LONG-TERM FOLLOW-UP OF TREATMENT OF BURKTT'S LYMPHOMA -SINGLE INSTITUTION EXPERIENCE

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1 LONG-TERM FOLLOW-UP OF TREATMENT OF BURKTT'S LYMPHOMA -SINGLE INSTITUTION EXPERIENCE 譚傳德, 劉美瑾, 陳博文, 吳茂青, 邱倫瑋, 陳鵬宇, 吳佳興, 李明媛, 曹美華, 黃玉儀 和信治癌中心醫院血液淋巴及幹細胞移植團隊 Tran-Der Tan* 1, Mei-Ching Liu1, Mau-Ching Wu1, Lun-Wei Chiou1, Bowen Chen2, Jia-Shin Wu3, Ming-Yuan Lee4, MeiHua Tsao4, Shing-Su Chen5, Yu-Yi Huang6, An-Chen Feng7 1Hematology and Medical Oncology, 2Pediatric Hematology and Oncology, 3Radiation Oncology, 4Pathology, 5Radiology, 6Nuclear Medicine, 7Clinical Research and Statistics, Koo Foundation Sun Yat-Sen Cancer Center, Taipei City, Taiwan, ROC

2 Histopathology of BL. Low-power (A) and high-power (B) field hematoxylin and eosin stain; CD20 (C), CD10 (D), MYC (E), and Ki67 (F) immunostains. Caron Jacobson, and Ann LaCasce Blood 2014;124: by American Society of Hematology

3 Changes in overall survival for BL patients across the 2 eras and grouped by gender or summary stage. Luciano J. Costa et al. Blood 2013;121: by American Society of Hematology

4 Table 3. Modified Magrath regimen of R-CODOX/R-IVAC Chemotherapy Day of administration R-CODOX Rituximab, 375 mg/m 2 D1* Cyclophosphamide, 800 mg/m 2 Doxorubicin, 50 mg/m 2 D1, D2 Vincristine, 1.4 mg/m 2 (cap 2 mg) D1, 15 Peg-filgrastim, 6 mg Methotrexate, 3000 mg/m 2 D15 IT methotrexate, 12 mg/cytarabine, 50 mg IT cytarabine, 50 mg Patients with baseline CNS disease should receive in addition (cycle 1 only): IT cytarabine, 50 mg IT methotrexate, 12 mg R-IVAC Rituximab, 375 mg/m 2 Ifosfamide, 1500 mg/m 2 (with MESNA) Etoposide, 60 mg/m 2 Cytarabine, 2000 mg/m 2 every 12 hours IT methotrexate, 12 mg Peg-filgrastim Patients with baseline CNS disease should receive in addition (cycle 1 only): IT cytarabine, 50 mg IT methotrexate, 12 mg D1 D3 D1 D3** D5 D15 D1 D1-D5 D1-D5 D1-D2 IVF, intravenous fluid; O, vincristine; Peg, pegylated. *During cycle 1, rituximab should be administered no earlier than day 3. **For high risk patients only. Methotrexate is administered as a bolus over 2 to 4 hours once urine ph. 7. Leucovorin 200 mg/m 2 IV given once 24 hours later and then 15 mg/m 2 every 6 hours until level is,0.1. IVF with 3 amps of sodium bicarbonate should be administered until methotrexate has cleared. D5 D6 D3 D5

5 The new england journal of medicine original article Low-Intensity Therapy in Adults with Burkitt s Lymphoma Kieron Dunleavy, M.D., Stefania Pittaluga, M.D., Ph.D., Margaret Shovlin, R.N., Seth M. Steinberg, Ph.D., Diane Cole, M.S., Cliona Grant, M.D., Brigitte Widemann, M.D., Louis M. Staudt, M.D., Ph.D., Elaine S. Jaffe, M.D., Richard F. Little, M.D., and Wyndham H. Wilson, M.D., Ph.D. METHODS We studied low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) in patients with untreated Burkitt s lymphoma. Two EPOCH-R regimens were tested: a standard dose-adjusted combination in human immunodeficiency virus (HIV) negative patients (DA-EPOCH-R group) and a lower-dose short-course combination with a double dose of rituximab in HIV-positive patients (SC-EPOCH-RR group).

6 Risk Gro up R1 R2 Definition Stage I + II, completely resected Stage I + II, not resected Stage III and LDH < 500 U/L R3 Stage III and LDH > 500 ~ <1000 U/L And CNS-neg. R4 Stage III+IV+B-ALL and LDH>1000 U/L or/and CNS-pos. Therapy Courses A B V A B A B V AA BB CC AA BB V AA BB CC AA BB CC TPOG 2010 B-NHL Drug Dose Days when administration Cytoreductive Prephase V Dexamethasone (orally/iv) 5 mg/m 2 1,2 Dexamethasone (orally/iv) 10 mg/ m Cyclophosphamide (IV) 200 mg/m 2 1,2 Course A Dexamethasone (orally) 10 mg/m Vincristine IV 1.5mg m 2 (max 2mg) 1 Ifosfamide (IV 1h) 800 mg/m MTX (4-hour infusion) 1g/m 2 1 TIT (MTX, HC, AraC) (12, 12, 24 mg) 1 Cytarabine (IV 1h) 150 mg/m 2 q12h 4,5 Etoposide (IV 1h) 100 mg/m 2 4,5 Course B Dexamethasone (orally) 10 mg/m Cyclophosphamide (1-hr ivf) 200 mg/ m Vincristine IV 1.5mg m 2 (max 2mg) 1 MTX (4-hour infusion) 1g/m 2 1 TIT (MTX, HC, AraC) (12, 12, 24 mg) 1 Epirubicin (IV 1h) 25 mg/m 2 4,5 Course AA & BB (the same as A & B), except MTX (24-hour infusion) 5g/m 2 1 Course CC Dexamethasone (orally) 20 mg/m Vincristine (IV) 1.5 mg/m 2 (max 2mg) 1 Cytarabine (IV 3h) 3g/m 2 q12h 1,2 Etoposide (IV 2h) 100 mg/m 2 q12h 3-5 TIT (MTX, HC, AraC) (12, 12, 24 mg) 5

7 A Freedom from Progression (DA-EPOCH-R) 100 B Overall Survival (DA-EPOCH-R) Patients (%) Patients (%) Years Years C Freedom from Progression (SC-EPOCH-RR) 100 D Overall Survival (SC-EPOCH-RR) Patients (%) Patients (%) Years Years E Freedom from Progression (Immunodeficiency-Associated Variant) 100 F Overall Survival (Immunodeficiency-Associated Variant) Patients (%) Patients (%) Years Years Figure 1. Kaplan Meier Estimates of Freedom from Disease Progression and Overall Survival. Panels A and B show the estimates of freedom from progression of disease and overall survival, respectively, among patients who received a dose-adjusted combination of etoposide, doxorubicin, and vincristine with cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R). Panels C and D show the estimates of freedom from progression and overall survival, respectively, among patients who received a short course of the combination therapy with a double dose of rituximab in each cycle (SC-EPOCH-RR). Panels E and F show the estimates of freedom from progression and overall survival, respectively, among patients who had the immunodeficiency-associated variant of Burkitt s lymphoma.

8 BACKGROUND Burkitt's lymphoma is a highly aggressive B cell lymphoma with poor outcome when treated with standard CHOP or like chemotherapy. However, the complete remission rate, disease free survival, and overall survival improved after the introduction of intensive chemotherapy. This is a retrospective study to compare the treatment outcome after intensive chemotherapy versus standard R- CHOP or like chemotherapy.

9 METHOD We surveyed Burkitt's lymphoma patients at our single institute in the past 20 years and to compare the outcome between intensive chemotherapy eg. CODOX-M/IVAC, Taiwan Pediatric Oncology Group (TPOG) protocol, or DA-EPOCH-R, versus standard R-CHOP or like chemotherapy.

10 RESULT Between 1995 and 2014, we treated 25 patients (9 males versus 16 females) of Burkitt's lymphoma with age between 5 and 71 and 13 of them were in stage I or II disease extent and 12 were in stage III or IV. In these 25 patients, 17 received intensive chemotherapy and all of them achieved durable survival (100%); 8 received standard R-CHOP chemotherapy with 3 achieved durable and 5 died of disease relapse or refractoriness. No patients died of treatment related mortality.

11 PATIENTS DEMOGRAPHICS Age Median (between 5 and 71) Sex (M/F) 9/16 Stage (I & II/III & IV) 13/12 ECOG (0/1/2 & 3) 11/12/2 Intensive/CHOP 17/8 CODOX-M/IVAC; TPOG; DA-EPOCH-R 10/4/3 LDH (H/N/Unknown) 13/10/2 Extranodal (head and neck/breast/ bowel/bone marrow 19 (76%) (6/1/6/6) LMB risk (A/B/C)* 5/16/4 *Lymphomes malins B (LMB) risk groups are defined as follows: group A includes patients with low-risk disease (resected stage I or abdominal stage II cancer), group B includes those with intermediate-risk disease (patients not in group A or C), and group C includes those with high-risk disease (central nervous system involvement, at least 25% blasts in bone marrow, or both characteristics).

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14 CONCLUSION 1. Intensive chemotherapy (eg. CODOX-M/IVAC and TPOG protocol) is feasbile for fit patients and can achieved far more better outcome and all the 14 patients got long-term survival despite one of them relapsed 3 years later but salvaged by ASCT successfully. 2. The effectiveness of DA-EPOCH-R needs to be followed longer. 3. However, it is still very difficult to deal with for more elderly or medical co-morbid patients.

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