NON HODGKINS LYMPHOMA: INDOLENT Updated June 2015 by Dr. Manna (PGY-5 Medical Oncology Resident, University of Calgary) Reviewed by Dr. Michelle Geddes (Staff Hematologist, University of Calgary) and Dr. Matt Cheung (Staff Hematologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. WHO CLASSIFICATION OF NON-HODGKIN LYMPHOMA **SUMMARY DOCUMENT FOCUSES ON FOLLICULAR LYMPHOMA**
A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: Second most frequent type of NHL. Accounts for 20-25% of all NHLs. Incidence increases with age. - Mortality: Median survival approximately 10-15 years RISK FACTORS - Genetic: Small numbers of cases appear to be familial. - Other: N/A B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Common Symptoms: Painless peripheral adenopathy in the cervical, axillary, inguinal, and/or femoral regions. Some patients present with asymptomatic abdominal masses or urinary tract obstruction. Approximately 20% present with B symptoms (fever, night sweats, unintentional weight loss). - Common Signs: Lymph node enlargement on CT imaging. INVESTIGATIONS - Laboratory: Lymph node pathology (excisional preferred), CBC and differential, creatinine, electrolytes, liver enzymes, LDH, calcium with albumin, viral screen (Hepatitis B surface antibody, Hepatitis B surface antigen, Hepatitis C antibody, HIV serology) - Diagnostic Imaging: CT of neck/chest/abdomen/pelvis. - Diagnostic Procedures: Bone marrow biopsy and aspirate PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: Nodular growth pattern on histology with effacement of normal lymphoid architecture. Presence of follicle center cells with mixture of centrocytes and centroblasts. - Immunophenotype: Presence of B cell markers. Positive for B cell antigens (CD19, CD20, CD79a, CD21, and CD10). Positive expression of surface immunoglobulin with light chain restriction. Negative for CD5, CD11c, CD23. Cytoplasmic Bcl-2 protein positive. - Relevant Cytogenetics: Cytogenetics show presence of t(14;18). - Relevant Molecular Biology: Evaluation of clonal immunoglobulin gene rearrangements and IgH/bcl2 fusion gene. STAGING - Ann Arbor Staging: Stage Description I Involvement of a single lymph node region or a single extranodal site II Involvement of two or more lymph node regions on the same side of the diaphragm III Involvement of lymph node regions on both sides of the diaphragm IV Diffused/disseminated involvement of one or more extra lymphatic organs or tissues with or without associated lymph node involvement Other B Symptoms: absence (A) or presence (B) or fever >38.5 C, drenching night sweats, and/or unexplained weight loss of >10% body weight in past 6 months E: Extranodal disease X: Bulky disease. Defined as mediastinal mass >1/3 thoracic diameter or any nodal mass >10cm in maximal diameter
TUMOR GRADING - Follicular lymphoma is classified into the following 3 histologic grades: o Grade 1: Low grade. 0-5 centroblasts per high power field (HPF) o Grade 2: Low grade. 6-15 centroblasts per HPF o Grade 3: >15 centroblasts per HPF Grade 3 further divided into 3A and 3B. 3B has presence of sheets of centroblasts and no centrocytes. 3B is treated as a high grade lymphoma. PROGNOSIS - The Follicular Lymphoma International Prognostic Index (FLIPI). Pre-dated Rituximab Chemotherapy Factors # of Factors Prognosis 5 year OS 10 year OS Age 60 0-1 Good 90% 71% Nodal area >4 Elevated LDH 2 Intermediate 78% 51% Stage III/IV Hb <120 3-5 Poor 53% 36% - The Follicular Lymphoma International Prognostic Index (FLIPI2). Factors # of Factors Risk 3 year OS 5 year OS Age >60 0 Good 91% 80% Marrow involvement Increased B2M 1-2 Intermediate 69% 51% Hb<120 Node >6cm 3-5 Poor 51% 19% C) TREATMENT LOCALIZED FOLLICULAR LYMPHOMA (Stage IA or Contiguous Stage IIA) - Goals of Therapy: To achieve effective and durable disease control with minimal toxicity and maintain quality of life. - Bottom Line General Approach: Involved field radiation therapy (IFRT) is considered standard of care. Consider observation if potential toxicity of IFRT outweighs potential benefits. - Important Phase III Clinical Trials: Reduced dose radiotherapy for local control in non-hodgkin lymphoma: a randomised phase III trial Lowry et al. Radiother Oncol. 2011; 100(1): 86-92. Regimen Low dose 24Gy in 12 fractions vs Standard dose 40-45Gy in 20-23 fractions Primary Endpoint ORR Patients with any histological subtype of NHL. Indolent predominantly follicular and marginal zone lymphoma. Size (N) 289 patients with indolent NHL (59% with FL grade 1/2) Results ORR: 92% low dose vs 93% standard dose No difference in local control, remission duration or overall survival Trend towards reduced toxicity in low dose arms In a large randomised trial, there was no loss of efficacy associated with radiotherapy doses of 24Gy in indolent NHL compared with previous standard doses of 40-45Gy
ADVANCED STAGE FOLLICULAR LYMPHOMA - for initiating treatment of FL o for initiation of chemoimmunotherapy should be based on the identification of symptoms defined by the GELF (Groupe pour l Etude de Lymphome Folliculaire) criteria. If any of the following are present: A tumor >7cm in diameter 3 nodes in 3 distinct areas, each >3cm in diameter Symptomatic spleen enlargement >16 on CT Organ compression Ascites or pleural effusion Presence of systemic symptoms Serum LDH or beta2-microglobulin levels greater than normal Hb value 100, neutrophil count 1.5, platelet count 100 o Clinical assessments every 3-6 months - Bottom Line General Approach o For symptomatic advanced stage disease (Grade 1,2, 3a), recommended therapy involves 6 cycles bendamustine-rituximab (BR) chemoimmunotherapy followed by 2 years of maintenance rituximab (rituximab every 3 months for total of 8 doses). o For Grade 3b follicular lymphoma, recommended therapy involves 6 cycles R-CHOP chemoimmunotherapy. Maintenance rituximab has not been proven effective following R- CHOP. - Important Phase III Clinical Trials: Chemoimmunotherapy studies Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open label, multicenter, randomised, phase 3 non-inferiority trial. The StIL Study Rummel et al. Lancet. 2013;381:1203-1210. Regimen Bendamustine & Rituximab (BR) vs R-CHOP Primary Endpoint PFS Age >18, ECOG 0-2, newly diagnosed stage III or IV indolent or mantle cell lymphoma Size (N) 499 patients (54% had follicular lymphoma) Results PFS: 69.5mo BR vs 31.2mo RCHOP No significant differences in ORR or OS between treatments BR better tolerated than RCHOP with lower rates of alopecia, infections, peripheral neuropathy, and stomatitis In patients with previously untreated indolent lymphoma, BR can be considered as a preferred 1 st line treatment approach to RCHOP because of increased PFS and fewer toxic effects
Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: The BRIGHT study Flinn et al. Blood. 2014; 123: 2944-2952 Regimen Primary Endpoint Size (N) Results Bendamustine & Rituximab (BR) vs R-CHOP/R-CVP Complete Response rate Newly diagnosed indolent NHL or mantle cell lymphoma. Age >18, ECOG 0-2. 447 patients (70% had follicular lymphoma) BR vs RCHOP/RCVP Complete Response: 31% vs 25% ORR: 97% vs 91% OS and PFS were not assessed Incidence of vomiting and drug hypersensitivity reaction higher in BR arm. Incidence of peripheral neuropathy/paresthesia and alopecia higher in RCHOP/RCVP arm These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safely profile Maintenance Rituximab Studies 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 Salles et al. Lancet 2010; 377:42-51 Regimen Primary Endpoint Patients who responded to 1 st line treatment with chemoimmunotherapy were randomized to 2 years Rituximab maintenance (375mg/m 2 IV q8wks) vs Observation PFS Previously untreated follicular lymphoma (grade 1,2, or 3a) needing systemic therapy. Age >18. 1217 patients Size (N) Results PFS: 74.9% Rituximab vs 57.6% Observation. Risk of progression reduced by 45% At 2 years, Rituximab group had significantly higher CR rates than observation. 71.5% vs 52.5% OS did not differ significantly between groups (HR 0.87) 2 years of rituximab maintenance therapy after immunochemotherapy as first line treatment for follicular lymphoma significantly improves PFS.
RELAPSED THERAPY FOR FOLLICULAR LYMPHOMA - Bottom Line General Approach o Relapse with both indolent or aggressive histology (histologic conversion) may occur. Therefore, biopsy for histological confirmation and re-staging should be performed if suggestive of aggressive transformation (ie) rapid growth or discordant growth between various disease sites. o Therapeutic recommendations for relapsed follicular lymphoma requires consideration of various factors as outlined below: Patient Factors Disease Factors Age Comorbidities Symptoms Goals of therapy / patient wishes Acceptance of risks/toxicities of treatment relative to potential benefit Stage Sites of involvement Grade Transformation Prior therapy Time from prior therapy (disease free interval) o Therapy should be individualized. Options include: Age <70 and no comorbidities Age <70 with comorbidities or >70? Palliative symptomatic care Consider high dose chemotherapy and autologous stem cell transplantation especially if early relapse after first line therapy Consider repeating initial treatment regimen especially if achieved initial remission greater than 5 years. Otherwise consider non-cross resistant combination chemotherapy for second line therapies (Rbendamustine, R-CVP, R-CHOP, R-fludarabine, etc.). Consider palliative involved field radiotherapy 4Gy in 2 fractions D) REFERENCES 1. Alberta Health Services Guidelines 2. UptoDate 3. Canadian Cancer Society 4. Odette Cancer Centre Guidelines 5. Lymphoma Canada