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THE CHILDHOOD LEUKEMIA

THE CHILDHOOD LEUKEMIA. Professor: Ma lian. Leukemia. Leukemia is a disease characterized by proliferation of immature white cells and is the most common malignancy of childhood. Acute leukemias account for the majority (97%) of cases. Leukemia.

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THE CHILDHOOD LEUKEMIA

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  1. THE CHILDHOOD LEUKEMIA Professor: Ma lian

  2. Leukemia • Leukemia is a disease characterized by proliferation of immature white cells and is the most common malignancy of childhood. • Acute leukemias account for the majority (97%) of cases.

  3. Leukemia The leukemias are classified according to the white blood cell line involved: • Acute lymphocytic leukemia (ALL) ----- cells of lymphoid lineage • Acute non-lymphocytic leukemia (ANLL) ----- cells of granulocytic or monocytic lineage.

  4. Acute lymphocytic leukemia • ALL account for 80% of childhood leukemia and has a peak in incidence between age 3 and 6 years. • It is slightly more common in boys than girls.

  5. Children with Down syndrome, Fanconi anemia ,and ataxiatelangiectasia are at particular risk of ALL . Siblings, especially twins, of children with leukemia are approximately twice as likely to have leukemia than is the general population . . Acute lymphocytic leukemia

  6. Acute lymphocytic leukemia • Some cases of childhood ALL may relate to hereditary or acquired mutation in the p53 gene. Taken in total , however , these predisposing circumstances or relationships account for only a small propotion of cases

  7. Clinical features • In most children with ALL , there is an acute onset of symptoms and signs arsing from infiltration of the bone marrow or other organs with leukemic blast cells . Most will have one or more of the following :

  8. Clinical features “4 Ps” • Pallor ---- anemia. • Pyrexia ---- concomitant infection or the desease itself. • Purpura ---- thrombocytopenia • Pain ---- Bone pain (pelvis , vertebral bodies , legs ), due to expansion of marrow cavity . Abdominal pain , due to liver and spleen distension .

  9. Expansion of marrow cavity

  10. Clinical features • asymtomatic lymphadenopathy and hepatosplenomegaly • the CNS , testes and the kidneys ---- the most commonly affected extramedullary sites • Infection---- due to neutropenia

  11. Clinical feature • Hepatosplenomegaly • reticuloendotheelial cell infiltration.

  12. Investigations Peripheral blood investigations reveal : • Anemia ---- normocytic , normochromic . • Thombocytopenia . • Neutropenia ---- total WBC may be low , normal , or high. • Blast cells .

  13. Investigations Bone marrow examination reveals : • Replacement of normal elements by leukemic cells. A diagnosis of leukemia should always be confirmed by bone marrow aspiration.

  14. Morphologies and histochemical classification Under light microscope , the system developed by FAB divides lymphablasts into 3 categories: • L1 : small ,scanty cytoplasm and inconspicuous nucleoli .(85% of cases ) • L2 : generally larger , more prominent nucleoli and abundant cytoplasm . • L3: large ,deep cytoplasmic basophilic and prominent cytoplasmic vacuolation , identical to the cells of Burkitt lymphoma .(1-2%)

  15. ALL-L1 ALL-L2 ALL-L3

  16. Differential diagnosis • Infectious mononcleosis • Histiocytosis X • Hypoplastic and aplastic anemia • Juvenile rheumatoid arthritis • ITP

  17. Treatment • Surportive therapy • Specific therapy • Prevention of CNSL • Treatment of TL • Transplantation of hemopoietic stem cell

  18. Specific treatment • Induction(VDLP/CODPL) • Consolidation(CAT/VM26+A) • Prevetion of extramedullary leukemia(HDMTX) • Maintenance(6-MP+MTX) • Intensify

  19. Surportive treatment • Treatment of infection. • Transfused blood and platelet • G-CSF and GM-CSF • Prevetion of tumor lysis syndrome • Alkalinization of urine • Hydration • Allopurinol • The other

  20. Prevetion of extramedullary leukemia • intrathecal MTX, Ara-C and DXM • HDMTX+CF

  21. Treatment of CNSL • intrathecal MTX, Ara-C and DXM(三联鞘内注射法) • HDMTX+CF(大剂量甲氨蝶呤-四氢叶酸钙) • cranial irradiation(颅脑放射治疗）

  22. Induction • 4 weeks of combination chemotherapy: • VDPL/CODPL • DNR (柔红霉素） • L-asparaginase（左旋门冬酰氨） • Vincristine (长春新碱） • Prednisolone（泼尼松） CODPL

  23. Maintenance • chemotherapy continues for 2 years from diagnosis : • 6-MP or 6-TG（硫鸟嘌呤）+ MTX • Former induction therapy should be carried on Periodically

  24. Consolidation • continued systemic therapy with blocks of “intensification” therapy for selected patients. • VM-26+Ara-c/VDP/VDPL • CAM(T) • CTX（甲氨蝶呤） • Ara-c（阿糖胞苷） • 6MP（巯嘌呤)(6-TG)

  25. Prognosis • The children can get much better prognosis than the the adult. Their 5-year survival rate is 70-80%, while their counterpart is 20-30%. • ANLL: 5-year survival rate is 40-50%

  26. 白血病细胞的遗传学特征 染色体数目 50的超二倍体急淋细胞97%以上含有3~4条21号染色体，21号染色体上有编码还原型四氢叶酸转运蛋白的拷贝基因，这种转运蛋白的高表达导致甲氨蝶呤的活性代谢产物多聚谷氨酰甲氨蝶呤在细胞内的高度累积，因此超二倍体急淋细胞对基于甲氨蝶呤的化疗异常敏感，这类病人的预后非常好，5年EFS为75%~90%。

  27. 白血病细胞的遗传学特征 美国COG组研究显示4、10和17三体也是独立的预后良好指标，这类病人7年EFS 90%，机理尚不清楚。

  28. 白血病细胞的遗传学特征 t(12;21)(p13;q22)易位形成的融合基因TEL/AML1见于 25%急淋患儿。研究表明这类白血病细胞对L-ASP高度敏感。st Jude儿童研究医院用含有L-ASP的强化疗治疗t(12;21) 阳性的ALL患儿获得较好效果。一般认为 t(12;21) 阳性患儿首次完全缓解期长且早期复发率低，但部分患儿晚期复发，复发后对化疗依然敏感，易获二次缓解。

  29. 白血病细胞的遗传学特征 t(1;19) (q23;q13)易位形成的E2A/PBX1融合基因多见于胞浆重链阳性的前B急淋。过去认为t(1;19)阳性急淋患儿发病时常伴有高白细胞数、高LDH及高CNS白血病发病率，预后不佳。但近年来强烈化疗已使其成为儿童急淋中预后最良好型之一，这部分患儿的5年EFS接近90%。

  30. 白血病细胞的遗传学特征 位于11q23的MLL基因可与30多种基因发生易位，统称MLL基因重排，见于6%的急淋患儿，其中最常见的为t(4;11) (q21;q23)易位形成的融合基因MLL/AF4，绝大多数婴儿白血病表达该融合基因。最近一个大宗病例统计显示任何MLL基因重排的ALL患儿预后都不好，长期EFS只有20%~25%，尤其MLL基因重排的婴儿比1岁以上患儿预后更差。t(4;11) 阳性婴儿白血病细胞对阿糖胞苷相对敏感。

  31. 白血病细胞的遗传学特征 t(9;22) (q34;q11)易位形成的融合基因BCR/ABL 见于3%~5%的儿童急淋，为预后最差的一类，尤其初诊白细胞≥50109/L、发病年龄≥10岁或强的松反应不良的患儿建议第一次缓解后即行异基因造血干细胞移植，以减少复发，提高总体生存率。

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