INITIAL WORK-UP

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1 中山醫學大學附設醫院淋巴癌診療指引 (Follicular Lymphoma grade1-2) 本臨床指引參考台灣國家衛生研究院與美國 NCCN 版本淋巴癌多專科醫療團隊編修 2017/12/21 Version /11/17 Version /11/19 Version /11/20 Version /11/21 Version /11/22 Version /11/23 Version /07/14 Version 1.0 癌症委員會主任委員癌症委員會執行長癌症防治中心主任團隊負責人

2 目錄一前言...2 二組織病理分類與分化...3 三分期...8 四淋巴癌臨床指引...9 五 FL International prognostic Index (FLIPI)...13 六化學治療原則七放射線治療原則八安寧緩和照護原則...16 九實症醫學...17 十參考文獻

3 一前言淋巴瘤, 是指由淋巴組織所衍生出的惡性腫瘤淋巴瘤的臨床表現, 常常是不正常的淋巴結腫大, 有時還會合併發燒, 體重減輕, 夜間盜汗等症狀, 也就是所謂的 B 症狀 (B Symptom) 這樣的腫瘤, 因其具有不正常增生與分化的特性, 所以淋巴瘤基本上都是惡性的為了在名稱上不會混淆, 惡性淋巴瘤反而能更精準的讓病人了解其罹患疾病的特性淋巴瘤大致上可分為兩大類, 一是何杰金氏淋巴瘤 (Hodgkin lymphoma), 一是非何杰金氏淋巴瘤 (Non-Hodgkin lymphoma) 約莫 80% 的淋巴瘤屬於非何杰氏金淋巴瘤, 而何杰金氏淋巴瘤佔約 20% 何杰金氏淋巴瘤與非何杰金氏淋巴瘤的區別在於組織型態的差異何杰金氏淋巴瘤的癌細胞常常會出現如貓頭鷹眼狀的細胞型態, 這類的細胞, 我們稱之為 Reed-Sternberg Cell (RS cell) 其癌細胞的免疫組織染色, 會呈現陽性的 CD15 以及 CD30 何杰金氏淋巴瘤的組織分類, 根據世界衛生組織 (WHO) 的分類, 可區分為兩大類,Lymphocyte predominant,nodular 以及典型 (classic) 何杰金氏淋巴瘤而典型何杰金氏淋巴瘤又細分為五大類, 分別是 Lymphocyte-rich classic HL, Nodular sclerosis, Mixed Cellularity, Lymphocyte depleted, 以及無法分類的典型何杰金氏淋巴瘤非何杰金氏淋巴瘤分類上則相對較複雜依照其細胞來源, 我們簡單的將非何杰金氏淋巴瘤區分為 B 細胞與 T 細胞兩大類非何杰金氏淋巴瘤臨床的分類可以將淋巴瘤分為低惡性度 (Indolent), 高惡性度 (Aggressive), 簡單的說, 如果低惡性度的淋巴瘤不治療, 病人尚可存活數月甚至數年, 如果高惡性度的淋巴瘤不治療, 病人恐怕只可存活數月最近世界衛生組織重新將非何杰金氏淋巴瘤做了分類, 2

4 二組織病理分類與分化 2016 年 WHO 淋巴瘤分類 (Classification of lymphoma) Mature B-cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma Monoclonal B-cell lymphocytosis* B-cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Splenic B-cell lymphoma/leukemia, unclassifiable Splenic diffuse red pulp small B-cell lymphoma Hairy cell leukemia-variant Lymphoplasmacytic lymphoma Waldenstr om macroglobulinemia Monoclonal gammopathy of undetermined significance (MGUS), IgM* m heavy-chain disease g heavy-chain disease a heavy-chain disease Monoclonal gammopathy of undetermined significance (MGUS), IgG/A* Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Monoclonal immunoglobulin deposition diseases* Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue 3

5 (MALT lymphoma) Nodal marginal zone lymphoma Pediatric nodal marginal zone lymphoma Follicular lymphoma In situ follicular neoplasia* Duodenal-type follicular lymphoma* Pediatric-type follicular lymphoma* Large B-cell lymphoma with IRF4 rearrangement* Primary cutaneous follicle center lymphoma Mantle cell lymphoma In situ mantle cell neoplasia* Diffuse large B-cell lymphoma (DLBCL), NOS Germinal center B-cell type* Activated B-cell type* T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the central nervous system (CNS) Primary cutaneous DLBCL, leg type EBV1 DLBCL, NOS* EBV1 mucocutaneous ulcer* DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK1 large B-cell lymphoma 4

6 Plasmablastic lymphoma Primary effusion lymphoma HHV81 DLBCL, NOS* Burkitt lymphoma Burkitt-like lymphoma with 11q aberration* High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements* High-grade B-cell lymphoma, NOS* B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma Mature T and NK neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK cells Aggressive NK-cell leukemia Systemic EBV1 T-cell lymphoma of childhood* Hydroa vacciniforme like lymphoproliferative disorder* Adult T-cell leukemia/lymphoma Extranodal NK-/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Monomorphic epitheliotropic intestinal T-cell lymphoma* Indolent T-cell lymphoproliferative disorder of the GI tract* Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides 5

7 S ezary syndrome Primary cutaneous CD301 T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gd T-cell lymphoma Primary cutaneous CD81 aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous acral CD81 T-cell lymphoma* Primary cutaneous CD41 small/medium T-cell lymphoproliferative disorder* Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Follicular T-cell lymphoma* Nodal peripheral T-cell lymphoma with TFH phenotype* Anaplastic large-cell lymphoma, ALK1 Anaplastic large-cell lymphoma, ALK2* Breast implant associated anaplastic large-cell lymphoma* Hodgkin lymphoma Nodular lymphocyte predominant Hodgkin lymphoma Classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma Lymphocyte-depleted classical Hodgkin lymphoma 6

8 Posttransplant lymphoproliferative disorders (PTLD) Plasmacytic hyperplasia PTLD Infectious mononucleosis PTLD Florid follicular hyperplasia PTLD* Polymorphic PTLD Monomorphic PTLD (B- and T-/NK-cell types) Classical Hodgkin lymphoma PTLD Histiocytic and dendritic cell neoplasms Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Indeterminate dendritic cell tumor Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Fibroblastic reticular cell tumor Disseminated juvenile xanthogranuloma Erdheim-Chester disease* 7

9 三分期淋巴瘤的分期, 是依照 Ann Arbor Staging System 來分期淋巴瘤一般分為四期, 簡單的說, 當淋巴瘤只侵犯單一區域淋巴結時, 稱為第一期當淋巴瘤侵犯兩個區域以上淋巴結, 且在橫膈膜同側時, 稱為第二期當淋巴瘤侵犯兩個區域以上淋巴結, 且在橫膈膜異側時, 稱為第三期當淋巴瘤侵犯淋巴組織以外的地方, 或是侵犯肝臟或骨髓時, 則稱為第四期這樣分期的目的, 是為了決定治療方式與評估預後簡單的說, 三, 四期病患的預後一般來說比一二期的病患差 8

10 四淋巴癌臨床指引 Workup Stage Induction therapy (grade 1-2) Response to therapy Follow up Physical Exam Performance status B symptoms CBC,differential/count LDH Uric acid(optional) Stage I,II (non- bulky) ISRT CRorPR NR Progressive disease ( 接流程圖 A) Hepatitis B C testing Beta-2-microglobulin(optional) SPEP and/or quantitative immunoglobulin levels(optional) Comprehensive metabolic panel CT scan with contrast and/or PET/CT(optional) Bone marrow biopsy Stage I,II (bulky) Immunotherapy ± chemotherapy or Immunotherapy ± chemotherapy (category 2B)or Observation CR or PR NR imaging follow-up every 6 mo>2 y and than annually Consider ISRT CR or PR Progressive disease ( 接流程圖 A) For transfor mation ( 接流程圖 B) Calculation of FLIPI Pregnancy testing in women of child-bearing age(optional) NR Progressive disease ( 接流程圖 A) Echocardiogram (optional) Discussion of fertility issues and sperm banking(optional) 9

11 Workup Stage Induction therapy (grade 1-2) Response to therapy Follow up Physical Exam Performance status B symptoms CBC,differential/count LDH Uric acid(optional) Hepatitis B C testing Beta-2-microglobulin(optional) SPEP and/or quantitative immunoglobulin levels(optional) Comprehensive metabolic panel CT scan with contrast and/or PET/CT(optional) Bone marrow biopsy Calculation of FLIPI Pregnancy testing in women of child-bearing age(optional) Echocardiogram (optional) Discussion of fertility issues and sperm banking(optional) Stage III, IV Indications for treatment: Candidate for clinical trial Symptoms Threatened end-organ function Cytopenia secondary to lymphoma Bulky disease Steady progression No Indication Indication present Observe Consider PET/CT scan imaging follow-up every 6 mo>2 y and than annually See Suggested Regimens or Clinical trial or Local ISRT (4 30 Gy) (palliation of locally symptomatic disease) Progressive disease ( 接流程圖 B) For transfor mation Progressive disease ( 接流程圖 A) 10

12 End-of- treatment responsen Optional extended therapy Follow-up Second-line and subsequent therapy 流程圖 A CR Or PR Consolidation or extended therapy or Observe Imaging followup every 6 mo>2y annually Progressive disease or For transformation ( 病程轉變見 Indications for treatment: Candidate for clinical trial Symptoms Threatened No indication Observe 流程圖 B) end-organ NR ( 病程轉變見流程圖 B) Rebiopsy For transformation function Cytopenia secondary to lymphoma Bulky disease Indication present ( Consider See Suggested Regimens or Clinical trialt or Local ISRT Steady progression PET/CT (4-30Gy) Patient preference scan) (palliation of locally symptomatic disease) 11

13 流程圖 B Histological transformation to diffuse large B-cell lymphoma Multiple prior therapies Minimal or no prior chemotherapy Histological Transformation To Diffuse Large B-cell Lymphoma Clinical trial or Radioimmunotherapy or Chemotherapy ± rituximab or± ISRT or Best Supportive Care Chemotherapy (anthracycline-based chemotherapy preferred unless contraindicated) first-line therapy) + rituximab ±ISRT Responsive disease CR PR NR or PD Consider high dose therapy with autologous or allogeneic stem cell rescue Observation or Clinical trial or Consider high dose therapy with autologous or allogeneic stem cell rescue Consider high dose therapy with autologous or allogeneic stem cell rescue or Clinical trial or Consider radioimmunotherapy or ConsiderISRT Clinical trial or Radioimmunotherapy or Palliative or best supportive care 12

14 五 FL International prognostic Index (FLIPI) Age 60 Stage Ⅲ-Ⅳ Hemoglobin level <12g/dL Serum LDH>ULN (upper limite of normal) Number of nodal sites 5 Risk group according to FLIPI chart Number of factors Low Intermediate High 六化學治療原則 (Principles of chemotherapy) Regimen Dosage Reference First- line RCHOP Rituximab 375 mg/m² i.v. on day 1 Cyclophosphamide 750 mg/m² i.v. on day 1 Doxorubicin 50 mg/m² i.v. on day 1 Vincristine 1.4 mg/m² i.v. on day 1(maximum dose of 2 mg) McKelvey EM. cancer 1976;38: Lenz G. J clin Oncol 2005;23: Hiddemann W.Blood 2005;106: Prednisone 100mg p.o. daily on day1-5 RCEOP Rituximab 375 mg/m² i.v. on day 1 Cyclophosphamide 750 mg/m² i.v. on day 1 Epirubicin 50 mg/m² i.v. on day 1 Vincristine 1.4 mg/m² i.v. on day 1(maximum dose of 2 mg) Prednisone 100mg p.o. daily on day1-5 13

15 Regimen Dosage Reference RCOP Rituximab 375 mg/m² i.v. on day 1 Cyclophosphamide 750 mg/m² i.v. on day 1 Vincristine 1.4 mg/m² i.v. on day 1(maximum dose of 2 mg) Prednisone 100mg p.o. daily on day1-5 Second- line DHAP±Rituximab Cisplatin 100 mg/m² CIVI over 24 h on day 1 Cytarabine 2000 mg/m² i.v. q12h x2 dose on day 2 Dexamethasone 40 mg/m² p.o./i.v. daily on day 1-4 Repeat cycle every21-28 d Velasquez WS. Blood 1988;71: ESHAP±Rituximab Etoposide 40 mg/m² i.v. daily on days 1-4 Methylprednisolone 500 mg/m² i.v. daily on days 1-5 Velasquez WS. J clin Oncol 1994;12: Cytarabine 2000 mg/m² CIVI on day 5 Cisplatin 25 mg/m² i.v. daily on days 1-4 Repeat cycle every21-28 d ICE±Rituximab Ifosfamide 5000 mg/m² CIVI over 24h on day 2 Mesna 5000 mg/m² CIVI over 24h on day 2 Carboplatin AUC 5 i.v. on day 2(maximum dose of 800 mg) Etoposide 100 mg/m² i.v. daily on days 1-3 Moskowitz CH0J clin oncol 1999;17: Kewalramans T. blood 2004;103: ±Rituximab 375 mg/m² i.v. 48 h before start of cycle 1 and on day 1 of each cycle Repeat cycle every d BR Rituximab 375 mg/m² i.v. on day 1 Bendamustine mg/m2 day

16 Irst-line (Therapy for Elderly) Regimen Dosage Reference FR Rituximab 375 mg/m² IVD on day 1 Fludarabine 25 mg/m² IVD on day 1-5 Rituximab Rituximab (preferred) (375 mg/m2 weekly for 4 doses) Single-agent alkylators (eg, chlorambucil or cyclophosphamide) ± rituximab 健保給付原則 : 1 Rituximab 注射劑 ( 如 Mabthera): 作為濾泡性淋巴瘤患者於接受含 rituximab 誘導化學治療後產生反應 ( 達 partial remission 或 complete remission) 之病患, 若在接受含 rituximab 誘導化學治療前有下列情形之一者, 得接受 rituximab 維持治療, 限用八劑, 每三個月使用一劑, 最多不超過二年 (1) 有單一腫瘤直徑超過 7 公分者 ; (2) 有超過三顆腫瘤直徑超過 3 公分者 ; (3) 脾臟腫大, 其長度超過 16 公分者 ; (4) 對 vital organs 造成擠壓者 ; (5) 周邊血中出現淋巴球增生超過 5000/mm3 者 ; (6) 出現任一系列血球低下者 (platelet<100,000/mm3, 或 Hb< 10gm/dL, 或 absolute neutrophil count<1500/mm3) 2 Fludarabine ( 如 Fludara Oral, Film -Coated Tablet 及 Fludara Lyophilized IV Injection ): 低惡性度 B 細胞非何杰金氏淋巴瘤 (Indolent B-Cell NHL) 病患, 歷經至少一種標準內容的烷化基藥劑 (alkylating agent) 的治療方法都無效, 或治療後雖有效但隨後疾病又繼續惡化的病人 3 Bendamustine( 如 Innomustine): 曾接受至少一種化療之和緩性非何杰金氏淋巴瘤, 六個月內曾以 rituximab 治療失敗之單一治療 15

17 七放射線治療原則 (Principles of radiation) Non-Hodgkin s lymphoma Disease Indication Target area Dose Note Follicular Lymphoma Stage I~II, CR a Non-bulky b contralateral testis to 30-36Gy Locoregional RT 30-36Gy 1. testicular lymphoma should include Stage I~II, CR a Bulky Locoregional RT 30-40Gy a Stage I~II, PR c Locoregional RT 40-50Gy a: complete response from previous chemotherapy b : with adverse effects such as elevated LDH, stage II, age > 60y, performance status ECOG > 2 c: partial response from previous chemotherapy 八安寧緩和照護原則若預期疾病難以治癒時, 病人存活期小於 6 個月便適合安寧療護 (Pomeranz & Brustman, 2005;Waldrop & Rinfrette, 2009) 若藉由症狀檢驗數據及確切的腫瘤診斷, 證實臨床上該惡性腫瘤已經廣泛侵犯或進展快速 ; 功能分數 (Palliative Performance Scale) 低於 70%; 拒絕進一步腫瘤治癒性治療, 或者在治療之下仍持續惡化者, 即可轉介緩和醫療團隊 ( 彭等,2006) 16

18 九實證醫學 Categories of Evidence and Consensus : Category 1: There is uniform NCCN consensus, based on high-level evidence, that the recommendation is appropriate. Category 2A: There is uniform NCCN consensus, based on lower- level evidence including clinical experience, that the recommendationis appropriate. Category 2B: There is nonuniform NCCN consensus (but no major disagreement), based on lower-level evidence including clinical experience, that the recommendation is appropriate. Category 3: There is major NCCN disagreement that the recommendation is appropriate. All recommendations are category 2A unless otherwise noted. 十參考文獻 (Reference) 1. NCCN Clinical Practice Guidelines in Oncology. Non- Hodgkin s Lymphomas V McKelvey EM. cancer 1976;38: Lenz G. J clin Oncol 2005;23: Hiddemann W.Blood 2005;106: Velasquez WS. Blood 1988;71: Velasquez WS. J clin Oncol 1994;12: Moskowitz CH0J clin oncol 1999;17: Kewalramans T. blood 2004;103: BLOOD, 19 MAY 2016 x VOLUME 127, NUMBER 20:

INITIAL WORK-UP

INITIAL WORK-UP 中山醫學大學附設醫院淋巴癌診療指引 (Diffuse Large B-cell Lymphoma) 本臨床指引參考台灣國家衛生研究院與美國 NCCN 版本淋巴癌多專科醫療團隊編修 2017/12/21 Version 8.0 2016/11/17 Version 7.0 2015/11/19 Version 6.0 2014/11/20 Version 5.0 2013/11/21 Version