Acute lymphoblastic leukemia

Japanese: 急性リンパ性白血病

Definition/Concept Acute lymphocytic leukemia is a neoplastic disease in which lymphocyte precursor cells (lymphoblasts) that are directed to differentiate into lymphocytes undergo transformation, stop differentiating, and undergo monoclonal proliferation. The bone marrow is the primary site of proliferation. In the WHO classification, it is divided into B lymphoblastic leukemia (B-ALL) and T lymphoblastic leukemia (T-ALL), and is considered synonymous with lymphoblastic lymphoma in terms of cellular affiliation. Generally, lymphoblastic leukemia is defined as a condition in which lymphoblasts account for 25% or more of the bone marrow. Various symptoms appear due to the impairment of normal hematopoiesis and organ infiltration by leukemic cells.
Classification
1) WHO classification:
In the 2008 WHO classification, acute lymphocytic leukemia is classified as a precursor lymphocytic neoplasm and is divided into B lymphoblastic leukemia/lymphoma and T lymphoblastic leukemia/lymphoma. When B lymphoblastic leukemia/lymphoma has recurrent (reproducible) genetic abnormalities, it is further subdivided according to the individual abnormalities (Table 14-10-10). Burkitt leukemia was included in acute lymphocytic leukemia in the 2001 WHO classification, but in the 2008 edition it is included in Burkitt lymphoma among mature B-cell neoplasms and classified as a subtype of Burkitt leukemia.
2) FAB classification:
In the conventional FAB classification based on morphology, acute lymphocytic leukemia is classified as having acute lymphocytic leukemia when blasts in the bone marrow account for 30% or more, myeloperoxidase (MPO) positivity is less than 3%, and lymphocytic plasminogen activator is positive. Morphologically, it is classified as L1, L2, or L3. L1 is a small cell type with unclear nucleoli, L2 is a large cell type with one or more nucleoli, and L3 is a large cell type characterized by basophilic cytoplasm and numerous vacuoles (Figure 14-10-13). There is little clinical difference between L1 and L2. L3 is synonymous with leukemic Burkitt lymphoma.
3) Classification by immunological surface phenotypes:
Acute lymphocytic leukemia is also classified according to the differentiation stage of lymphoblasts. Based on the expression pattern of surface phenotypes, B cells are classified into early B precursor (pro-B), common B, and pre-B stages, and T lymphocytes are classified into pro-T, pre-T, cortical T, and medullary T stages based on their differentiation stage in the thymus (Table 14-10-11).
Causes and EtiologyAcute lymphoblastic leukemia is thought to be a tumor caused by genetic abnormalities, but the cause of its onset is unclear. There have been reported cases of it being induced by radiation exposure, organic solvents, and anticancer drugs.
Epidemiology: The estimated age-adjusted incidence rate of all leukemia in Japan (2006) is 5.1 per 100,000 people per year, of which the incidence rate of acute lymphoblastic leukemia is estimated to be approximately 1 per 100,000 people per year. Approximately two-thirds of cases occur in childhood, and the incidence increases again in the elderly. The ratio of B-cell to T-cell leukemia is approximately 4:1.
Pathophysiology and molecular pathology In acute lymphoblastic leukemia, genetic abnormalities occur in lymphocyte precursor cells that are oriented to differentiate into lymphocytes, leading to abnormal differentiation and increased cell proliferation, resulting in the proliferation of blast cells. Genetic abnormalities are frequently observed, and include (1) fusion gene formation due to chromosomal translocation, (2) rearrangement of immunoglobulin genes or T cell receptor genes with specific genes, (3) gene deletion, (4) change in chromosome number, and (5) point mutation. When caused by errors in the translocation or gene rearrangement process, abnormalities in transcription control occur and tumors develop, which are closely related to the disease type and prognosis. In the WHO classification, cases with recurrent genetic abnormalities are classified as independent disease types. Mutations in the PAX5 gene are observed in approximately one-third of B-ALL cases, and rearrangements of the T cell receptor gene with the NOTCH1 gene, HOX11 (TLX1), HOX11L2 (TLX3), and TAL1 genes have been frequently reported in T-ALL.
B-lymphoblastic leukemia with recurrent genetic abnormalities
1) B-ALL with t(9;22)(q34;q11.2); BCR-ABL1:
A reciprocal translocation between chromosomes 9 and 22 results in the presence of the Philadelphia (Ph) chromosome on chromosome 22. A BCR-ABL1 chimeric gene is generated at the translocation site, and the constant increase in tyrosine kinase activity of the ABL1 gene is believed to be the cause of tumorigenesis. Chimeric proteins of 190 kDa and 210 kDa are formed at the cleavage site of the BCR gene. The majority of children are 190 kDa, but half of adults are 210 kDa. The frequency increases with age, and the condition is seen in approximately 25% of adults. It is considered to have a poor prognosis.
2) t(v;11q23): B-ALL with MLL rearrangement:
Translocations are found between the MLL gene at 11q23 and other chromosomes. Translocations include t(4;11)(q21;q23), t(11;19)(q23;p13), and t(9;11)(p22;q23). t(4;11) is the most common type, resulting in the formation of the MLL-AF4 chimeric gene. This condition is more common in infants and is characterized by a marked increase in white blood cells and central nervous system infiltration. It is considered to have a poor prognosis.
3) B-ALL with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1):
This results in the formation of the TEL-AML1 (ETV6-RUNX1) chimeric gene. This abnormality is thought to occur early in the development of leukemia. It is common in young children, and the prognosis for children is considered to be extremely good.
In addition, hyperdiploid B-ALL is the most common type in children and has an extremely good prognosis. Hypodiploid B-ALL has a poor prognosis. B-ALL associated with t(5;14)(q31;q32);IL3-IGH is a rare disease type characterized by eosinophilia. B-ALL associated with t(1;19)(q23;p13.3);E2A-PBX1 (TCF3-PBX1) has shown improved prognosis with effective intensive chemotherapy.
Clinical symptoms Clinical symptoms of acute lymphocytic leukemia include those caused by the suppression of normal hematopoiesis due to the proliferation of leukemic cells, those caused by the proliferation and infiltration of leukemic cells, and those caused by the destruction of tumor cells. 1) Symptoms caused by the suppression of normal hematopoiesis include anemia (general fatigue, shortness of breath, facial pallor), susceptibility to infection due to neutropenia (bacterial infection, fungal infection, fever), and bleeding tendency due to thrombocytopenia (petechia, purpura), and sometimes disseminated intravascular coagulation. 2) Symptoms caused by the infiltration of leukemic cells include lymphadenopathy, hepatosplenomegaly, mediastinum enlargement (T-lymphoblastic), and other organ damage throughout the body. In acute lymphocytic leukemia, central nervous system infiltration and testicular infiltration are common. 3) Tumor lysis syndrome (hyperuricemia, renal damage, disseminated intravascular coagulation) caused by the destruction of leukemic cells often occurs at the start of treatment in cases with a marked increase in white blood cells.
Test results
1) Peripheral blood findings:
The white blood cell count is often increased, but may also decrease. Blast cells are usually present. Normocytic anemia and thrombocytopenia are observed.
2) Bone marrow findings:
The bone marrow shows normoplasia or hyperplasia with an increase in MPO-negative blasts. Occasionally, the blasts become so dense that the bone marrow cannot be aspirated (dry tap).
3) Blood biochemistry findings:
The proliferation and destruction of leukemic cells causes elevated LDH and uric acid levels and kidney damage. If organ infiltration or infection occurs, abnormalities in test results related to each organ and in tests associated with infection will appear.
A definitive diagnosis is made by bone marrow examination. Acute lymphocytic leukemia is diagnosed when MPO-negative lymphoblasts account for 25% or more of the nucleated cells in the bone marrow. Lymphoblasts are identified by a comprehensive assessment based on morphological images of stained specimens, cell surface antigens, and chromosomal and genetic tests, and are classified as B-cell or T-cell.
Differential diagnosis: MPO-negative blasts can also be seen in acute myeloid leukemia (M0, M5, M7). In this case, diagnosis is based on lymphocyte surface antigens and TdT positivity. In BCR-ABL1-positive cases, differentiation from lymphoid blast crisis of chronic myeloid leukemia is necessary. In the case of blast crisis, the BCR-ABL1 chimeric gene is also positive in the neutrophil fraction and can be detected by the FISH method. Leukemic transformation of malignant lymphoma is differentiated based on lymphocyte surface antigens, chromosomes, etc. Reactive lymphocytosis is seen in viral infections, etc., and polyclonal mature lymphocytes increase, but differentiation is based on viral tests, etc.
Course and prognostic factors Poor prognostic factors for acute lymphoblastic leukemia include age (over 35 years old), high white blood cell count (over 30,000/μL for B-ALL and over 100,000/μL for T-ALL), and chromosomal abnormalities [t(9;22), t(4;11), hypodiploid chromosomes]. Chromosomal abnormalities that are associated with good prognosis include t(12;21), t(1;19), and hyperdiploidy. Response to treatment is also an independent prognostic factor. There is a high proportion of cases with poor prognostic chromosomal abnormalities in adults.
Recent treatment outcomes for adult acute lymphoblastic leukemia have been a complete remission rate of approximately 80%, and a long-term survival rate of approximately 35%. On the other hand, in childhood acute lymphoblastic leukemia, complete remission rates of over 90% and long-term survival rates of approximately 80% have been achieved with more intensive chemotherapy. In BCR-ABL1 (Ph)-positive leukemia, the combination of ABL1 tyrosine kinase inhibitors (imatinib, dasatinib) and chemotherapy can achieve a remission rate of over 90% and a three-year survival rate of 60%. In Japan, hematopoietic stem cell transplantation for acute lymphoblastic leukemia has resulted in a five-year survival rate of 50-60%.
TreatmentThe aim is to eradicate leukemia cells through combination chemotherapy. The treatment phase consists of induction therapy and post-remission therapy (consolidation therapy and maintenance therapy). Induction therapy uses vincristine, prednisolone, and anthracyclines (daunorubicin, doxorubicin), which are highly sensitive to lymphatic tumors, and L-asparaginase and cyclophosphamide are often added. In consolidation therapy, in addition to the drugs used in induction therapy, high-dose cytarabine and methotrexate are combined. Maintenance therapy is performed for 2 to 3 years in adults as well, mainly with oral 6-mercaptopurine and methotrexate, as this has been shown to improve prognosis in children. Central nervous system relapse is observed in approximately 30% of acute lymphocytic leukemia patients, so prophylactic administration such as intrathecal injection of methotrexate is performed. In young adults, improved treatment outcomes have been seen with an intensified protocol similar to that used in children.
For BCR-ABL1 (Ph)-positive leukemia, the treatment outcome has improved significantly with the combination of ABL1 tyrosine kinase inhibitors and chemotherapy. Allogeneic hematopoietic stem cell transplantation should be considered for cases with poor prognostic factors and for Ph-positive acute lymphoblastic leukemia in the first remission phase.
Complications and supportive care During chemotherapy, fever associated with neutropenia (febrile neutropenia) occurs in most cases, and antibiotics are administered similarly to sepsis. In addition, prophylactic administration of G-CSF is performed during the neutropenic phase. Transfusions for anemia and thrombocytopenia, and sufficient fluid replacement and administration of uric acid production inhibitors to prevent tumor lysis syndrome are recommended. [Onishi Kazunori]
■ References
Bassan R, Hoelzer D: Modern therapy of acute lymphoblastic leukemia. J Clin Oncol, 29: 532-543, 2011.
Pui CH, Relling MV, et al: Acute lymphoblastic leukemia. N Engl J Med, 350: 1535-1548, 2004.
Pui CH, Robison LL, et al: Acute lymphoblastic leukaemia. Lancet, 371
: 1030-1043, 2008.

Table 14-10-10
WHO Classification of Acute Lymphoblastic Leukemia (2008) and Its Incidence and Prognosis ">

Table 14-10-10

Table 14-10-11
Immunologic classification of acute lymphoblastic leukemia

Table 14-10-11

Acute lymphoblastic leukemia (eligibility for hematopoietic stem cell transplantation)

(3) Acute lymphoblastic leukemia (ALL)
Prognostic factors that have been reported as prognostic factors for ALL include age, white blood cell count at first visit (>30,000/μL), chromosomal abnormalities with poor prognosis, and time to achieve remission (>4 weeks). In addition to the Philadelphia (Ph) chromosome, chromosomal abnormalities such as t(4;11) and complex karyotypes are known to be associated with poor prognosis.
b. Indication of hematopoietic stem cell transplantation in first remission A meta-analysis combining clinical trials using genetic randomization for ALL in first remission showed that the overall survival rate was significantly higher in the group with a donor in analyses of all patients and in analyses of high-risk patients only. Therefore, allogeneic transplantation in first remission is recommended for cases with poor prognostic factors, but it is also worth considering transplantation in first remission even for standard-risk patients.
c. Transplantation for ALL in second or subsequent remissions The success rate of allogeneic transplantation for ALL in second or subsequent remissions is around 30%, and considering that a cure cannot be expected with conventional chemotherapy, there is no problem with the suitability of allogeneic transplantation. However, for patients who are refractory to the initial remission induction therapy, the long-term disease-free survival rate is only 10-20% even after allogeneic transplantation.
d. Treatment of Philadelphia (Ph) chromosome-positive ALL Because chemotherapy outcomes for Ph chromosome-positive ALL are extremely poor, early allogeneic transplantation after induction of remission, including transplantation from an unrelated donor, was recommended. Although chemotherapy outcomes have improved significantly with the introduction of imatinib, it is still unclear whether long-term survival is possible, and at present it is recommended to perform allogeneic transplantation while maintaining remission after chemotherapy combined with imatinib. [Kanda Yoshinobu]
■ References
Koreth J, Schlenk R, et al: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA, 301: 2349-2361, 2009.
Cutler CS, Lee SJ, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood, 104: 579-585, 2004.
Oliansky DM, Czuczman M, et al: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of diffuse large B cell lymphoma: update of the 2001 evidence-based review. Biol Blood Marrow Transplant, 17: 20-47 e30, 2011.

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　急性リンパ性白血病は，リンパ球への分化を方向づけられたリンパ球前駆細胞（リンパ芽球）が形質転換により分化を停止し，単クローン性増殖をきたすようになった腫瘍性疾患である．骨髄を増殖の主座とする．WHO分類ではBリンパ芽球性白血病（B-ALL）とTリンパ芽球性白血病（T-ALL）に分けられ，リンパ芽球性リンパ腫とは細胞帰属の点から同義とされている．一般的には骨髄においてリンパ芽球が25％以上占める場合をリンパ芽球性白血病と定義している．正常造血の障害，白血病細胞の臓器浸潤により種々の症状を呈する．
分類
1）WHO分類：
急性リンパ性白血病は，WHO分類2008年版では，前駆リンパ球系腫瘍のなかに分類され，Bリンパ芽球性白血病/リンパ腫，Ｔリンパ芽球性白血病/リンパ腫に分けられる．Bリンパ芽球性白血病/リンパ腫は，反復性（再現性のある）遺伝子異常を有する場合さらに個々の異常により細分類される（表14-10-10）．Burkitt白血病はWHO分類2001年版で急性リンパ性白血病に含まれていたが，2008年版では成熟B細胞腫瘍の中でBurkittリンパ腫に包括され，Burkitt白血病亜型として分類された．
2）FAB分類：
従来の形態学に基づくFAB分類では，骨髄における芽球が30％以上で，ミエロペルオキシターゼ（MPO）陽性率が3％未満，リンパ球形質陽性の場合に急性リンパ性白血病に分類される．形態学的にL1，L2，L3に分類される．L1は小細胞型で核小体不明瞭，L2は大細胞型で核小体を1個以上有し，L3は大細胞で好塩基性の細胞質と多数の空胞を特徴とする（図14-10-13）．L1，L2の臨床的な差は乏しい．L3はBurkittリンパ腫の白血病化したものと同義である．
3）免疫学的表面形質による分類：
急性リンパ性白血病はリンパ芽球の分化段階によっても分類される．表面形質の発現パターンによりB細胞ではearly B precursor（pro-B），common B，pre-B期に分類され，Tリンパ球も胸腺内での分化段階によりpro-T，pre-T，cortical T，medullary T期に分類される（表14-10-11）．
原因・病因
　急性リンパ性白血病は遺伝子異常に基づく腫瘍と考えられるが，その発症原因は明らかではない．放射線被曝，有機溶剤，抗癌薬による誘発事例の報告がある．
疫学
　わが国の白血病全体の推定年齢調整罹患率（2006年）は年間10万人あたり5.1人であり，このうち急性リンパ性白血病の罹患率は年間10万人あたり約1人と推定される．小児期に約2/3が発症し，高齢者で再度増加する．B細胞性とＴ細胞性の比率は約4：1である．
病態生理・分子病態
　急性リンパ性白血病は，リンパ球への分化を方向づけられたリンパ球前駆細胞に遺伝子異常が生じ，分化の異常，細胞増殖の亢進がもたらされ芽球が増殖する．遺伝子異常は高頻度に認められ，①染色体転座により融合遺伝子が形成される場合，②免疫グロブリン遺伝子またはT細胞受容体遺伝子と特定の遺伝子との再構成が生ずる場合，③遺伝子の欠失，④染色体数の変化，⑤点突然変異がある．転座あるいは遺伝子再構成過程のエラーによる場合は転写制御の異常が生じ腫瘍化すると考えられ，これらは病型や予後に大きく関連する．WHO分類では，反復性遺伝子異常を認める場合は独立した病型として分類されている．B-ALLでは約1/3にPAX5遺伝子の変異が認められ，T-ALLではNOTCH1遺伝子変異，HOX11（TLX1），HOX11L2 （TLX3），TAL1遺伝子などとＴ細胞受容体遺伝子との再構成が高頻度に報告されている．
反復性遺伝子異常を伴うBリンパ芽球性白血病
1）t（9；22）（q34；q11.2）；BCR-ABL1を伴うB-ALL：
9番染色体と22番染色体の相互転座により22番染色体にフィラデルフィア（Philadelphia：Ph）染色体を認める．転座部位にBCR-ABL1キメラ遺伝子を生じ，ABL1遺伝子のチロシンキナーゼ活性の恒常的な亢進が腫瘍化の原因とされている．BCR遺伝子の切断部位により190 kDa，210 kDaのキメラ蛋白が形成される．小児では190 kDaが大半であるが，成人では210 kDaが半数を占める．年齢に伴い頻度が高くなり，成人では約25％に認められる．予後不良とされる．
2）t（v;11q23）：MLL再構成を伴うB-ALL：
11q23にあるMLL遺伝子とほかの染色体との間に転座を認める．転座はt（4；11）（q21；q23），t（11；19）（q23；p13），t（9；11）（p22；q23）などがある．t（4；11）が最も多くMLL-AF4キメラ遺伝子が形成される．乳児に多く，白血球著増，中枢神経浸潤が特徴である．予後不良とされる．
3）t（12；21）（p13；q22）；TEL-AML1（ETV6-RUNX1）を伴うB-ALL：
TEL-AML1（ETV6-RUNX1）キメラ遺伝子を生ずる．この異常は白血病発症過程の早期に生ずると考えられている．幼児に多く，小児ではきわめて予後良好とされる．
　その他，高2倍体B-ALLは小児では最も高頻度に認められ，きわめて予後良好である．低2倍体B-ALLは予後不良である．t（5；14）（q31；q32）；IL3-IGHを伴うB-ALLは好酸球増加を特徴とするまれな病型である．t（1；19）（q23；p13.3）；E2A-PBX1（TCF3-PBX1）を伴うB-ALLは強化した化学療法が有効で予後が改善した．
臨床症状
　急性リンパ性白血病の臨床症状は，白血病細胞の増殖に伴う正常造血の抑制によるもの，白血病細胞の増殖・浸潤によるもの，腫瘍細胞の崩壊によるものがある．①正常造血の抑制によるものとして，貧血（全身倦怠感，息切れ，顔面蒼白），好中球減少に伴う易感染性（細菌感染，真菌感染，発熱），血小板減少に伴う出血傾向（点状出血，紫斑）があり，ときに播種性血管内凝固症を生ずる．②白血病細胞の浸潤によるものとしては，リンパ節腫脹，肝脾腫，縦隔腫大（Tリンパ芽球性）をはじめとして全身の臓器障害をきたす．急性リンパ性白血病では中枢神経浸潤，精巣浸潤が多い．③白血病細胞の崩壊による腫瘍崩壊症候群（高尿酸血症，腎障害，播種性血管内凝固症）は，白血球著増例の治療開始時に多く生ずる．
検査成績
1）末梢血所見：
白血球数は多くの場合増加するが，減少する場合もある．通常芽球が出現する．正球性貧血，血小板減少を認める．
2）骨髄所見：
骨髄は，正形成ないし過形成でMPO陰性芽球の増加を認める．ときに芽球が過密となり，骨髄が吸引できない場合がある（dry tap）．
3）血液生化学所見：
白血病細胞の増殖・崩壊によりLDHの上昇，尿酸の上昇，腎障害を認める．また臓器浸潤，感染を伴う場合は，各臓器に関連する検査値や感染症に随伴する検査異常を呈する．
診断
　確定診断は骨髄検査により行う．MPO陰性のリンパ芽球が骨髄有核細胞の25％以上を占める場合に急性リンパ性白血病と診断する．リンパ芽球の同定は染色標本による形態像と細胞表面抗原，染色体・遺伝子検査により総合的に判断し，B細胞性とＴ細胞性に分ける．
鑑別診断
　MPO陰性芽球は急性骨髄性白血病（M0，M5，M7）でも認められる．この場合は，リンパ球系表面抗原やTdT陽性により判定する．BCR-ABL1陽性例では，慢性骨髄性白血病のリンパ性急性転化との鑑別が必要となる．急性転化の場合は，好中球分画においてもBCR-ABL1キメラ遺伝子が陽性となりFISH法で検出できる．悪性リンパ腫の白血化は，リンパ球表面抗原，染色体などにより鑑別する．反応性リンパ球増加はウイルス感染症などで認められ，多クローン性の成熟リンパ球が増加するが，ウイルス検査などにより鑑別する．
経過・予後因子
　急性リンパ性白血病の予後不良因子は，年齢（35歳以上），白血球数高値（B-ALLでは3万/μL以上，T-ALLでは10万/μL以上），染色体異常［t（9；22），t（4；11），低2倍体染色体］があげられる．予後良好な染色体異常は，t（12；21），t（1；19），高2倍体である．また治療に対する反応性も独立した予後因子である．成人では予後不良染色体異常をもつ症例の割合が高い．
　近年の成人急性リンパ性白血病の治療成績は完全寛解率約80％，長期生存率は約35％である．一方，小児急性リンパ性白血病ではより強化した化学療法により90％以上の完全寛解率と約80％の長期生存が得られている．BCR-ABL1（Ph）陽性白血病ではABL1チロシンキナーゼ阻害薬（イマチニブ，ダサチニブ）と化学療法の併用により寛解率90％以上，3年生存率60％が得られる．急性リンパ性白血病に対する造血幹細胞移植の日本の治療成績は5年生存率50～60％が得られている．
治療
　多剤併用化学療法により白血病細胞の根絶を目指す．治療相は寛解導入療法と寛解後療法（地固め療法，維持療法）からなる．寛解導入療法はリンパ系腫瘍に感受性の高いビンクリスチン，プレドニゾロンおよびアントラサイクリン系薬剤（ダウノルビシン，ドキソルビシン）が使用され，さらにl-アスパラギナーゼやシクロホスファミドが加えられることが多い．地固め療法では寛解導入療法に使用した薬剤に加え，大量シタラビンとメトトレキサートが組み合わされる．維持療法は，小児で予後の改善が認められることから，成人でも6-メルカプトプリンとメトトレキサートの内服を中心に2～3年間実施される．急性リンパ性白血病では中枢神経再発が約30％に認められるためメトトレキサートの髄腔内注射などの予防投与が行われる．若年成人では小児と同様の強化したプロトコールにより治療成績の改善が認められる．
　BCR-ABL1（Ph）陽性白血病に対しては，ABL1チロシンキナーゼ阻害薬と化学療法の併用により治療成績が著しく向上した．同種造血幹細胞移植は，予後不良因子をもつ症例およびPh陽性急性リンパ性白血病に対し第一寛解期での実施を検討する．
合併症・支持療法
　化学療法時には，好中球減少に伴う発熱（発熱性好中球減少症）を大半で生じ，敗血症に準じて抗菌薬投与が行われる．また，好中球減少期にはG-CSFの予防投与が行われる．貧血，血小板減少に対する輸血，腫瘍崩壊症候群予防のための十分な補液と尿酸生成阻害薬の投与が推奨される．［大西一功］
■文献
Bassan R, Hoelzer D: Modern therapy of acute lymphoblastic leukemia. J Clin Oncol, 29: 532-543, 2011.
Pui CH, Relling MV, et al: Acute lymphoblastic leukemia. N Engl J Med, 350: 1535-1548, 2004.
Pui CH, Robison LL, et al: Acute lymphoblastic leukaemia. Lancet, 371
: 1030-1043, 2008.

表14-10-10
急性リンパ性白血病のWHO 分類（2008 年）と頻度・予後">

表14-10-10

表14-10-11
急性リンパ性白血病の免疫学的形質による分類">

表14-10-11

急性リンパ性白血病(造血幹細胞移植の適応の考え方)

（3）急性リンパ性白血病（acute lymphoblastic leukemia：ALL）
a.予後予測因子
　ALLの予後因子として，年齢，初診時白血球数（＞30000/μL），予後不良の染色体異常，寛解到達までの期間（＞4週間）などが報告されている．染色体異常としては，フィラデルフィア（Ph）染色体以外にも，t（4;11），複雑核型などが予後不良であることが知られている．
b.第一寛解期における造血幹細胞移植の適応
　第一寛解期ALLに対するgenetic randomizationを行った臨床試験を統合したメタアナリシスでは，全患者を対象とした解析と高リスク患者のみを対象とした解析においてドナーあり群の全生存率が有意に上回るということが示されているため，予後不良因子を有する症例に対しては第一寛解期での同種移植が推奨されるが，標準リスク群患者においても第一寛解期移植を検討する価値がある．
c.第二寛解期以降のALLに対する移植
　第二寛解期のALLに対する同種移植の成績は30％前後であり，通常の化学療法では根治は期待できないことを考えると，同種移植の適応に問題はない．一方，初回寛解導入不応例に対しては，同種移植を行っても長期無病生存は10～20％にすぎない．
d.フィラデルフィア（Ph）染色体陽性ALLの治療
　Ph染色体陽性ALLについては化学療法の成績が著しく不良であるため，非血縁者間移植を含めて，寛解導入後早期の同種移植が推奨されていた．イマチニブの導入によって化学療法の成績は著しく向上しているが，長期生存が可能であるかどうかはまだ不明であり，現時点ではイマチニブ併用化学療法を行った後に寛解を維持している間に同種移植を行うことが推奨される．［神田善伸］
■文献
Koreth J, Schlenk R, et al: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA, 301: 2349-2361, 2009.
Cutler CS, Lee SJ, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood, 104: 579-585, 2004.
Oliansky DM, Czuczman M, et al: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of diffuse large B cell lymphoma: update of the 2001 evidence-based review. Biol Blood Marrow Transplant, 17: 20-47 e30, 2011.

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