Acute leukemia

Japanese: 急性白血病 - きゅうせいはっけつびょう（英語表記）Acute leukemia

What is the disease?

Blood plasma ( Conclusion ) It is made up of a liquid component called the erythrocyte (90% water) and cellular components called blood cells floating in it. Blood cells include red blood cells that carry oxygen to the body, white blood cells that fight pathogens that invade the body, and platelets that attach to blood vessels and stop bleeding.

All these blood cells are in the space inside the bones ( Bone marrow ( Kotsui ) The bone marrow, which is the factory that produces blood cells, contains many Hematopoietic stem cells ( Public interest ) (The "seed" cells of blood.) These hematopoietic stem cells replicate themselves and differentiate, grow, and mature in the bone marrow to become various types of blood cells, which are then released into the blood.

In this way, the human body maintains a constant supply of blood cells necessary to sustain life. Acute leukemia is a disease in which abnormalities occur in the process in which hematopoietic stem cells repeatedly differentiate and proliferate in the bone marrow to grow into mature blood cells.

In acute leukemia, defective cells that stop growing during the process of becoming mature blood cells from hematopoietic stem cells ( Blast cells ( School ) The defective cells (called leukemia cells) begin to multiply in the bone marrow.

When these useless defective products take up most of the bone marrow, which is the factory for blood cells, normal blood cannot be produced. The blast cells continue to grow and eventually overflow from the bone marrow, causing damage to the liver and spleen ( Hizo ) In organs such as infiltration ( Shinjun ) Then, the lump ( Mass ( Production ) ) and cause swelling in organs.

What is the cause?

" after anticancer drug or radiation treatment Secondary leukemia ( Rainbow Life Discovery Hospital ) ", but the cause of most leukemia is unknown.

How symptoms manifest

Symptoms of acute leukemia can be divided into symptoms caused by the inability to produce normal blood and symptoms caused by the proliferation of blast cells (Figure 3).

Symptoms of no longer having space to make healthy blood cells (white blood cells, red blood cells, and platelets) include:

① Red blood cells that carry oxygen throughout the body decrease, Fatigue ( Health test ) You may experience shortness of breath when you exercise.

② White blood cells that fight against pathogens that invade from outside ( Granulocytes ( Curry ) and lymphocytes) decrease, pneumonia ( Haien ) When acute leukemia causes an infection, a high fever is often the only symptom.

③ A decrease in platelets makes bleeding more likely. Not only does it make it harder for blood to stop flowing when you're injured, but it can also cause bruises even when you're not doing anything. Nosebleeds ( Bishukket ) In severe cases, cerebral hemorrhage or gastrointestinal bleeding (bleeding from the stomach, duodenum, etc.) may occur.

On the other hand, the cells that have proliferated in the bone marrow do not remain there but flow into the bloodstream, and may infiltrate various organs such as the liver, spleen, lymph nodes, and gums, causing swelling of these organs. In addition, the blast cells may gather together and form lumps, which may press on nerves and cause various symptoms.

Testing and diagnosis

When a patient visits a hospital complaining of physical discomfort, acute leukemia may be suspected due to abnormalities in blood tests (increase or decrease in blood cell count, appearance of abnormal cells). If leukemia is suspected, a bone marrow test will be performed to confirm the diagnosis.

Because bone marrow is a blood factory, normally the aspirated bone marrow blood should contain a variety of cells at various stages of maturation, from young hematopoietic stem cells to mature cells just before shipment. However, in the case of leukemia patients, the bone marrow is filled with immature leukemia cells that have become tumors (Figure 3).

Acute leukemia is broadly classified into acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) based on the results of staining of the cells (peroxidase staining), and each type is further classified according to the results of tests on chromosomes, surface markers, etc. The reason why it is important to classify acute leukemia in detail is that the treatment method or response to treatment differs depending on each type of leukemia, which helps determine the treatment plan.

Treatment methods

If left untreated after being diagnosed with acute leukemia, the patient will die within a few days to a few weeks. Therefore, once a diagnosis is confirmed, the patient must be hospitalized and treatment must begin immediately.

Remission induction therapy

Treatment begins with combination chemotherapy, which involves administering a combination of several anticancer drugs. This is called remission induction therapy (Figure 4).

The purpose of this treatment is to reduce the number of leukemia cells overflowing in the bone marrow to less than one percent to one thousandth, creating space in the bone marrow and restoring normal hematopoiesis. The state in which the number of leukemia cells is less than one percent (a state in which they cannot be found under a microscope) and the blood count returns to normal is called complete remission (CR). The word "cure" is not used because the state is one in which leukemia cells are hiding somewhere in the body, even if they cannot be seen.

The anticancer drugs used for remission induction therapy for acute myeloid leukemia and acute lymphoblastic leukemia are slightly different.

In myeloid cases, a combination of idarubicin or daunorubicin and cidarabine is generally used, while in lymphoid cases, a combination of endoxan, daunorubicin (or doxorubicin), vincristine, prednisolone, cyclophosphamide, and L-asparaginase is generally used. Complete remission is achieved in 65-80% of myeloid cases and 70-90% of lymphoid cases.

However, all chemotherapy drugs not only kill leukemia cells, but also damage normal blood cells, so after the administration of anticancer drugs, blood production temporarily stops. Red blood cells and platelets can be replenished by blood transfusion, but white blood cells cannot be transfused. The decrease in white blood cells leads to the infection of bacteria, fungi ( Shinkin ) The risk of infection by mold increases, so antibiotics and antifungal drugs are administered to prevent and treat infection. Granulocytes ( Curry ) There is a drug called GCSF, but it is only used when it is determined that there is little possibility that GCSF will increase the proliferation of leukemia cells.

Other side effects include nausea, vomiting, hair loss, mouth ulcers, and diarrhea.

Post-remission therapy

Even if you achieve complete remission, if you stop treatment, the leukemia cells remaining in your body will start to grow again, and the leukemia will recur. Therefore, even after you achieve complete remission, you will continue treatment to reduce the number of leukemia cells remaining in your body to zero. Post-remission ( Conversation ) This is called chemotherapy (Figure 5, Table 11). In acute lymphocytic leukemia, leukemia cells often remain in the central nervous system, so anticancer drugs may be administered directly into the fluid that surrounds the central nervous system (cerebrospinal fluid).

Post-remission therapy can be either continuing chemotherapy for 1-2 years or undergoing hematopoietic stem cell transplantation following chemotherapy. The choice of which method to use is determined by a comprehensive evaluation of factors such as chromosomal abnormalities in leukemia cells, age, and time to achieve complete remission. Generally, transplantation is performed for patients considered to be at high risk of recurrence, while chemotherapy is continued for patients at low risk of recurrence.

However, this method cannot be used as an indicator for treatment selection for patients in the intermediate prognosis group, where the risk of recurrence cannot be predicted, and these prognostic factors are not necessarily absolute. Therefore, recently, MRD ( Minimal residual disease ( Bishozan hospital ) ) to observe progression and determine treatment methods.

Treatment results

In the case of acute myeloid leukemia, the treatment outcome varies slightly depending on the type of disease, but chemotherapy can be expected to cure 20-50% of cases, and transplantation can be expected to cure 40-70% of cases. If the disease recurs, chemotherapy alone cannot be expected to cure the disease, and transplantation is the only definitive treatment, which can be expected to cure 20-50% of cases.

On the other hand, in the case of acute lymphoblastic leukemia, the cure rates through chemotherapy and transplantation are 15-35% and 45-55%, respectively, which are slightly lower than those of acute myeloid leukemia.

New Treatments

Neither chemotherapy nor transplants selectively attack leukemia cells, and they also damage normal organs and tissues. However, the mechanism of leukemia onset (molecular pathology) has been elucidated for some acute leukemias, and treatments that target the molecular pathology ( Molecular targeting ( Cultural ) therapy) is being attempted.

Acute myeloid leukemia, a type of acute myeloid leukemia Promyelocytic ( National psychiatric deficiency ) A typical example is all-trans retinoic acid (ATRA) therapy for leukemia, which achieves complete remission in 90% of patients and cures 70-80% of patients.

In addition, a drug called Mylotarg, which combines an anticancer drug with an antibody that specifically binds to a protein called CD33 that is found on the cell surface of acute myeloid leukemia, has also been used in treatment with good results.

What to do if you notice an illness

If acute leukemia is suspected due to abnormalities in blood tests, you should immediately visit a medical institution with a hematologist to receive detailed examinations and treatment.

Mariko Yabe, Akiko Yamane, Shinichiro Okamoto

Figure 3. Pathology and symptoms of acute leukemia
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Figure 3. Pathology and symptoms of acute leukemia

Figure 4 Treatment of acute leukemia (first stage)
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Figure 4 Treatment of acute leukemia (first stage)

Figure 5 Treatment of acute leukemia (second stage)
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Figure 5 Treatment of acute leukemia (second stage)

Table 11 Postremission therapy
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Table 11 Postremission therapy

Source: Houken “Sixth Edition Family Medicine Encyclopedia” Information about the Sixth Edition Family Medicine Encyclopedia

Japanese:

どんな病気か

　血液は血漿(けっしょう)と呼ばれる液体成分（90％が水分）とそのなかに浮かぶ血球という細胞成分からできています。血球には体に酸素を運ぶ赤血球、体に侵入してくる病原体と闘う白血球、そして血管に付着して出血をとめる血小板などがあります。

　これらの血球はすべて骨のなかの空間（骨髄(こつずい)）でつくられます。血球の製造工場である骨髄にはたくさんの造血幹細胞(ぞうけつかんさいぼう)（血液の“種”の細胞）があります。この造血幹細胞は自分自身を複製するとともに骨髄のなかで分化・増殖・成熟を繰り返してさまざまな種類の血球となり、血液のなかに送り込まれます。

　このようにして人間の体では、血液中の各血球はなくなることなく常に生命維持に必要な数が保たれています。造血幹細胞が骨髄のなかで分化・増殖を繰り返して成熟した血球に成長してゆく過程に異常が起こる病気のひとつが急性白血病です。

　急性白血病では、造血幹細胞から成熟した血球となる過程の途中で成長することをやめてしまった不良品（芽球(がきゅう)または白血病細胞といいます）ができ、この不良品が骨髄中でどんどんと増えていきます。

　役に立たない不良品が血球の工場である骨髄の大部分を占めてしまうと、正常な血液をつくることができなくなります。増殖を続ける芽球はやがて骨髄からあふれ出て、肝臓や脾臓(ひぞう)などの臓器に浸潤(しんじゅん)して、塊（腫瘤(しゅりゅう)）をつくったり、臓器のはれを起こします。

原因は何か

　抗がん薬や放射線などの治療のあとで起こる「二次性白血病(にじせいはっけつびょう)」もありますが、大部分の白血病の原因は不明です。

症状の現れ方

　急性白血病の症状は、正常な血液をつくることができなくなることによる症状と、芽球の増殖による症状に分けることができます（図3）。

　正常な血球（白血球、赤血球、血小板）をつくるスペースがなくなってしまうことによる症状には次のようなものがあります。

①体中に酸素を運ぶ赤血球が減ることで、倦怠感(けんたいかん)や体を動かした時の息切れなどが起こります。

②外から侵入してくる病原体と闘う白血球（顆粒球(かりゅうきゅう)やリンパ球）が減ることで、肺炎(はいえん)やそのほかの感染症が起こりやすくなります。急性白血病で感染症を起こした時には、高熱が唯一の症状であることが多いようです。

③血小板が減ることで出血が起こりやすくなります。けがをした時に血が止まりにくくなるだけではなく、何もしていないのにあざができたり、鼻出血(びしゅっけつ)が起きたり、重症な場合は脳出血や消化管の出血（胃、十二指腸などからの出血）が起こることもあります。

　一方、骨髄のなかに増殖した細胞はそこだけにとどまらずに血液のなかに流れていき、肝臓、脾臓、リンパ節、歯肉などのいろいろな臓器に浸潤して臓器のはれを起こすことがあります。また、芽球が集まって塊をつくり、その塊が神経などを圧迫していろいろな症状を示すこともあります。

検査と診断

　体の不調を訴えて病院を受診した時に、血液検査の異常（血球数の増加・減少、異常細胞の出現）により急性白血病が疑われます。白血病が疑われた場合は骨髄の検査を行い、診断を確定します。

　骨髄は血液の工場なので、本来であれば吸引した骨髄血のなかには、まだ若い造血幹細胞から出荷直前の成熟した細胞に至るまで、各成熟段階のさまざまな細胞がみられるはずですが、白血病の患者さんの場合、腫瘍化した未成熟な白血病細胞で埋めつくされています（図3）。

　急性白血病はその細胞の染色（ペルオキシダーゼ染色）の結果によって急性骨髄性白血病（AML）と急性リンパ性白血病（ALL）に大別され、さらに染色体、表面マーカーなどの検査結果によっておのおのが細かく分類されます。なぜ急性白血病を細かく分類することが大切かというと、個々の白血病によって治療法あるいは治療に対する反応性が異なり、治療方針を決定するのに役立つからです。

治療の方法

　急性白血病と診断されたあと治療しないで放置すると、数日から数週間で死亡します。したがって診断が確定すれば入院し早急に治療を開始する必要があります。

●寛解(かんかい)導入療法

　治療はまず数種類の抗がん薬を組み合わせて投与する併用化学療法を行います。これを寛解導入療法といいます（図4）。

　この治療の目的は、骨髄中に満ちあふれる白血病細胞を百分の1から千分の1以下に減らし、骨髄にスペースをつくって正常の造血を回復させることです。白血病細胞が百分の1以下（顕微鏡では見つからない状態）になり、血球数が正常化する状態を完全寛解（CR）といいます。治癒という言葉を使わないのは、見えなくても体のどこかに白血病細胞がひそんでいる状態だからです。

　急性骨髄性白血病と急性リンパ性白血病では、寛解導入療法に使用する抗がん薬が少し異なります。

　骨髄性の場合はイダルビシンまたはダウノルビシンとシダラビンの併用が、リンパ性の場合はエンドキサン、ダウノルビシン（またはドキソルビシン）、ビンクリスチン、プレドニゾロン、シクロホスファミド、Lアスパラギナーゼの併用が一般的に行われています。骨髄性では65～80％、リンパ性では70～90％の割合で完全寛解が達成されています。

　しかし、いずれの化学療法も、白血病細胞を殺すのみならず、正常な血液細胞も障害してしまうので、抗がん薬投与後は一時的に血液がつくられない状態になります。赤血球、血小板は輸血で補うことができますが、白血球は輸血することができません。白血球の減少に伴って細菌、真菌(しんきん)（カビ）による感染症のリスクが高まるので、抗生剤、抗真菌薬を投与し、その予防および治療を行います。白血球を増やすGCSF（顆粒球(かりゅうきゅう)コロニー刺激因子）という薬剤がありますが、GCSFが白血病細胞を増やす可能性が低いと判断された時にのみ使用します。

　そのほかに、吐き気、嘔吐、脱毛、口内炎、下痢などの副作用が認められます。

●寛解後療法

　完全寛解したからといって、治療を中止してしまうと、体のなかにまだ残っている白血病細胞が再び増殖を開始し、白血病は再発してしまいます。したがって完全寛解が達成されたあとも、継続して体に残っている白血病細胞をゼロにするように治療を続けます。これを寛解後(かんかいご)療法といいます（図5、表11）。急性リンパ性白血病では中枢神経に白血病細胞が残っていることが多いので、中枢神経を包んでいる液体（髄液）のなかに直接抗がん薬を投与することがあります。

　寛解後療法には化学療法を1～2年継続する方法と、化学療法に続いて造血幹細胞(ぞうけつかんさいぼう)移植を行う方法があります。どちらを選択するかは白血病細胞の染色体異常、年齢、完全寛解達成までの時間などの因子を総合的に評価して決めます。再発のリスクが高いと思われる患者さんには移植を、再発のリスクが低い患者さんには化学療法を継続するのが一般的です。

　しかしこの方法では、再発のリスクを予測できない予後中間群の患者さんに関しては治療選択の指標とはなりませんし、これらの予後因子は必ずしも絶対的なものではありません。そこで最近では、完全寛解に入ったあとの水面下の白血病細胞の量を、白血病の遺伝子異常などを利用して明らかにするMRD（微少残存病変(びしょうざんぞんびょうへん)）を用い、その推移をみて治療法を決定する試みもなされています。