만성 골수성 백혈병. Chronic myeloid leukemia (CML)

다양한 혈액종양질환을 정리하고 있습니다.

우선, 골수증식성 종양에는 다음과 같은 질환군들이 있습니다.

 

 

위에서부터 차례대로 나열하면 다음과 같습니다.

 

- 만성 골수성 백혈병

- 만성 호중구 백혈병

- 진성 적혈구 증가증

- 원발성 골수 섬유화증 : 전섬유화 단계(초기), 섬유화 단계(말기)

- 본태성 혈소판 증가증

- 만성 호산구 백혈병

- 골수 증식성 종양, 분류 불가능

 

이들 중 첫 번째 질환, 만성 골수성 백혈병에 대해 알아보겠습니다.

(라이언 이모티콘이 CML을 가리키고 있습니다!ㅋㅋ)

 

1. Definition

Chronic myeloid leukemia (CML), BCR-ABL1 positive, is a myeloproliferative neoplasm(MPN) in which granulocytes are the major proliferative component.

It arises in a hematopoietic stem cell and is characterized by the chromosomal translocation t(9;22)(q34.1;q11.2), which results in the formation of the Philadelphia(Ph) chromosome, containing the BCR-ABL1 fusion gene.

The natural history of untreated CML is biphasic or triphasic. An initial indolent Chronic Phase(CP) is followed by an Accelerated Phase(AP), a Blast Phase(BP) or both.

 

2. Localization

In Chronic Phase(CP), the leukemic cells are minimally invasive and mostly confined to the blood, bone marrow, spleen, and liver. 

In Blast Phase(BP), the blasts can infiltrate any extramedullary site, with a predilection for spleen, liver, lymph nodes, skin, and soft tissue.

 

3. Clinical features

Most patients with CML are diagnosed in CP, which usually has an insidious onset. 

Common findings at presentation include fatigue, malaise, weight loss, night sweats, and anemia, and about 50% have palpable splenomegaly.

Without effective therapy, most cases of CML progress from CP to BP (directly or via AP) within 3~5 years after diagnosis.

With targeted TKI therapy and careful monitoring, the incidence of AP and BP has decreased, and the 10-year overall survival rate for CML is 80~90%.

 

4. Microscopy

Chronic phase. CP

The peripheral blood shows leukocytosis, due to neutrophils in various stages of maturation, with peaks in proportions of myelocytes and segmented neutrophils. Blasts typically account for <2% of the WBCs. Absolute basophilia and eosinophilia are common. Platelet counts are normal or increased to 1000K/uL; marked thrombocytopenia is uncommon in CP.

Bone marrow specimens are hypercellular, with marked granulocytic proliferation and a maturation pattern similar to that in the PB. There is no significant dysplasia. Blasts usually account for <5% of the marrow cells. The proportion of erythroid precursors is usually significantly decreased. Megakaryocytes may be normal or slightly decreased in number, but 40~50% of cases exhibit moderate to marked megakaryocytic proliferation. The megakaryocytes are smaller than normal and have hyposegmented nuclei; referred to as "dwarf" megakaryocytes, but are not true micromegakaryocytes observed in MDS. Eosinophils and basophils are usually increased, and pseudo-Gaucher cells are common.

Pseudo-Gaucher cells

Accelerated phase. AP

Blast Phase. BP

(1) ≥ 20% blasts in blood or bone marrow

(2) The presence of an extramedullary proliferation of blasts

→ Extramedulary blast proliferations are most common in the skin, lymph nodes, bone, and CNS, but can occur anywhere.

BP로 진행된 환자들의 예후는 무척 안 좋습니다ㅜㅜ

 

5. Immunophenotype

Immunophenotypic data on CML-CP suggest that the expression of CD7 on CD34+ cells has adverse prognostic significance, where as a normal CD34+ stem-cell population, lacking expression of abnormal markers(e.g. CD7, CD56, CD11b), predicts a better response to TKI therapy.

 

6. Genetic profile

At diagnosis, 90~95% of cases of CML have the characteristic t(9;22)(q34.1;q11.2) reciprocal translocation that results in the Ph chromosome, der(22)t(9;22). This translocation fuses sequences of the BCR gene on chr 22 with regions of ABL1 gene on chr 9.

 

Imatinib competes with ATP for binding to the BCR-ABL1 kinase domian, thus preventing phosphorylation of tyrosine residues on its substrates. Interruption of the oncogenic signal in this way is effective for control of the disease, particularly when used early in CP. However, the emergence of subclones of leukemic progenitor cells  that have BCR-ABL1 point mutations that alter amino acids and prevent the binding of the inhibitor to the BCR-ABL1 kinase domain can lead to drug resistance. The 2nd, 3rd generation TKIs (e.g. nilotinib, dasatinib, bosutinib, ponatinib) can circumvent this form of drug failure.

 

The molecular basis of transformation from CP to AP/BP is still unknown. Progression is usually associated with clonal evolution; at the time of transformation to AP/BP, 80% of cases demonstrate cytogenetic changes in addition to the Ph chromosome, including an extra Ph chromosome, isochromosome 17q, and gain of chromosome 8 or 19, the so-called major route karyotypic abnormalities.

 

 

Ref)

The WHO Classification of Tumours of Haematopoietic and LymphoidTissues, IARC 2017