clinical practice guidelines

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1 Annals of Oncology 22 (Supplement 6): vi59 vi63, 2011 doi: /annonc/mdr388 Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up M. Dreyling 1, M. Ghielmini 2, R. Marcus 3, G. Salles 4 & U. Vitolo 5 On behalf of the ESMO Guidelines Working Group* 1 Department of Medicine III, University Hospital Grosshadern, LMU Munich, Germany; 2 Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland; 3 Haematology, Kings College Hospital, Longon, UK; 4 Service d He matologie, Centre Hospitalier Lyon-Sud, Pierre-Benite, France; 5 Haematology II, Centro Universitario Ricerca Oncologica Ospedale Molinette, Torino, Italy incidence Follicular lymphomas are the second most frequent subtype of nodal lymphoid malignancies in Western Europe. The annual incidence of this disease has rapidly increased during recent decades and has risen from 2 3/ during the 1950s to 5 7/ recently. diagnosis Diagnosis is only based on a surgical specimen/excisional lymph node biopsy. Core biopsies should only be performed in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the possible heterogeneity of follicular lymphoma grading difficult to appreciate on core biopsies. Fine needle aspirations are inappropriate for a reliable diagnosis. The histological report should give the diagnosis according to the World Health Organization (WHO) classification. Grading of lymph node biopsies is performed according to the number of blasts/high power field (Table 1). Follicular lymphoma grade 3B (with sheets of blasts) is considered an aggressive lymphoma and treated alike (see clinical recommendation DLBCL) [1]. When possible, additional biopsy material should be stored fresh frozen to allow additional molecular (currently still investigational) analyses. *Correspondence to ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; clinicalguidelines@esmo.org Approved by the ESMO Guidelines Working Group: August 2002, last update April This publication supersedes the previously published version Ann Oncol 2010; 21 (Suppl 5): v181 v183. Conflict of interest: Professor Dreyling has reported that he has received support for research from Bayer, Mundipharma and Roche, and that he is a member of the advisory board of Roche. Professor Ghielmini, Professor Marcus, Professor Salles and Professor Vitolo have reported no conflicts of interest. staging and risk assessment Since treatment substantially depends on the stage of the disease, initial staging should be thorough particularly in the small proportion of patients with early stages I and II (5 10%) (Table 2). Initial work-up should include a computed tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy. An additional positron emission tomography (PET) scan is not recommended according to the updated consensus [2]. In rare cases PET scan may be useful to confirm localized stage I/II [IV, C]. A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH) and uric acid as well as screening tests for human immunodeficiency virus (HIV) and hepatitis B and C are required. The staging is given according to the Ann Arbor system (Table 2) with mention of bulky disease, when appropriate. For prognostic purposes, a Follicular Lymphoma-specific International Prognostic Index (FLIPI, Table 3: >4 involved nodal sites, elevated LDH, age >60 years, advanced stage III/ IV, hemoglobin <12 g/dl) should be determined [I, A] [3, 4]. A revised FLIPI2 (incorporating b2 microglobuline, diameter of largest lymph node, bone marrow involvement and hemoglobin level) has been recently suggested for patients requiring treatment [5]. RNA expression analysis suggests a more favorable clinical course in cases with infiltrating T cells in comparison with cases with unspecific macrophage bystander cells [6]. However, this technique is not yet applicable in clinical routine, and immunohistochemistry studies have reported conflicting data recently. treatment plan first line stage I II. In the small proportion of patients with limited non-bulky stages I II, radiotherapy (involved or extended field, ª The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com

2 Annals of Oncology Table 1. Grading of follicular lymphoma Table 3. FLIPI risk factors Grade Description 1 5 blasts/high power field blasts/high power field 3A >15 blasts/high power field, centroblasts with intermingled centrocytes 3B >15 blasts/high power field, pure sheets of blasts Table 2. Ann Arbor classification Stage I(I E ) II (II E ) III (III E, III s ) IV Gy) is the preferred treatment having a curative potential [II, B] [7]. In selected cases a watchful waiting may be discussed to avoid the side effects of radiation (e.g. cervical, sicca syndrome; abdominal, myeloablative suppression) [8]. In patients with large tumor burden or adverse prognostic features, systemic therapy as indicated for advanced stages should be applied and the role of radiation consolidation is not proven [IV, B]. stage III IV. induction. Area of involvement One lymph node region or extralymphatic site (I E ) Two or more lymph node regions or at least one lymph node region plus a single localized extralymphatic site (II E )on the same side of the diaphragm Lymph node regions or lymphoid structures (e.g. thymus, Waldeyer s ring) on both sides of the diaphragm with optional localized extranodal site (III E ) or spleen (III S ) Diffuse or disseminated extralymphatic organ involvement A, no symptoms. B, unexplained fever of >38 C, drenching night sweats or loss of <10% body weight within 6 months. In the majority of patients with advanced stage III and IV disease, no curative therapy is yet established. Since the natural course of the disease is characterized by spontaneous regressions in up to 25% of cases and varies significantly from case to case, therapy should be initiated only upon the occurrence of symptoms including B-symptoms, hematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion or rapid lymphoma Parameter Definition of risk factors FLIPI 1 FLIPI 2 Nodal sites >4 lymph node regions Long diameter of largest lymph node >6 cm Age Above 60 years Above 60 years Serum Elevated lactate Elevated b2 microglobulin marker dehydrogenase stage Advanced (III IV Bone marrow involvement according to Ann Arbor) Hemoglobin <12 g/dl <12 g/dl With 0 1 risk factors, low risk; 2, intermediate risk; 3 5, high risk. progression [I, A]. In four randomized trials an early initiation of therapy in asymptomatic patients did not result in any improvement of disease-specific survival or overall survival (OS) [9]. In a recent study, early initiation of rituximab resulted in improved progression-free survival (PFS; 80% vs 48%, P <0.001), but the benefit on long-term outcome has to be determined [10]. If complete remission and long PFS are to be achieved, rituximab in combination with chemotherapy [such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), purine analog-based schemes: FC (fludarabine and cyclophosphamide) or FM (fludarabine and mitoxantrone) or Bendamustine] should be used [I, B] [11]. In cases with (histologically or clinically) suspected transformation to aggressive lymphoma, an anthracyclinebased regimen should be preferred. Four prospective first-line trials and two salvage trials as well as a systematic meta-analysis confirmed an improved overall response, PFS and OS when rituximab was added to chemotherapy (Table 4) [12 16]. Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab remains an alternative in patients with low risk profile or contraindications for a more intensive chemoimmunotherapy [III, B] [17, 18]. In hepatitis B patients, specific recommendations (HBV monitoring, antiviral therapy) should be followed [19]. consolidation/maintenance. Meta-analysis of the pre-rituximab era suggests a potential benefit of interferon-a maintenance therapy that has to be balanced against toxicity [20]. Rituximab maintenance for 2 years improves PFS (75% vs 58% after 3 years, P <0.0001) [I, B] [21]. Radioimmunotherapy consolidation prolongs PFS after chemotherapy but its benefit following rituximab combinations has not been established [I, B] [22]. Myeloablative radiochemotherapy followed by autologous stem cell transplantation prolongs PFS but not OS in four randomized trials and therefore represents no standard of care outside of trials [I, A] [23 26] vi60 Dreyling et al. Volume 22 Supplement 6 September 2011

3 Annals of Oncology clinical practice guidelines relapsed disease A repeated biopsy is strongly recommended to rule out a secondary transformation into aggressive lymphoma. Selection of salvage treatment depends on efficacy of prior regimens. In early relapses (<12 months), a non-crossresistant scheme should be preferred (e.g. Bendamustine after CHOP or vice versa). Rituximab should be added if the previous antibody-containing scheme achieved >6 12 months duration of remission [IV,C]. Radioimmunotherapy represents an effective therapeutic approach especially in elderly patients with co-morbidities not appropriate for chemotherapy. Otherwise, it should be applied preferably as consolidation [27]. Rituximab maintenance for up to 2 years has a favorable side effect profile and, based on a systematic meta-analysis, substantially prolongs PFS and OS in relapsed disease even after antibody-containing induction in patients who have not received antibody as first-line therapy [I, A] [28]. High-dose chemotherapy with autologous stem cell transplantation prolongs PFS and OS and should be especially considered in patients with short-lived first remissions after R-containing regimens, but its role has to be redefined in the rituximab era [I, B] [29, 30]. In selected younger patients with high-risk profile, a potentially curative allogeneic stem cell transplantation Table 4. Combined chemoimmunotherapy in follicular lymphoma (first line) Study Total no. of patients Median follow-up Overall response Time to treatment failure Overall survival (months) Marcus 2008 [14] R-CVP months 81% (P <0.0001) 27 (P <0.0001) 83% (4 years) (P = 0.029) Hiddemann 2005 [12] R months 96% NR (P <0.001) 90% (2 years) (P = ) CHOP Herold 2007 [13] R-MCP months 92% (P = ) NR (P <0.0001) 87% (P = ) Salles 2008 [15] R-CHVP-Ifn months 81% (P = 0.035) NR (P <0.0001) (high FPLIPI: P = 0.025) Rummel 2009 [11] Bendamustine-R months 92.7% NR 84% (4 years) P, significance levels in comparison with chemotherapy only. Table 5. Recommended treatment strategies outside of clinical studies Low tumor burden High tumor burden Stage I/II Stage III/IV Stage III/IV (<65 years) Stage III/IV (>65 years) Radiotherapy (involved field) Gy In selected cases: watchful waiting Relapse/progress Chemoimmunotherapy In selected cases: palliative radiation (e.g. 2 2 Gray) Watch and wait In symptomatic cases: consider rituximab monotherapy Chemoimmunotherapy (e.g.. R-CHOP, R-CVP, BR) In selected cases: Rituximab monotherapy Chemoimmunotherapy (e.g. R-CHOP, R-CVP, BR) In selected cases: rituximab monotherapy CR/PR: Rituximab maintenance (single application every 2 months up to 2 years) Insufficient response: consider radioimmunotherapy consider ASCT after salvage Dependent on first-line regimen and remission duration: Chemoimmunotherapy: e.g. BR, R-CHOP, R-FC Discuss high dose consolidation with autologous ASCT Rituximab maintenance (single application every 3 months, up to 2 years) Alternatively radioimmuntherapy In selected cases: discuss allogeneic transplantation Chemoimmunotherapy (e.g. R-CVP, BR, R-CHOP) In selected cases: R-chlorambucil Rituximab monotherapy CR/PR: Rituximab maintenance (single application every 2 months up to 2 years) Insufficient response: consider radioimmunotherapy Dependent on first-line regimen and remission duration: Chemoimmunotherapy: e.g.. BR, R-CHOP, R-FC Rituximab maintenance (single application every 3 months, up to 2 years) Alternatively radioimmuntherapy Volume 22 Supplement 6 September 2011 doi: /annonc/mdr388 vi61

4 Annals of Oncology (preferably with dose-reduced conditioning) may be discussed in relapsed disease [31, 32]. response evaluation Adequate radiological tests should be performed midterm and after completion of chemotherapy. Patients with insufficient or lacking response should be evaluated for early salvage regimens. PET scan-ct to evaluate response quality remains investigational in this disease, until future study confirms its predictive value [33]. Minimal residual disease (MRD) analysis at the end of the treatment has some prognostic impact, but should not guide therapeutic strategies outside of clinical studies [34]. follow-up The following recommendation are based on consensus rather than on evidence: History and physical examination every 3 months for 2 years, every 4 6 months for an additional 3 years, and subsequently once a year with special attention to transformation and secondary malignancies including secondary leukemia [V, D]. Blood count and routine chemistry every 6 months for 2 years, then only as needed for evaluation of suspicious symptoms. Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and 5 years. Minimal adequate radiological or ultrasound examinations every 6 months for 2 years and annually thereafter. Regular CT scans are not mandatory outside of clinical trials. MRD screening may be performed in clinical studies but should not guide therapeutic strategies. note Levels of Evidence [I V] and Grades of Recommendation [A D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the expert authors and the ESMO faculty. literature 1. Ott G, Katzenberger T, Lohr A et al. Cytomorphologic, immunhisto-chemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 2002; 99: Cheson B, Pfistner B, Juweid ME et al. 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Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98 J Clin Oncol 2010; 28: Ziakas PD, Karsaliakos P, Mylonakis E. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance. Haematologica 2009; 94: Rohatiner AZ, Gregory WM, Peterson B et al. Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 2005; 23: Salles G, Seymour J-F, Offner F et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2010; 377: Morschhauser F, Radford J, van Hoof A et al. 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5 Annals of Oncology clinical practice guidelines 23. Lenz G, Dreyling M, Schiegnitz E et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Blood 2004; 104: Sebban C, Mounier N, Brousse N et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d Etude des Lymphomes de l Adulte (GELA). Blood 2006; 108: Ladetto M, Ed Marco F, Benedetti F et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008; 111: Gyan E, Foussard C, Bertrand P et al. High dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS. Final results with a median follow-up of nine years. Blood 2009; 113: Dreyling M, Trumper L, von Schilling C et al. Results of a national consensus workshop: therapeutic algorithm in patients with follicular lymphoma role of radioimmunotherapy. Ann Hematol 2007; 86: Vidal L, Gafter-Gvili A, Leibovici L et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2009; 101: Schouten HC, Qian W, Kvaloy S et al. High-dose therapy improves progressionfree survival and survival in relapsed follicular non-hodgkin s lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003; 21: Sebban C, Brice P, Delarue R et al. Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol 2008; 26: Van Besnien K, Loberiza FR, Bajorunaite R et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003; 102: Khouri IS, McLaughlin P, Saliba RM et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 2008; 111: Trotman J, Fournier M, Lamy T et al. Result of FDG PET-CT imaging after immunochemotherapy induction is a powerful and independent progsnotic indicator of outcome for patients with follicular lymphoma. Blood 2010; 116: 372 (#855). 34. Rambaldi A, Carlotti E, Oldani E et al. Quantitative PCR of bone marrow BCL2/ IgH+ cells at diagnosis predicts treatment response and long-term outcome in follicular non-hodgkin lymphoma. Blood 2005; 105: Volume 22 Supplement 6 September 2011 doi: /annonc/mdr388 vi63