ALL in children and adolescents 2015/12/10 學術會議 ALL in children and adolescents M111 縱貫組 陳建賓

Outline Introduction Early Signs and Symptoms Pathologic Features Medication Summary

Early Signs and Symptoms Introduction A_L：The most common form, approximately 30% of all childhood malignancies ALL being five times more common than AML(acute myeloid leukemia)：25 % (5：1) Since 1980, 5 years survival rate：85 % Q：approximately 30% of all childhood malignancies ? A：3.4 cases per 100,000 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptons The most common presenting symptoms of ALL are nonspecific. Lymphadenopathy Peripheral blood abnormalities Bone pain Headache Testicular enlargement  Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Lymphadenopathy  About 50% of children with ALL presents. Usually is nontender, firm, rubbery, and matted. 位置 判定 Epitrochlear nodes >5 mm. Inguinal nodes >15 mm Cervical nodes >20 mm is nontender, firm, rubbery, and matted 無壓痛、硬、粗糙、黯淡的表面 肱骨內上髁、鼠蹊、頸 Introduction Early Signs and Symptoms Pathologic Features Medication

Peripheral blood abnormalities Anemia、bleeding、fever Approximately 50 percent of children have WBC counts <10,000/microL, and 20 percent have an initial leukocyte count>50,000/microL . Approximately one-half of children with ALL present with bleeding (including petechiae and purpura) and three-quarters have a platelet count<100,000/microL at the time of diagnosis. , lethargy, nuchal rigidity 昏睡，頸僵直 Introduction Early Signs and Symptoms Pathologic Features Medication

Peripheral blood abnormalities Atypical cells in the peripheral blood Unexplained depression of more than one peripheral blood element (cytopenias). Cytopenias are defined as an absolute neutrophil count (ANC) of <500/microL, Hgb <8 g/dL, or a platelet count <150,000/microL. Unexplained lymphadenopathy or hepatosplenomegaly associated with cytopenias should be performed for the following indications: 與血細胞減少相關的不明原因的淋巴結腫大或肝脾腫大 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Bone pain Presenting symptom in 21 to 38 percent. Young children with such pain may present with limp or refusal to bear weight. Even it’s common to children or adolescents. Early bone marrow examination should be considered in any child who has persistent bone pain and peripheral blood abnormalities. Particularly affecting the long bones. Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Bone pain Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Headache  Uncommon (<5 percent of cases), but in TAIWAN：1/10 leukemia involving the central nervous system (CNS) can present with symptoms of increased intracranial pressure, including headache, vomiting, lethargy, and/or nuchal rigidity. Rarely, leukemia can present with cranial nerve abnormalities Introduction Early Signs and Symptoms Pathologic Features Medication

Testicular enlargement In Taiwan, Painless unilateral testicular enlargement can be a presenting sign of ALL , Presenting symptom in 1/200 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Pathologic Features Morphology：FAB system： Lymphoblast, before 2008 Immunophenotype：WHO system： CD markers, after 2008 Cytogenetics：Not specifically used for diagnosis FAB：French-American-British L1 lymphoblasts are small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli. Most children with ALL cases (85 to 89 percent) are classified as having FAB L1 小細胞胞漿少，凝結核染色質和模糊的核仁 ALL-L1: small uniform cells ALL-L2: large varied cells ALL-L3: large varied cells with vacuoles (bubble-like features) Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Morphology 分類 機率 描述 L1 85-89% small uniform cells L2 14% large varied cells L3 1% large varied cells with vacuoles (bubble-like features) usually has mature B cell characteristics FAB：French-American-British L3 lymphoblasts have deep cytoplasmic basophilia with prominent cytoplasmic vacuolation. L3 morphology correlates with a more guarded prognosis. The L3 cell usually has mature B cell characteristics and often is treated using drugs effective for highly aggressive B cell lymphoma variants.  Less than 1 percent of cases of ALL in children are classified as FAB L3  有很深的胞質嗜鹼性具有突出的胞漿空泡化 Introduction Early Signs and Symptoms Pathologic Features Medication

Morphology 分類 機率 描述 L1 85-89% small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli L2 14% large varied cells L3 1% large varied cells with vacuoles (bubble-like features) FAB：French-American-British L1 lymphoblasts are small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli. Most children with ALL cases (85 to 89 percent) are classified as having FAB L1 小細胞胞漿少，凝結核染色質和模糊的核仁 ALL-L1: small uniform cells ALL-L2: large varied cells ALL-L3: large varied cells with vacuoles (bubble-like features) Introduction Early Signs and Symptoms Pathologic Features Medication

Morphology 分類 機率 描述 L1 85-89% small uniform cells L2 14% larger cells with a moderate amount of cytoplasm, dispersed chromatin, and multiple nucleoli survival rate differences between L1 and L2 are not significant L3 1% large varied cells with vacuoles (bubble-like features) FAB：French-American-British L2 lymphoblasts are larger cells with a moderate amount of cytoplasm, dispersed chromatin, and multiple nucleoli . In some studies, L2 has been associated with worse prognosis than has L1 . However, when patients are stratified according to age, sex, and initial WBC, differences in prognosis between L1 and L2 are no longer observed . Eleven to 14 percent of cases of ALL in children are classified as FAB L2 較大的細胞與適量的細胞質的，分散的染色質，和多個核仁。 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Morphology 分類 機率 描述 L1 85-89% small uniform cells L2 14% large varied cells L3 1% deep cytoplasmic basophilia with prominent cytoplasmic vacuolation, usually has mature B cell characteristics FAB：French-American-British L3 lymphoblasts have deep cytoplasmic basophilia with prominent cytoplasmic vacuolation. L3 morphology correlates with a more guarded prognosis. The L3 cell usually has mature B cell characteristics and often is treated using drugs effective for highly aggressive B cell lymphoma variants.  Less than 1 percent of cases of ALL in children are classified as FAB L3  有很深的胞質嗜鹼性具有突出的胞漿空泡化 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Immunophenotype The immunologic subtype of the tumor cells is used in the risk group stratification of childhood ALL, also treatment. 分類 機率 CD markers B-precursor lineage 70-80% CD10+,19+, and sometimes CD20+  T-precursor lineage 14% 90% CD 2+, 3+, 4+, 5+, 7+, and 8+ 10% CD8-, CD5dim： high rate of remission failure (57 to 75 percent) and a poor overall survival Markers used to classify cells by lineage are the same as those used in adult ALL Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Immunophenotype The immunologic subtype of the tumor cells is used in the risk group stratification of childhood ALL, also treatment. 分類 機率 CD markers B-precursor lineage 70-80% CD10+,19+, and sometimes CD20+ Leukemic lymphoblasts with the L3 morphology (described above) usually have markers for mature-B cell ALL  Markers used to classify cells by lineage are the same as those used in adult ALL Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Immunophenotype The immunologic subtype of the tumor cells is used in the risk group stratification of childhood ALL, also treatment. 分類 機率 CD markers  T-precursor lineage 16% 90% CD 2+, 3+, 4+, 5+, 7+, and 8+ 10% CD8-, CD5dim： high rate of remission failure (57 to 75 percent) and a poor overall survival Markers used to classify cells by lineage are the same as those used in adult ALL Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Cytogenetics Not specifically used for diagnosis, But an essential part of the risk group stratification of childhood ALL and help to guide therapy.  poor outcome t(9;22) BCR/ABL translocation- Philadelphia chromosome 3-4% Pre-B t(variable; 11q23) 5 % pediatric 60% infants A notable exception is that the classification of childhood ALL does not include either t(5;14)(q31;q32) nor t(1;19)(q23;p13.3) in the risk group stratification due to their rarity and uncertain prognostic value, respectively favorable prognosis t(12;21) ETV6/RUNX1  (formerly referred to as TEL/AML1)  20-25% Pre-B Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Medication Pre-Treatment Treatment Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Pre-Treatment Initial evaluation：include clinical examination, and bone marrow aspiration and biopsy. Diagnosis ： The diagnosis and classification of leukemia are based upon specialized tests that are performed on cells derived from a bone marrow aspirate or tissue biopsy specimens, and Lumbar Puncture. Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment Due to ALL has better response to chemotherapy, generally do not consider stem cell transplantation. 7% patients, including those with the Philadelphia chromosome, chromosome numbers were few and difficult to remission, when eased, if tissue antigens matched sibling transplants do best. 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment According to TPOG : By Age、CBC、Special chromosome translocation, we can make the classification of standard risk, high risk, very high risk. Each has different treatment. 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment There are two risk groups in childhood ALL. They are described as: Standard (low) risk: Includes children aged 1 to younger than 10 years who have a white blood cell count of less than 50,000/µL at diagnosis. High risk: Includes children 10 years and older and/or children who have a white blood cell count of 50,000/µL or more at diagnosis. NCI standard http://www.cancer.gov/types/leukemia/patient/child-all-treatment-pdq#section/_26 2015/10/30 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment Treatment to standard risk and high risk： Boys：about 3 years Girls：about 2.5 years Treatment to very high risk about 2 years 治療計畫可分為引導緩解期、鞏固療法、再次引導緩解、脊髓液注射、維持療法等階段。 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。 引導緩解 再引導緩解 鞏固療法 維持療法 脊髓液注射 停止 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment 引導緩解期 使血球數目正常，而達到『緩解』狀態，此時白血病細胞應小於5%，這個階段的目標是『除惡務盡』，所以治療較重，須要住院治療至少3週。常使用Prednisolone、Vincristine、Epirubicin（或Idarubicin）、L-asparaginase等藥物（視不同治療方案而定）。 再次引導緩解 再次給予類似引導緩解的藥物，在治療初期就儘量消滅白血病細胞至最少量，以提高治療效果。 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment 藥名 劑量 Prednisolone PREDNISOLONE TAB 5 MG (VPP) 成人：5~60 mg/day (max：250mg) 兒童：OR 0.5~2mg/kg/day，分三次 Vincristine VINCRISTINE INJ 1 MG/ML 1 ML 成人：0.4-1.4mg/m2 一星期一次 兒童：1.5-2.0mg/m2 一星期一次 Idarubicin  ZAVEDOS INJ 5 MG 成人：12mg/m2 持續三天 兒童：10mg/m2 持續三天 L-asparaginase LEUNASE INJ 5000 IU 50~200 ku/kg/day or 50~200 ku/kg/2days 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment 鞏固療法 即更換藥物組合，把殘留的癌細胞消滅，常使用高劑量MTX、6-MP等藥物（視不同治療方案而定），此種療法約需8-11週，每2週需住院治療5天左右。 藥名 劑量 MTX METHOTREXATE INJ 100 MG/ML 10 ML 2.5mg/kg IV每14天一次 6-MP MERKAPTOPURIN TAB 50 MG (6-MP) 初劑量：成人及小孩均為2.5mg/kg body weight/day，一次服用。 維持劑量：症狀改善後，改服維持劑量2.5mg/kgbodyweight/day。 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。x/kg：x/m^2=1：30 m^2 = 身高(m)平方*22 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment 脊髓液注射 在引導緩解及鞏固治療的同時，即進行中樞神經系統的預防，即將抗癌藥物打入脊髓鞘內（即腰椎注射、背針）。抗癌藥物可以循著脊髓液循環，消滅躲在腦膜内的癌細胞。同時也留置脊髓液，檢查中樞神經系統是否受到侵犯。 最高危險群（very high risk）的病童視病情需要可接受顱部放射線照射，或以定期腰椎注射代替。 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。腰椎注射可以在門診治療，醫師可能會使用鎮靜或麻醉藥物使病童暫時睡著，以利執行；或使用止痛貼劑使病童較不感到疼痛。執行時，病童應採抱膝拱背姿勢，呈蝦米狀。 打完腰椎注射須俯臥，墊高臀部，躺30分鐘至1小時，讓藥物可以有效隨脊髓液循環，保護腦部。等待不覺得暈眩、嘔吐後，就可以回家休息。 Introduction Early Signs and Symptoms Pathologic Features Medication

Early Signs and Symptoms Treatment 維持療法 鞏固期結束後即進入維持期，定期口服或注射抗癌藥物，常使用Dexamethasone、Vincristine、Ara-C、Endoxan、6MP、MTX等藥物，這個階段約74週到146週不等（視不同治療方案而定），通常在門診治療即可。 由台灣兒童癌症研究群（Taiwan Pediatric Oncology Group, TPOG）擬定的。 另外在治療的過程中，每週3天早晚口服Baktar（通常在週一、三、五吃，方便記憶），用來預防肺囊蟲肺炎。除非顆粒性白血球（顆粒球、中性球）低時醫師特別指示暫停服用，否則應按時吃藥，直到治療結束後數個月（視不同治療方案而定）才可停藥。白血病化學治療容易發生此種特殊肺炎，死亡率很高，而Baktar可有效預防此肺炎。（另請參閱本會其他衛教手冊） Introduction Early Signs and Symptoms Pathologic Features Medication

Summary ALL is the most common form of cancer in children. The peak incidence occurs between 2-5 y/o. Children with certain genetic and immunodeficiency syndromes are at increased risk. The most common presenting symptoms of ALL are nonspecific: fever, infection, bleeding, bone pain, or lymphadenopathy. 1.These include Down syndrome, Neurofibromatosis type 1, Bloom syndrome, and ataxia telangiectasia. 2.Unexplained persistence of any of these common signs or symptoms should prompt consideration of malignancy as a possible cause.

Summary The diagnosis and classification of leukemia are based upon specialized tests (morphology, immunophenotype, and cytogenetics) that are performed on leukemic lymphoblasts or myeloblasts derived from bone marrow or tissue biopsy specimens. Children who are suspected of having leukemia should be referred to a pediatric cancer center for evaluation and treatment. 1.These include Down syndrome, Neurofibromatosis type 1, Bloom syndrome, and ataxia telangiectasia. 2.Unexplained persistence of any of these common signs or symptoms should prompt consideration of malignancy as a possible cause.

Reference UPTODATE： 1.Overview of the presentation and diagnosis of acute lymphoblastic leukemia in children and adolescents 2. Risk group stratification and prognosis for acute lymphoblastic leukemia in children and adolescents 中華民國兒童癌症基金會-兒童白血病