between 10 and of The histology of is B-cell lymphoma and all are The disease is usually and by but tissue biopsy is recommended that may present with similar The overall is considered However, in recent case appears higher than of treatment with a OS in the of The therapy for has not been established and may limit treatment in RIS is usually resulting in an of 75% in one and have reported a OS of The of RIS, chemotherapy and an of 75% and OS of at years in one series with no in chemotherapy with CNS such as including methotrexate with is the standard for immunocompetent CNS but may be challenging to due to renal failure or SOT in this approach has been adopted in patients with some from immunocompetent CNS lymphoma can be considered on a however, most trials The of rituximab to chemotherapy in CNS lymphoma has shown to and in selected patients for chemotherapy rituximab with RIS may be et al. demonstrated with and in patients with in patients following transplant or SOT of and a OS of in studies are to this but it may be an in selected patients where available. Significant has been described in patients with PTLD with with of to 50% following It is to as in this patient of if the risk of is for all cycles of treatment should be is an risk for which can be by Given the degree of immunosuppression in patients with PTLD, should be to and particularly if treatment is associated with as with or should be considered in all patients and in those with a of for should in patients with PTLD with guidance from the transplant physician or team. Patients with B or C should be in conjunction with a monitoring of liver function is required treatment, and monitoring of B should be considered as the guidance outlined by NICE or as directed by the Patients with HIV should be under care with HIV The of therapy has chemotherapy more in the with may be considered after of PTLD as the risk of of PTLD after is The and analysis reported in patients who 9 and 1 the renal all patients were and of were after a of approximately two A more recent review of patients reported that of PTLD after was with only one patient PTLD at two The of on the specific organ and clinical A number of small studies have for renal transplantation between 29 and following treatment of In patients where has been there has been no reported of PTLD at Therefore, it is to for the patient’s immune system to to the of A of one year should be considered as a on the organ and clinical The at the of this guideline were The to the and the guidelines for support in this also to for the initial and who is medical from and for with the The the the of this All have a of to the and which may be on has from and has from and has from and has from and and from and has from and and from and has from and from and have no of to of the group inform the group if available that the of the recommendations in this document or it The document be by the relevant and the be three years to for that may have been The document be and from the guidelines if it If recommendations are an be published on the guidelines the and information in this guidance is to be and accurate at the of to the the the for the of this All the and to the and of this developed developed Fig 1 and Table