NON HODGKINS LYMPHOMA: AGGRESSIVE Updated June 2015 by Dr. Manna (PGY-5 Medical Oncology Resident, University of Calgary)

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1 NON HODGKINS LYMPHOMA: AGGRESSIVE 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 DIFFUSE LARGE B CELL LYMPHOMA (DLBCL)**

2 A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: Accounts for 30% of all NHLs in the developed world - Mortality: Approximately 66% will survive for 5 years or more after diagnoses RISK FACTORS - Genetic: Male predominance, Caucasians have higher rates familial aggregation of patients with DLBCL observed - Other: HIV, Richter s transformation from CLL (or transformation from other indolent non-hodgkin lymphomas) PREVENTION & SCREENING - Assess patients with established CLL for Richter s transformation B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Common Symptoms: Rapidly enlarging symptomatic mass, commonly nodal enlargement in neck or abdomen. Systemic B symptoms (fever, weight loss, drenching night sweats) - Common Signs: Lymph node enlargement on lymphoid survey (examination of Waldeyer s ring, head and neck, axillary and chest, abdomen, inguinal regions). Signs related to mass and compression of nearby structures (ie) SVC syndrome if mediastinal mass. - Common Presentations: Extranodal involvement in up to 40%. Extranodal sites include GI tract, bone, testis, spleen, Waldeyer ring, and salivary gland. Bone marrow involvement in 11-27% or cases and can be discordant low grade B-cell lymphoma. INVESTIGATIONS - Laboratory: Lymph node pathology (excisional preferred), CBC and differential, creatinine, electrolytes, liver enzymes, LDH, calcium, viral screen (Hepatitis B surface antibody, Hepatitis B surface antigen, Hepatitis C antibody, HIV serology) - Diagnostic Imaging: PET/CT of neck/chest/abdomen/pelvis. Echo or MUGA for baseline cardiac function prior to anthracycline. - Diagnostic Procedures: Bone marrow biopsy and aspirate not required if staging PET/CT performed. Lumbar puncture (CSF for flow cytometry) and MRI Brain with gadolinium if suspect CNS involvement. PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: Large B lymphoid cell morphology. Immunohistochemistry CD20+, CD19+, CD10+/-, bcl6+ (60-90%), MUM1+ (35-65%). - Common Extranodal Sites: CNS (leptomeningeal), testicular, skin - Relevant Molecular Biology: Evaluation of c-myc, bcl-2, and bcl-6 status (by FISH or immunohistochemistry). Evaluation of cell of origin by gene expression profile analysis (if available). Using this information, an individual case may be further subclassified as Germinal center B cell (GCB) DLBCL, Activated B cell (ABC) DLBCL (or non-gcb DLBCL), or Double hit DLBCL. For example: o GCB type: CD10+, bcl6+, MUM1- o ABC type: CD10 -, bcl6-, MUM1+ o Double hit: c-myc translocation + gene rearrangement of bcl-2

3 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 PROGNOSIS - International Prognostic Factor Index (IPI) o Dependent on five prognostic factors: Age >60, Performance Status 2, elevated LDH, Extranodal Site >1, Stage III/IV o Revised IPI for DLBCL following RCHOP chemotherapy Factors # of Factors 4 year PFS 4 year OS Age > % 95% ECOG 2 Elevated LDH % 79% Extranodal Site >1 Stage III/IV % 55% C) TREATMENT NON-BULKY LIMITED STAGE DLBCL - Bottom Line General Approach: Nonbulky (<10cm), limited stage (Ann Arbor Stage I or II) DLBCL are treated with combined modality therapy consisting of R-CHOP chemoimmunotherapy (Rituximab, Cyclophosphamide, Vincristine, Doxorubicin, Prednisone) and involved field radiation therapy (IFRT). Interim PET/CT to determine post therapy IFRT. - Also acceptable R-CHOP x 3-4 cycles + IFRT if no stage adjusted IPI factors; R-CHOP x 6 cycles (with or without IFRT for local control) if >=1 stage adjusted IPI factors

4 - Important Phase III Clinical Trials: Studies involving addition of Rituximab CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good prognosis diffuse large-b-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Pfreundschuh et al. Lacet Oncol. 2006; 7(5): 379. Mechanism of Action of Experimental Drug 6 cycles CHOP-like (CHOP, CHOEP, MACOP-B) vs 6 cycles R-CHOP Rituximab: anti-cd20 monoclonal antibody Event free survival Inclusion: age 18-60, no IPI risk factors, stage II-IV disease, or stage I disease with bulky disease. 824 patients RCHOP vs CHOP-like 3yr EFS: 79% vs 59% 6yr PFS: 80.2% vs 63.9% 6yr OS: 90.1% vs 80% Rituximab added to 6 cycles of CHOP is an effective treatment for young patients with good prognosis DLBCL Studies involving radiotherapy for localized DLBCL Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-hodgkin s lymphoma. SWOG 8736 trial Miller et al. NEJM. 1998;339(1):21.

5 8 cycles CHOP vs 3 cycles CHOP + IFRT PFS, OS, Toxic effects Localized, intermediate- or high-grade NHL (75% were DLBCL) 401 patients CHOP + IFRT vs CHOP alone 5yr PFS: 77% vs 64% 5yr OS: 82% vs 72% Life threatening toxic effects: 61/200 vs 80/201 Toxicity LV function decreased in 7 pts with CHOP alone vs no cardiac events in those receiving CHOP + IFRT 3 cycles CHOP + IFRT are superior to 8 cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-hodgkin s lymphoma. Other comments A reanalysis of this showed that the OS curves overlapped in long-term follow-up with a continuous pattern of relapse outside of radiation field for people who got abbreviated chemo + rads. Only those patients with no IPI risks did well with abbreviated chemo + rads CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Group d Etude des Lymphomes de l Adulte. GELA LNH 93-4 trial. Bonnet et al. JCO. 2007; 25(7): cycles CHOP + IFRT vs 4 cycles CHOP alone EFS Age >60yo with localized stage I or II aggressive lymphoma with no adverse prognostic factors of the IPI 576 patients CHOP + IFRT vs CHOP alone 5yr EFS: 64% vs 61% 5yr OS: 68% vs 72% CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low risk localized aggressive lymphoma in elderly patients. However, patients who received IFRT had a lower rate of relapse at the site of initial disease ADVANCED STAGE DLBCL - Bottom Line General Approach: Advanced stage (Ann Arbor Stage III or IV) or bulky disease (>10cm) DLBCL are treated with combined modality therapy consisting of R-CHOP 6 cycles +/- IFRT (if post therapy PET/CT positivity). Consider autologous stem cell transplant (ASCT) if high IPI risk factors (>3)

6 - Important Phase III Clinical Trials: Studies involving addition of Rituximab Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial. RICOVER-60 Pfreundschuh et al. Lancel Oncol. 2008;9(2): or 8 cycles R-CHOP-14 vs 6 or 8 cycles CHOP-14 EFS Elderly age 61-80yo 1222 patients 6 CHOP-14 vs 8 CHOP-14 vs 6 RCHOP-14 vs 8 RCHOP-14 3yr EFS: 47.2% vs 53% vs 66.5% vs 63.1% 3yr OS: 67.7% vs 66% vs78.1% vs 72.5% 6 RCHOP-14 improved EFS, PFS and OS compared to 6 CHOP-14. Of the four regiments assessed in this study, 6 cycles RCHOP-14 is the preferred treatment for elderly patients. CHOP Chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. GELA LNH-98.5 Coiffier et al. NEJM. 2002;346(4): cycles CHOP vs 8 cycles R-CHOP EFS Elderly age with untreated DLBCL 399 patients RCHOP vs CHOP Rate of CR: 76% vs 63% 2yr EFS: 57% vs 38% 2yr OS: 70% vs 57% The addition of rituximab to the CHOP regiment increases the complete response rate and prolongs event free and overall survival in elderly patients with DLBCL without a clinically significant increase in toxicity Studies involving intensity of RCHOP therapy Dose-dense rituximab-chop compared with standard rituximab-chop in elderly patients with diffuse large B-cell lymphoma:a randomised phase 3 trial. GELA LNH03-6B study Delarue et al. Lancet Oncol. 2013;14(6): 525. Inclusion 8 cycles RCHOP every 14 days vs 8 cycles RCHOP every 21 days Event free survival Inclusion: age and at least one adverse prognostic factor 602 patients RCHOP14 vs RCHOP21 3yr EFS: 56% vs 60% Grade 3-4 neutropenia: 74% vs 64% Red blood cell transfusion: 47% vs 31% In elderly patients with DLBCL, a 2-week RCHOP regimen did not improve efficacy compared with the 3-week standard schedule.

7 RELAPSED DLBCL - Bottom Line General Approach: If transplant eligible, treat with R-DICEP or R-GDP followed by high dose therapy/asct. If not transplant eligible, treat with palliative therapy (such as decreased GDP, CEPP, PEPC, or IFRT). OTHER TREATMENT CONSIDERATIONS FOR DLBCL - Cardiac: anthracycline induced cardiomyopathy or arrhythmia, change doxorubicin to etoposide. - Liver/Increased Bilirubin: Dose reduce doxorubicin and vincristine. - Hepatitis B: Treat with Lamivudine or Tenofovir - Neuropathy: dose reduce or omit vincristine - HIV: HAART therapy, caution with rituximab if CD4 count less 50 - Diabetes: Prednisone induced - BPH/Urinary Retention: Cyclophosphamide induced hemorrhagic cystitis - CNS Prophylaxis: No role for intrathecal chemo. Consider high dose methotrexate if high risk features such as involvement of sinuses, testes, or adrenals. (and dual translocation) - GCSF Support: Consider secondary prophylaxis if develop febrile neutropenia during therapy. - Advanced stage GCB type DLBCL: standard 6 cycles R-CHOP - Advanced stage ABC type DLBCL: consider enrollment in clinical trial evaluating incorporation of novel agents (ie) RCHOP plus lenalidomide, or ibrutinib, or bortezomib. -Dual translocation consider enrolment in trial or consider R-EPOCH (based on cohort/case series data suggesting poor outcomes with R-CHOP) D) REFERENCES 1. Alberta Health Services Guidelines 2. UptoDate 3. Canadian Cancer Society 4. Odette Cancer Centre Guidelines