East Midlands Cancer Network Guidelines for diagnosis and management of mature T cell and NK cell lymphomas (excluding cutaneous T cell lymphoma)

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1 East Midlands Cancer Network Guidelines for diagnosis and management of mature T cell and NK cell lymphomas (excluding cutaneous T cell lymphoma) Written by: Dr Chris Fox with input from Dr Fiona Miall and Dr Andy Haynes Consultation Group EMCN Haematology NSSG Summary Lymphomas of mature T cell and NK cell origin are a group of biologically and clinically heterogeneous malignancies. Most subtypes behave aggressively and resistance to conventional chemotherapy regimens is common. Compared to their B cell counterparts, patients with T/NK lymphoma more often have a poorer performance status at diagnosis, extranodal disease, B symptoms and unfavourable prognostic indices. With the possible exception of Alk-positive anaplastic large cell lymphoma, there is no consensus on the optimal therapy for these diseases and the 5-year survival following CHOP-like regimens is approximately 30% in most studies. Where possible, patients should be enrolled into clinical study protocols. Patients with high-risk disease should be considered for intensive first-line therapy, including autologous and allogeneic stem cell transplant for appropriately selected patients. This guideline excludes the mature T cell leukaemias and the cutaneous T cell lymphomas Diagnosis Expert haematopathological review of tissue biopsies incorporating morphology, immunohistochemistry, flow cytometry and molecular genetic data is essential for accurate diagnosis and sub-classification in particular. Lymph node excision is preferred but core biopsy may be sufficient in some cases or for extra-nodal sites. Fine-needle aspirate per se is insufficient. Correlation with clinical features is critical and re-biopsy may be required in some cases. Staging Standard blood tests should include all routine haematology and biochemistry, serum LDH, immunoglobulins and beta-2 microglobulin. All patients should be tested for HIV, Hepatitis B and C. CMV, EBV and HTLV serology and PCR may be required in selected cases. ECOG performance status should be recorded. IPI should be recorded. Written By: Dr Chris Fox Authorised by: EMCN Haem NSSG Page Number: 1/6

2 Bone marrow aspirate and trephine biopsy is required and has prognostic value. Whole body CT scan with contrast. The vast majority of T-NHLs are FDG-avid and up to 18% of patients may be upstaged as compared to conventional CT[1]. Pre-treatment staging with FDG-PET is recommended (but not mandated) for patients with T-NHL prior to active therapy. Prognosis Applying the IPI (as validated for DLBCL) can effectively stratify T-NHL although a large proportion of cases are assigned an intermediate or high-risk score. A modified IPI for T cell lymphomas provides better separation of risk groups and delineates prognosis based on age, LDH, bone marrow involvement and PS[2]. For specific subtypes such as NK/T lymphoma, the predictive value of a low IPI is particularly poor and more disease-specific scores (NK-IPI) should be applied. Treatment Delivery CHOP or CHOP-like first-line regimens can be delivered at level IIA, salvage therapy or intensive first-line therapy can be delivered at level IIB. Autologous and allogeneic stem cell transplant should be delivered at a JACIE-accredited BMT unit. All patients should be offered the opportunity to participate in an approved clinical trial protocol if available. Recommendations for Therapy FIRST-LINE 1. Systemic Alk-positive Anaplastic Large T cell lymphoma. This subtype should be distinguished from the primary cutaneous entity and from Alknegative disease. a. Stage IA ALK+ALCL with no adverse prognostic features by IPI should be treated with 3-4cycles of CHOP or CHOEP followed by radiotherapy. b. Stage IB-IV should receive 6 cycles of CHOP or CHOEP chemotherapy 2. Extra-nodal NK/T lymphoma (nasal-type) [ENKTL]. This subtype is very rare in the UK. Most cases have an NK genotype/phenotype but approximately 15% have a cytotoxic CD8+ phenotype. EBV-positivity of the tumour as determined by EBER in-situ hybridisation is a requisite for diagnosis. a. Patients with localised disease (IE/IIE) should receive radiation with 50-55Gy. Evidence supports an improved outcome with the use of additional chemotherapy although the optimal regimen has not been examined in a randomised study. High-expression of P-glycoprotein (PGP) by the tumour cells makes anthracycline and vinca alkyloid agents less desirable. Two recent phase II studies examined non- PGP, non-cross resistant chemotherapy regimens (Etoposide/Ifosfamide/Cisplatin/Dexamethasone) either concurrent with or following radiotherapy with very encouraging outcomes[3, 4] and superior to previous studies with radiotherapy-alone or radiotherapy-chop combinations. Such an approach is recommended for stage IE-IIE ENKTL. Other similar regimens such as Written By: Dr Chris Fox Authorised by: EMCN Haem NSSG Page Number: 2/6

3 ESHAP, IVAC or GemP could also be considered. For frailer patients, oral Fludarabine/Cyclophosphamide or CHOP/CHOEP are reasonable options, with the former regimen favoured in view of MDR1/PGP expression. A lack of good data makes formal recommendations difficult in this group of patients; individualised decisions may be required. b. Patients with advanced stage disease, extranasal disease or relapsed/refractory ENKTL have a dismal prognosis with conventional chemotherapy. However, recent data on L-asparaginase-containing regimens such as AspMetDex[5] or the SMILE regimen[6, 7] appear active (Pegylated L-asparaginase is recommended- see Lunning, M et al Blood ASH Annual Meeting Abstracts, Nov 2011; 118: 2688.). Responding patients should be considered for autologous or allogeneic stem cell transplant. 3. Enteropathy-associated T-cell lymphoma. An aggressive tumour of the small bowel usually associated with antecedent coeliac disease. Many patients have a poor performance status and nutritional deficiency at diagnosis. a. CHOP or CHOP-like therapy alone results in long-term survival for <10% patients and although may be appropriate for elderly patients, is not recommended as sole therapy for those fit enough for a more intensive approach (see (b)). However, as in the current NCRI protocol, one cycle of CHOP may be a pragmatic initial choice to improve performance and nutritional status prior to commencing an IVE-based protocol. b. Where possible, patients should be entered into a clinical trial. The current NCRI Phase II study, based on published experience[8, 9], employs an approach based on IVE, high-dose-mtx and consolidated by a BEAM-conditioned autologous stem cell transplant in CR1. Such an intensive approach should be considered for all sufficiently fit patients, preferably within the NCRI study. c. All patients should receive dietetic/nutritional/gastroeneterology support where appropriate and many may require enteral or parenteral feeding concurrent with therapy. 4. Peripheral T cell lymphoma (not otherwise specified) Angioimmunoblastic T cell lymphoma Alk-negative Anaplastic Large T cell lymphoma a. Although no randomised trial has demonstrated superiority of other regimens over CHOP for these poor-prognosis tumours, long-term survival with this approach in most studies does not exceed 30% and early disease progression is common. Patients should be ideally offered participation in a clinical study. b. Where a clinical trial protocol is not available, the following regimens are reasonable to consider as first-line induction therapy in sufficiently fit patients:- i. CHOP or CHOEP (Note disease progression during CHOP/CHOEP is common and early intensification to ii, iii or iv is recommended where possible. CHOEP may improve the quality of response over CHOP and a 14-day cycle is preferred, to enable prompt intensification.) ii. IVE with/without high-dose MTX ( Newcastle protocol ) iii. ESHAP Written By: Dr Chris Fox Authorised by: EMCN Haem NSSG Page Number: 3/6

4 iv. GemP - with/without high-dose MTX. c. Consolidation with autologous HSCT in first CR should be considered for suitable, chemo-sensitive patients[10]. d. For high-risk patients, where long-term survival with conventional therapy may be as low as 10-30%, an allogeneic stem cell transplant should be considered in first response, particularly for those who fail to achieve CR with first-line therapy. No published data exist comparing autologous versus allogeneic SCT in T-NHL and this decision is best made on a patient-by-patient basis, taking into account prognostic features, quality of response to first-line therapy, donor availability, predicted transplant-related mortality and patient s wishes. Good evidence exists for a potent graft-versus-lymphoma effect[11, 12] but a stable remission prior to allograft is critical; chemoresistance is a substantial problem for relapsed T cell lymphoma and a stable second remission may not be achieved. 5. Hepato-splenic gamma-delta T cell lymphoma a. This is an extremely rare, aggressive subtype with a dismal prognosis. No 5 year survivors were recorded in the largest international T cell study to-date (Vose et al). Such patients should be considered for a first-remission allogeneic stem cell transplant as long-term survivors are reported after such an approach. b. There is no robust evidence for a particular chemotherapy regimen but dose- and time-intense non-cross-resistant regimens are favoured; such as CODOX-M/IVAC or other established Ifosphamide-based regimen(s) alternating with Platinum or Methotrexate-based protocols. Interim and end-of treatment imaging Data on the predictive value of interim PET-CT is extremely limited and this should only be undertaken in the context of a clinical trial. End of treatment and pre-sct PET-CT for T-NHL offers improved sensitivity over conventional CT for the detection of residual disease and is recommended. Caution however should be applied to the specificity of FDG-avidity in this context and biopsy-confirmation should be considered before further treatment decisions are made. The minimum standard for end-of-therapy restaging is conventional contrastenhanced CT in which case a repeat CT scan is usually performed 3 months later to clarify remission status. Relapsed/Refractory T-NHL 1. The outcome of relapsed and refractory T-NHL is poor. Re-biopsy should always be performed where feasible and clinical trial options should be considered. 2. Treatment decisions will be influenced by nature of first-line therapy, duration of first-remission and biological fitness/performance status. 3. For patients with an initial remission of >1 year and demonstrable chemosensitivity at relapse (e.g. PET-negative response to first-line salvage therapy), consolidation with autologous-hsct may be considered in CR2. However, the prognosis of relapsed T-NHL is poor and chemo-resistance is common. Allogeneic SCT should be considered for those patients relapsing Written By: Dr Chris Fox Authorised by: EMCN Haem NSSG Page Number: 4/6

5 after autologous SCT or with other high-risk features at relapse; for example a short first remission (<1 year) and/or failing to achieve a CR with first-line salvage regimens. Good evidence exists for a graft-versus T cell lymphoma effect[11, 12] although a stable response is required before proceeding to allo-sct; second-line salvage therapy is required for those not achieving a CR to first-line salvage. Salvage options: IVE ESHAP ICE GemP Mini-BEAM SMILE HD-MTX and/or high-dose cytarabine may also be considered where additional CNS-directed therapy is indicated Brentuximab (for relapsed/refractory ALCL, usage within licence, prior funding approval may be required) Paliative options: Vinblastine with/without Dexamethasone Gemcitabine with/without Dexamethasone Oral cyclophosphamide/corticosteroid (continuous therapy) These agents may also be appropriate as first-line therapy to prolong PFS and improve quality of life for elderly patients ineligible for more intensive therapies. In particular the published data on cyclophosphamide/prednisolone (ref 16) should be considered in this context. Novel agents where accessible, appropriate and funded Novel agents: For refractory disease or patients ineligible for an auto- or allo-sct, a number of novel agents with activity in T-NHL have recently emerged with promising response data and should be considered as therapeutic options either through a clinical trial, compassionate use programs or via CDF funding. Clinical Trials In set-up at NUH: Pralatrexate[14] Romidepsin[15] (or other approved HDAC inhibitors) 1. CHEMO-T (CHOP versus GemP) 2. CHOP versus CHP-Brentuximab (Seattle Genetics commercial study) Written By: Dr Chris Fox Authorised by: EMCN Haem NSSG Page Number: 5/6

6 References 1. Cahu, X., et al., 18F-fluorodeoxyglucose-positron emission tomography before, during and after treatment in mature T/NK lymphomas: a study from the GOELAMS group. Ann Oncol, (3): p Gallamini, A., et al., Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood, (7): p Kim, S.J., et al., Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma study. J Clin Oncol, (35): p Yamaguchi, M., et al., Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/t-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol, (33): p Jaccard, A., et al., Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood, (6): p Yamaguchi, M., et al., Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/Tcell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol, (33): p Yamaguchi, M., et al., Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci, (5): p Sieniawski, M., et al., Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. Blood, (18): p Bishton, M.J. and A.P. Haynes, Combination chemotherapy followed by autologous stem cell transplant for enteropathy-associated T cell lymphoma. Br J Haematol, (1): p Dearden, C.E., et al., Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma). Br J Haematol, (4): p Kyriakou, C., et al., Allogeneic stem cell transplantation is able to induce longterm remissions in angioimmunoblastic T-cell lymphoma: a retrospective study from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol, (24): p Corradini, P., et al., Graft-versus-lymphoma effect in relapsed peripheral T- cell non-hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol, (11): p Fanale, M.A., et al., A Phase I Weekly Dosing Study of Brentuximab Vedotin in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies. Clin Cancer Res, (1): p O'Connor, O.A., et al., Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol, (9): p Coiffier, B., et al., Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy. J Clin Oncol, Tucci, A. et al., Continuous oral cyclophosphamide and prednisolone as a valuable treatment option for peripheral T cell lymphoma. British Journal of Haematology, 152, Written By: Dr Chris Fox Authorised by: EMCN Haem NSSG Page Number: 6/6