Guidelines for the management of Agressive non Hodgkin ...



Aggressive Non-Hodgkin Lymphoma (NHL)Haematological PathwayforSouth Wales Cancer NetworkDocument Control SheetOrganisationSouth Wales Cancer NetworkSpecialty/ProjectHaematological Site Specific GroupDocument TitleAggressive Non-Hodgkin Lymphoma (NHL)Document Number05/019VersionAuthor/sRatified by1.0Dr Clare RowntreeDr Eve Gallop-EvansDr W IngramApproved byApproval dateDate of next reviewSouth Wales Haematology Cancer Network Group19/07/1518/07/16Guidelines for the management of Aggressive non Hodgkin lymphomas in adultsSouth Wales Cancer Guidelines 2015Wherever possible, it is recommended that patients are entered into national trials. Preference should be given to NCRN-accredited portfolio studies. DIAGNOSISRequired investigations at diagnosis for all patients with suspected lymphomaFBC, blood film and cell markers as appropriate Excision biopsy. An adequate core biopsy may be appropriate if surgical biopsy cannot be readily obtained. Fine needle aspirate should not be performed except in suspected cases of T- lymphoblastic lymphoma or Burkitt lymphoma (usually in children or young adults) when a diagnosis can be made on the morphology and immunophenotype and therapy can be urgent. Major surgery should be avoided if at all possible.All hospitals should have agreed pathways with local surgeons for patients who have failed an US guided core biopsy to proceed rapidly to a surgical biopsy to prevent delays in diagnosis.If possible, unfixed node should be sent to the All Wales Lymphoma Panel (AWLP) lab. (divided node to be transported in separate saline and formalin pots). Request forms accompanying the specimen must include relevant clinical and laboratory information, including previous pathological diagnosesHistopathology procedures and standards Each MDT meeting should have at least one designated Pathologist from the All Wales Lymphoma Panel (AWLP) who will review material from all new lymphoma diagnoses.All lymphomas are to be reported according to the WHO classification system and should include relevant prognostic biomarkers where possible.For the majority of cases a preliminary source report should be available within 5 working days of receiving the specimen and an AWLP report should be available within 10 working days. More complex cases, and those requiring extensive immunohistochemistry and/or molecular analysis will take longer to report. Production of an interim report is recommended in such cases.STAGINGStaging and pre-treatment investigationsClinical history including any history of immunosuppression Documentation of presence or absence of B symptomsClinical examinationECOG Performance statusAnn Arbor stagingIPI scoreFBC and blood film, liver and renal function, LDH, bone profile, immunoglobulins, beta-2 microglobulin and protein electrophoresisHIV, HBsAg, HBcAb and HBsAb and Hep C Ab testing Neck/chest/abdomen/pelvis CT Bone marrow examination for patients with Burkitt’s lymphoma (BL), Lymphoblastic lymphoma (LBL) and DLBCL. There may be circumstances in DLBCL where the patient already has stage IV disease and a marrow won’t affect treatment options or where the patient is not having treatment with curative intent where a marrow is not necessary. There should therefore be an element of physician choice for patients with DLBCL Immunophenotyping of peripheral blood or bone marrow or lymph node biopsy material when appropriate Current BCSH guidelines for intrathecal CNS prophylaxis should be followed where patients are being treated with curative intent. Cerebrospinal fluid examination should be performed in patients who have clinical signs of CNS disease. It should also be performed after the first lumbar puncture in patients with paranasal sinus, breast, epidural or testicular involvement where IT therapy is part of their planned treatment. Cytological assessment by cytospin and immunophenotyping (by flow cytometry) if cells are seen. Intrathecal prophylaxis should be administered at time of first CSF examination in these patients. Unless a lumbar puncture is required diagnostically, the first examination of CSF should be after the first dose of immuno-chemotherapyPET scanning at diagnosis improves the staging procedure and may occasionally alter initial therapy. A baseline PET is now standard of care for all cases of aggressive lymphoma. However, there may be specific circumstances when a patient needs urgent treatment and a timely PET scan is not realisticAn echocardiogram and ECG should be performed for all patients being considered for anthracycline based therapy who are over the age of 70 years or who have cardiac risk factors, including hypertension. A guideline relating to cardiac monitoring of patients receiving anthracycline based therapy is currently in progress and the current guidance is likely to change.Fertility preservationAll men should be offered the option for sperm storageAll women of childbearing potential should be offered the option for egg collection and storage prior to starting chemotherapy.However, the following should be notedCHOP based chemotherapy is unlikely to be sterilisingEgg collection will delay treatment starting by approximately 1 monthPatients who are unwell from their lymphoma are unlikely to get a good egg harvest and should get on with treatment urgentlySupportive careTumour lysis riskPatients with large tumour bulk, raised LDH and tumours with a very high turnover rate ie BL and LBL should be considered for Rasburicase treatment prior to chemotherapy to reduce the tumour lysis risk.All other patients should be considered for allopurinol during their first cycle of chemotherapy. There is no need to continue allopurinol with subsequent cycles once the disease has shown a good response to treatment, unless the patient is known to suffer from gout and is already on the drug prophylactically.Use of growth factorsPrimary prophylaxis with growth factors should be used with BL regimens,LBL regimens, primary CNS lymphoma regimens as well as some of the salvage regimens. GCSF is an integral component of the CHOP-14 regimen.Primary GCSF prophylaxis should also be considered for patients over 70 years of age if they are receiving anthracycline based regimens.Secondary prophylaxis should be considered for patients on R-CHOP / CHOP with 1 or more episodes of febrile neutropenia.ProphylaxisAntifungal prophylaxis should be given to patients with LBL (until maintenance) and BL only. NOTE- azoles should be avoided with vincristine.PCP prophylaxis should be given to patients with LBL until 6 weeks post maintenance therapyAciclovir prophylaxis should be given to patients with LBL, BL and those receiving CHOP-14. It should also be considered for patients with angioimmunoblastic T cell lymphoma even if they are receiving CHOP-21.Patients on CHOP based therapy do not need routine anti microbial prophylaxis. However, local microbiology guidelines should be followed for patients with recurrent neutropenic sepsis despite secondary GCSF prophylaxis Monitoring and DischargeEnd of treatmentPatients being treated with curative intent who are not in remission by CT criteria at the end of their planned therapy should have a PET scan. The timing of this scan is important and should be at least 3 weeks post treatment and, if they have received radiotherapy, ideally 3 months post completion of therapy.There is no role for interim PET scans outside a trial in the management of patients with aggressive non Hodgkin lymphomas.Patients in complete remission (CR) by at the end of therapy do not require any further routine scans unless there is clinical cause for suspicion or they are required as part of a trial protocol. Follow upClinic visits3-monthly in year 14-6 monthly in years 2, 3 (depending on stage and risk factors)Annually in years 4, 5 Recommend discharge at 5 years unless patients are left with long term sequelae from their disease or treatment where on going follow up is deemed to be in their best interests. Patients should have a discharge care plan at time of discharge that is sent to the GP and copied to the patientRoutine investigations:Thorough history and physical examinationEnquiry about presence of B symptomsPerformance statusFull blood count, renal and liver function and LDH if high index of suspicionThyroid function tests annually following radiotherapy to neck/mediastinum. An echocardiogram should also be considered for all patients who have received anthracycline based therapy after 12 months post treatment follow up. This is particularly important for women of childbearing age who are considering getting pregnant.Large B cell lymphomas The following should be treated according to this guideline:Diffuse large B cell lymphoma (DLCBL)Primary mediastinal DLBCLFollicular lymphoma, grade 3bTreatment approaches differ according to the following factors:StageDisease bulk (<10cm vs. 10cm)IPI risk groupPresence of primary extranodal diseaseLocalised disease - non-bulky Stage IPatients over the age of 70 years with non-bulky stage I disease by PET scan (in a conventional site where RT would not induce too much toxicity) should receive 3 courses of R-CHOP chemotherapy and involved site radiotherapy (ISRT). If the sequelae of radiotherapy are undesirable e.g. dry mouth, 6 courses of R-CHOP can be given as an alternative. This approach may also be appropriate for patients not fit for 6 cycles of R-CHOP because of comorbidities.Patients with a life expectancy of > 10 years should have 6 cycles of R-CHOPAdvanced disease –bulky stage I, II-IVAll eligible patients should be considered for studies where appropriate.All patients with advanced disease treated outside of clinical trials should receive Rituximab-CHOP21 in accordance with NICE guidance. Most patients will not need more than 6 cycles of R-CHOP (plus an option for 2 extra Rituximab infusions). Patients with a poor performance status due to their lymphoma often benefit from a treatment pre phase with vincristine and steroids starting at day -7 of course 1 and this is recommended in this setting.Patients with an ejection fraction between 40 and 50% may be treated with anthracyclines though consideration should be given to alternatives such as R-GCVP or R-CVP. It should be noted that R-CVP is not thought to be curative in this setting.Patients eligible for high dose therapy presenting with a high risk disease eg triple hit lymphomas, may be considered for an autograft in first remission. Such cases must be discussed at a specialist lymphoma MDT with transplant colleaguesThe current recommendation for patients with primary mediastinal DLBCL who are young and fit is that they should receive RCHOP 14 or 21 + RT. Restaging and management of partial responsePatients entered into clinical trials should be restaged as per trial protocol.All other patients should be restaged with a CT scan after 4 courses of R-CHOP chemotherapy. There may be patients where interim scanning is not required and this should be a clinical decision. Of note, a recent audit in Cardiff showed that no treatment decisions were made on the interim scan alone for patients receiving R-CHOP and it may be reasonable for patients that are clearly clinically responding to treatment complete their first line planned therapy before having further imaging. Note that any patients who had marrow disease at diagnosis must have a repeat marrow at the end of treatment showing clearance of the disease to be classified as having achieved a CR. Those in PR after 6 cycles of treatment by CT criteria should be restaged with FDG-PET scanning. Those with a positive PET scan should be considered for salvage therapy if deemed fit enough for high dose therapy. Those not fit for salvage therapy should be considered for radiotherapy consolidation or palliation. Of note, there are occasions where patients are not fit enough for high dose therapy but are suitable for second line treatment with a regimen such as R-GDP and this can be considered at this stage, with MDT agreement. In general, re-biopsy of suspicious lesions should be considered.Management of primary refractory disease and first relapseThese patients should first receive salvage treatment with a non-cross-resistant regimen. Ideally patients should have a repeat biopsy at relapse. If the lymphoma remains CD20+ then patients should receive rituximab with their salvage chemotherapyAll patients with relapsed or refractory high grade lymphomas must be discussed at a lymphoma MDT, ideally with a member of the bone marrow transplant team being present. The plan for salvage, stem cell collection, restaging and potential progress to high dose therapy should be clearly documented at that discussion. If a bone marrow transplant consultant is not present at that discussion then a copy of the minutes must be circulated to them at that point so that a clinic appointment slot can be provisionally allocated.All currently accepted salvage regimens for DLBCL offer the prospect of approximately a 50% response rate. Patients not on a clinical study should receive 2 courses of R-GDP chemotherapy as salvage. The reason for putting this regimen as the preferred first choice is that it can be given in the out patient setting and has an improved toxicity profile compared to the more standard regimens such as R-ESHAP. However, clinicians may chose to use in-patient regimens in specific patients where agreed by the lymphoma MDT. If the patient responds to 2 cycles of salvage treatment, stem cells should then be harvested prior to conditioning with BEAM and stem cell re-infusion. This can either be done off the back of a third cycle of salvage, with a cyclophosphamide prime or a GCSF prime. Due to the scheduling of the GDP regimen with chemotherapy at day 1 and day 8, stem cell collection off the back of that regimen is not advised. Note- any patients with previously documented marrow involvement need to have a repeat marrow to confirm clearance of marrow disease prior to a stem cell harvest.Patients not responding to 2 courses of R-GDP should be changed to R-ESHAP, R-ICE or R-IVE. Pixantrone single agent, which is now NICE approved for patients in this setting, can also be considered. If the patient achieves a complete remission then stem cell harvest and BEAM autograft should be carried out. Patients who progressed through first-line salvage therapy are very unlikely to have a sustained response to second or third line salvage therapy and consideration should be given to palliation. Likewise, patients not responding to 2 lines of salvage therapy should also be considered for palliative therapy. Regimens such as CCEP and single agent pixantrone should be considered in these circumstances.Summary of TreatmentLocalised diseaseStage I, I.e.non-bulkyR-CHOP x 3 + ISRT(>70 yrs of age with no additional risk factors)Advanced disease in patients aged >18 years or localised disease in patients <70 yearsStage II-IVTherapy as per trials aboveR-CHOP21 (if not on trial) except PMBCL in who receive RCHOP14 in young fit ptsPrimary refractory/relapsed diseaseR-GDP x2responseno response R-ICE / R-IVE / R-ESHAPPBSCH responseno response BEAM autograft PBSCH Pixantrone CCEP /palliationBEAM autograft Burkitt lymphomaPatients under 60 should still be treated according to the LY10 protocol with the addition of rituximab. R-CODOX-M x 3 for Low Risk diseasei.e. they must have at least 3 of the factors identified below:-Normal LDH levelWHO performance status 0-1Ann Arbor stage I-IINumber of extra-nodal sites (e.g. bone marrow, GI tract, CNS) 1R-CODOX-M/R-IVAC x 2 for High Risk diseaseAll remaining patients are high risk. They should have 2 or more of the following features:Raised LDH levelWHO performance status 2-4Ann Arbor stage III-IVNumber of extra nodal sites >1Some patients over 60 may be suitable for R CODOX-M/R IVAC but it can be very toxic in older patients. 3 cycles of R-CODOX-M with a reduced dose of methrotrexate is recommended in these patients. IVAC does have an associated excess mortality in patients over 60 years and is generally not recommended. However, cases should be considered on an individual basis. R-CHOP plus intrathecal chemotherapy is recommended for those not suitable for intensive therapy. Peripheral T-cell lymphomasGenerally the T-cell lymphomas have a poorer response to therapy and shorter survival than the B-cell lymphomas. Prognostic factors should be taken into account to decide initial therapy. Autograft in first remission should be considered for fit patients, particularly those with a high IPI at presentation and those with very poor prognosis disease such as angio immunoblastic T cell disease.TreatmentAll eligible patients should be considered for the current trial – CHEMO-TAll patients not on a trial should receive 6 cycles of CHOP (21 or 14). If good response, consider autograft in first CR for patients under 70 years who are deemed fit enoughIf CR or PR is not achieved to initial therapy, patients should go on to a salvage regimen as for DLBCL. .Intestinal T-cell lymphomaCHOP is standard therapy but consideration of high dose chemotherapy and autologous bone marrow transplantation for suitable patients should be made. In fit patients, consider the ‘Newcastle’ approach using 1 cycle of CHOP followed by 3 courses of IVE and intermediate dose methotrexate. Responding patients then proceed to autograft Lymphoblastic lymphoma (LBL)Patients should be treated on an ALL protocol in either Swansea or Cardiff. Patients under 25 years of age are eligible for UKALL 2011 and should be referred to the TYA PTC for inclusion into this trial where possible.Patients aged 25-60 years should be treated according to the UKALL 14 protocol (an amendment to UKALL 14 is planned to allow patients with LBL to enter this trial).Patients should NOT be considered for an allograft if responding well as data suggests a worse outcome compared to chemotherapy alone.There is no proven role for mediastinal RT for patients who are responding well to treatment. However, RT should be considered for patients not achieving a PR after phase II induction.Patients not in remission after phase II induction are likely to do very badly and consideration should then be given to allografting. All such cases should be discussed at the Cardiff lymphoma / BMT MDT as this is a rare situation that is difficult to manageElderly patients with T-LBL are very rare and should be treated palliatively. UKALL 60+ contains some helpful regimens for treatment of elderly patients with lymphoblastic disease.There is no role for autografting patients with Lymphoblastic disease, based on UKALL 12 data and EBMT registry data. Primary CNS lymphoma (PCNSL)All patients under 75 years should be considered for chemotherapy as first line treatment if they are sufficiently fit. Chemotherapy should consist of a regimen that includes HD-MTX doses of 3000mg/m2 delivered over a maximum of 2-3 hours in combination with HD-Ara-C at intervals of not more than 2-3 weeks. The recent IELSG 32 trial has shown a 2 year FFS survival benefit of 37% with the addition of Rituximab in arm B of the study (15% with HD MTX and AraC, 53% with HD MTX, AraC and Rituximab). Importantly the addition of Rituximab did not increase the toxicity of the regimen. The results from this trial will be presented at Lugano 2015.Chemotherapy recommendations4 cycles of MTX 3500mg/m2 over 3-4 hours on d1 followed by cytarabine 2000mg/m2 BD on d 2 and 3 plus Rituximab days -5 and day 1 (as per the IELSG 32 trial arm B). GCSF d 8-14 recommendedPatients not thought to be able to tolerate such therapy should receive up to 6 cycles of MTX 3500mg/m2 every 2 weeks. The addition of Rituximab should be considered.In patients under 60 years of age, the standard approach is to offer WBRT consolidation to patients achieving a CR unless there is a significant neurocognitive deficit following chemotherapy. However, there is increasing evidence for a Thiotepa / BCNU conditioned autograft as consolidation as an alternative to WBRT and this should be considered in responding patients. In patients aged 60 years or over, neurocognitive side-effects are more likely to outweigh potential benefits and WBRT is not recommended as part of first line therapy in those responding to chemotherapy. Patients with residual disease post chemo should be offered RT following discussion of the risks versus benefits of combined modality treatment. Dexamethasone is the treatment of choice for short-term palliation but should be avoided before biopsy where clinically possible.Whole brain radiotherapy alone can provide effective palliation but should not be used as first-line therapy in patients who are sufficiently fit to receive chemotherapy because there is a high rate of relapse with a median survival of 12-18 months 21Salvage optionsR-IE (Ifosfamide and etoposide) has been shown to have some effect in patients not responding to HD-MTX based regimens and should be considered in younger patients.Neurocognitive assessment at diagnosis, after treatment and at least annually afterwards should be performed. This ideally should be assessed by a clinical neuropsychologist but if not available, a MMSE should be recorded.Secondary CNS lymphoma (SCNSL) Secondary CNS lymphoma has a very poor outcome. Treatment options depend on whether patients present with secondary CNS lymphoma at diagnosis or at relapse and whether patients are eligible for an autograft.There is some evidence for IDARAM but this is a very toxic regimen and not appropriate for the majority of patients.Treatment options are similar to those used for primary CNS lymphoma if disease is isolated to the CNS. Patients achieving a CR should be considered for a BEAM or thiotepa / BCNU autograft as consolidation.HIV related lymphomas High grade B-cell NHL is an AIDS defining illness and is over 100 times more common in HIV seropositive patients than in the general population.Prognostic features for AIDS related NHL:Major adverse prognostic factorsMinor adverse prognostic factorsPrior AIDS diagnosisBone marrow involvementCD4 count <100/lExtranodal diseaseECOG performance status >2Raised serum LDHPrimary cerebral origin Age >35 yearsGood prognosis is defined by <2 minor adverse prognostic factors.Poor prognosis is defined by >1 major adverse prognostic factor.HIV+ patients should be treated along same lines as non HIV patients. HIV+ patients are likely to be on anti-retrovirals which may interact with chemotherapy. This is not a reason to delay or decrease doses of chemotherapy. Dose adjustments may be considered if toxicity occurs.Sperm cryopreservation is available at Chelsea and Westminster if appropriateDLBCLStandard treatment is with R-CHOP 21 and anti-retrovirals. The use of Rituximab is contentious (especially in patients with CD4<50/l). However with appropriate prophylaxis (septrin, fluconazole +/- aciclovir) and preemptive G-CSF and prompt treatment of opportunistic infection Rituximab should be considered for all patients. Management should be coordinated closely with HIV physician.Patients should be given CNS prophylaxis according to the same criteria as HIV negative patients. Burkitt Lymphoma. HIV+ patients with Burkitt lymphoma should also receive RCODOX-M/RIVAC as the outcome has shown to be equivalent to HIV-ve patients.Autografting Good results in patients with HIV related lymphoma recommend that patients should proceed to autografting for the same indications as non-HIV lymphoma patients. Forward planning and liaison with the stem cell laboratories is essentialPost-transplant lymphoproliferative disease (PTLD) This is a collection of clinically and pathologically diverse tumours associated with iatrogenic immunosuppression following transplantation. In the majority of cases tumourigenesis results from a defect in EBV-specific cytotoxic T-cell activity leading to uncontrolled EBV-driven outgrowth of latently infected B-lymphocytes.Below are guidelines for patients with PTLD post solid organ transplantation. PTLD occurring after BMT should be discussed with the BMT team.Initial Managementa) Reduce immunosuppression - produces tumour regression in 20-50% of cases though this may not be possible before other therapy is instituted if the patient is unwellb) Single agent Rituximab (the efficacy of this can be ‘predicted’ according to the ‘PTLD score’ (Choquet et al, 2007)c) If localised disease, radiotherapy may be suitableIf no response / aggressive disease treat with R-CHOPUse of antivirals as treatment of PTLD or as prophylaxis against PTLD is not recommended.Levels of immunosuppressive agents such as tacrolimus must be monitored and kept to a therapeutic minimum, even when patients are receiving multi agent chemotherapy. This needs to be done in conjunction with the patient’s medical /transplant team.Transformed lymphomaTransformed follicular NHL (not synchronous)Patients with transformed disease should received R-CHOPx6-8 or if they have received this previously they can receive R-ESHAP or R-GDP x 2-3. In view of the data showing poor outcome following transformation in the pre rituximab era (1-2yr) autografting was generally advocated for patients who achieved a CR/PR. One group of patients who enjoyed a longer survival following transformation were those who received no prior therapy for their low grade disease and who achieved a CR following treatment of the transformed disease. This group is now not recommended to have an autograft. ................
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