INITIAL EVALUATION. See Page 2 for Clinical Presentations and Primary Treatment

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1 DIAGNOSIS INITIAL EVALUATION ESSENTIAL: Hematopathology review of all slides with at least one paraffin block representative of the tumor. Rebiopsy if consult material is nondiagnostic. FNA s are generally inadequate. Recommend core or excisional biopsy. Adequate immunophenotyping to establish diagnosis - Paraffin Panel: - CD3, CD10, CD20, CD45 (LCA), Ki-67, BCL2, BCL6, and TdT - Flow cytometry immunophenotyping (optional if paraffin IHC has been performed): kappa/lambda light chains, IgM, CD3, CD5, CD10, CD19, CD20, CD45, and TdT Molecular genetic analysis - For Burkitt lymphoma: FISH to detect MYC gene rearrangements - For Double-hit lymphoma: FISH to detect the BCL2 and BCL6 gene rearrangements OF USE IN CERTAIN CIRCUMSTANCES: FISH for BCL2 and BCL6 rearrangements In situ hybridization: EBER STRONGLY RECOMMENDED: FNA or core biopsy for tissue banking by protocol Perform gene mutation panel if available Physical exam: Performance status (ECOG) B symptoms (fever, sweats, weight loss) CBC with differential, albumin, AST, ALT, total bilirubin, alkaline phosphorus, serum calcium, uric acid, phosphate, magnesium, BUN, creatinine, LDH Screening for HIV1and 2, hepatitis B and C (HBcAb, HBaAg, HCVAb) Chest X-ray, PA and Lateral CT with contrast of neck, chest, abdomen and pelvis Echo or MUGA Lumbar Puncture with cytology evaluation Bilateral bone marrow biopsy with aspirate PET/CT Scan Useful in selected cases: UGI/barium enema/endoscopy MRI of brain with gadolinium or CT of brain Pregnancy test in women of childbearing potential Discussion of fertility issues and sperm banking See Page 2 for Clinical Presentations and Primary Treatment

2 INDUCTION THERAPY Burkitt Lymphoma 1 Dose adjusted Rituximab and EPOCH (Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin) with intrathecal chemotherapy and GCSF 2 Rituxmab and HCVAD (Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone) alternately with Rituximab and Methotrexate and Cytarabine with intrathecal chemotherapy and GCSF Rituximab and CODOX-M/ Rituximab and IVAC (Cyclophosphamide, Vincristine, Doxorubicin, high-dose Methotrexate alternately with Ifosphamide, Etoposide, high-dose Cytarabine) with intrathecal chemotherapy and GCSF 2 Double- Hit or Triple- Hit Lymphoma 1 Regimens as above for Burkitt Lymphoma Consideration of consolidation in 1 st complete remission with high dose chemotherapy and Autologous Stem Cell Transplantation (ASCT) in selected patients continued on the next page 1 R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone is not adequate adequate therapy 2 GCSF: Granulocyte Colony-Stimulating Factor (Filgrastin or Pegfilgrastim) 5

3 RESPONSE EVALUATION 1 FOLLOW-UP Complete Response (CR) Recommend to continue: Routine follow-up and management with infectious disease specialists Routine cancer screening tests with primary cancer physician Year -2: Every 3-4 months Repeat CT s with contrast Years 3-5: Every 6 months Repeat CT s with contrast Year 5 and beyond Partial response (PR), Stable Disease, Progressive Disease and recurrence Consider non-overlapping chemotherapy option per DLBCL guidelines Consider high dose chemotherapy plus ASCT for patients who enter into second remission with good performance status and well controlled concomitant medical issues 1 By Revised Response Criteria for Malignant Lymphoma( see suggested readings)

4 SUGGESTED READINGS Aukema, SM et al. (2011). Double-hit B-cell lymphomas. Blood 117(8): Barnes JA, LaCasce AS, Feng Y, et al. (2011). Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt s lymphoma: a retrospective analysis. Ann Oncol 22: Blum KA, Lozanski G, Byrd JC, et al. (2004). Adult Burkitt leukemia and lymphoma. Blood 104: Cheson, BD, Pfistner, B, Juweid, ME, et al. (2007). Revised Response Criteria for malignant Lymphoma. J Clin Oncol 25; 5: Dunleavy K, Little RF, Pittaluga S, et al. (2008). A prospective study of dose-adjusted (DA) EPOCH with rituximab in adult with newly diagnosed Burkitt lymphoma: A regimen with high efficacy and low toxicity. Annals of Oncology 19 (suppl_4):iv Dunleavy K, Pittaluga S, Shovlin M, et al. (2013). Low-intensity therapy in adults with Burkitt s lymphoma. N Engl J Med 369(20): doi: /NEJMoa Griffin TC, Weitzman S, Weinstein H, et al. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD10+) non-hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children s Oncology Group. Pediatr Blood Cancer, 52: Magrath I, Adde M, Shad A. et al. (1996). Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14: Mead GM, Sydes MR, Walewski J, et al. (2002). An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt s lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 13: LaCasce A, Howard O, Lib S, et al. (2004). Modified magrath regimens for adults with Burkitt and Burkitt-like lymphoma: preserved efficacy with decreased toxicity. Leuk Lymphoma, 45: Oki Y, Noorani M, Davis RE, et al. (2013). Double hit lymphoma; MD Anderson Experience. ASH 55 th Annual Meeting and Exposition. Abstract #1776 Rizzieri DA, Johnson JL, Byrd JC, et al. (2014). Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia Group B study Br J Haematol, 165: Thomas DA, Faderl S, O Brien S, et al. (2006). Chemoimmunotherapy with hyper-cvad plus rituximab for the treatment of adult Burkitt and Burkitt type lymphoma or acute lymphoblastic leukemia. Cancer 106: Thomas DA, Kantarjian HM, Cortes J, et al. (2008). Long-term outcome after hyper-cvad and rituximab chemoimmunotherapy for Burkitt (BL) or Burkitt-like (BLL) leukemia/lymphoma and mature B-cell acute lymphocyte leukemia (ALL) [abstract]. Blood 112:Abstract 1929.

5 DEVELOPMENT CREDITS This practice guideline is based on majority expert opinion of the Lymphoma Center Faculty at the University of Texas MD Anderson Cancer Center. It was developed using a multidisciplinary approach that included input from the following medical oncologists, radiation oncologists, surgical oncologists, and interventional radiologists: Michelle Fanale, MD Ŧ L. Jeffrey Medeiros, MD Yasuhiro Oki, MD Chelsea Pinnix, MD Jason Westin, MD Ŧ Core Development Team Lead

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