What Is Chronic Myelomonocytic Leukemia?

Chronic myelomonocytic leukaemia (CMML) is a chronic myeloid leukemia. hair

Chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a rare blood disease in clinical practice, and its clinical manifestations, survival time, and routine blood tests are diverse.

1 Chronic myelomonocytic leukemia 1 disease introduction

Chronic myelomonocytic leukaemia (CMML) is a chronic myeloid leukemia. hair

The prevalence rate is about 1 to 2/100 000 / year, most of which occur after the age of 60, and the ratio of men and women is about 1.5 to 3: 1. The specific cause is unknown. There is no specific chromosome ectopic. Common clinical symptoms are fever, infection, bleeding, fatigue, weight loss, night sweats, etc., about half of patients have hepatosplenomegaly. The median survival time of patients with CMML is about 20 months, which may be related to the proportion of bone marrow blasts. There is currently no specific treatment.

2 Chronic myelomonocytic leukemia 2 disease classification

Chronic myelomonocytic leukemia (CMML) was previously considered to be a subtype of myelodysplastic syndrome (MDS), because it has the characteristics of bone marrow dysplasia and bone marrow proliferation. In 2001, WHO hematopoietic and lymphocytes Tumor classification classified CMML as myelodysplastic / myeloproliferative disease (MDS / MPD).

In the 1950s, Beattie, SINN, Pearson and others successively reported "chronic mononuclear leukemia" [1-3]. In 1972, Hurdle et al. [4] first reported 6 patients with CMML. Morphological classification suggestion, separate MDS classification, formally proposed that CMML is included in MDS. In 2001, the WHO classification scheme classified hematopoietic and lymphoid tissue tumors into four groups: myeloid tumors, lymphoid tumors, histiocytic and dendritic cell tumors, and mast cell disorders. Sexually transmitted diseases (MDS / MPD).

WHO classified MDS / MPD is a group of myeloid diseases, which has the dual characteristics of bone marrow pathological hematopoiesis and bone marrow proliferation. The disease types include: chronic myeloid monocyte leukemia (CMML), atypical chronic myeloid leukemia (aCML), and juvenile myeloid monocyte leukemia (JMML). Previously attributed to MPD or MDS. There is always controversy as to whether CMML is MPD or MDS. The FAB proposed to divide CMML into MDS-like CMML (MDS? Like CMML) and MPD-like CMML (MPD? Like CMML) according to the level of its white blood cell count. CMML has no difference in biological behavior and prognosis. So far, no cytogenetic and molecular biological differences have been found in these two CMML. It is clinically observed that CMML with low white blood cells, such as splenomegaly, will eventually become "proliferative" and a significant increase in white blood cells will appear. Based on the above reasons, the new WHO classification no longer divides CMML into two subtypes, but classifies it into the new disease classification concept of MDS / MPD. The WHO classification subdivides CMML into two subtypes, CMML? 1 and CMML? 2, based on bone marrow and peripheral blood blasts.

3 Molecular biological characteristics of chronic myelomonocytic leukemia 3

MDS / MPD is a new myeloid tumor proposed in the WHO classification standard. The JAK2 gene mutation rate in MDS / MPD? U patients is 18.8% (3/16 cases), and the JAK2 gene mutation rate in CMML patients is 12.5% (2 / 15 cases), and the detection rate of JAK2 gene mutation in MDS patients is only 1.4%, suggesting that the incidence of MDS / MPD? U and CMML patients is closer to that of MPD.

Ph chromosome positive is one of the characteristics of chronic myelogenous leukemia, and it is negative in CMML. To date, no chromosomal translocation is unique to CMML. Genetic abnormalities are found in 20% to 30% of patients. These include abnormalities in the number and structure of chromosomes such as +8, del (20 q), -7, del (11q), but these chromosomes are abnormal in other myeloproliferative diseases and myeloproliferative disorders. Also seen in the syndrome. Cases with eosinophilia often appear as t (5; 12) (q33; p13), causing the TEL gene to be linked to the platelet-derived growth factor receptor (PDGFbR) gene, which is about 2% 5% of CMML patients. Some patients showed that the huntingtin protein (HIP1) gene and the aforementioned gene (PDGFbR) were fused to form t (5; 7) (q33; q11.2). A few treatment-related CMMLs can also manifest as t (11; 16) (q23; p13), forming a fusion of MLL and CBP genes. There are also reports of t (1; 13) (p36; q21), t (7; 11) (p15; p15), and t (8; 9) (p11; q34).

4 Clinical manifestations of chronic myelomonocytic leukemia 4

The incidence rate is about 1 to 2 / 100,000 / year, and the male to female ratio is about 1.5 to 3: 1. Most patients develop the disease over 50 years old, and about 75% of the patients over 60 years old. Mainly manifested in two groups of symptoms, that is, symptoms related to bone marrow pathological hematopoiesis and symptoms related to bone marrow proliferation.

Patients with reduced blood cells due to abnormal bone marrow hyperplasia can manifest as weakness, palpitations, paleness, low fever, infection or bleeding. The characteristics of bone marrow proliferation are: abnormal monocyte proliferation, and these cells have infiltration characteristics, such as extramedullary infiltration of skin, glands, gums, bones, lymphadenopathy, hepatosplenomegaly, and even giant spleen. Some authors have reported that [5] Of the 24 patients, 50% had liver enlargement, 45.8% had splenomegaly, and 20.8% had lymph node involvement.

According to the characteristics of CMML, CMML can be divided into chronic phase, accelerated phase, and acute change phase. Patients in the chronic phase are relatively stable, asymptomatic or have only low fever, fatigue, etc., and hepatosplenic lymphadenopathy is rare. After entering the accelerated phase, the disease progresses rapidly, especially those with significantly increased mononuclear cells. The disease is very serious, and most of them die of bleeding, infection or organ failure before acute change. There is also a lack of an accelerated phase and a transition from a chronic phase to an acute change.

5 Clinical diagnosis of chronic myelomonocytic leukemia 5

1 Chronic myelomonocytic leukemia 1 laboratory test

Blood routine tests are diverse. Often manifested as anemia and increased leukocytes, mainly increased granulocytes and monocytes. The absolute number of peripheral blood mononuclear cells is> 10 × 109 / L, and naive monocytes can appear. Granulocytes often show an increase in mature granulocytes, with or without abnormal development of granulocytes, and immature granulocytes can be seen. Granulocytopenia can also occur in some patients. Most patients have reduced platelets, but some patients have normal or increased platelet counts.

Bone marrow puncture examinations show a large difference in the degree of hyperplasia, most of which are significantly active or extremely active, and there are also patients with low hyperplasia. Granulocytes and monocytes increase. Primordial granulocytes are mostly> 5%, and protolymphocytes are also> 5%, but the sum of the two is <20%. Red and megakaryoid proliferation decreased. All three lines have different degrees of pathological hematopoiesis. The red lines are typically characterized by giant juvenile degeneration, nuclear fragmentation, petal-like nuclei, multinuclear red blood cells, and mature red blood cells basophilic stippling. Granulopathic hematopoiesis is characterized by reduced particles, too few nuclear lobes (P? H malformations), and vacuoles in the cytoplasm. Too many particles are a pathological manifestation with poor specificity. The typical pathological hematopoietic cells of megakaryocytes are small megakaryocytes, lymphoid megakaryocytes, single round nuclear megakaryocytes, and multiple round nuclear megakaryocytes.

Plasma and urine lysozyme levels are almost always high. This lysozyme is secreted by monocytes and is proportional to the number of monocytes in the body.

2 Diagnosis of chronic myelogenous leukemia 2

WHO's diagnostic criteria for CMML have not changed much from FAB. (1) Persistent peripheral blood mononuclear cell increase> 1 × 109 / L; (2) Ph (-), BCR / ABL (-); (3) Peripheral cells in peripheral blood and bone marrow <20%; (4) One or more cell lines in the myeloid line have abnormal development. If there is no developmental abnormality or minimal, but other conditions are met, and the following manifestations are present, CMML can still be diagnosed: bone marrow cells have acquired cytogenetic clones The abnormality, or the increase of monocytes has lasted for more than 3 months, and all causes that can cause monocytes are excluded; (5) If the primordial cells in peripheral blood are <5%, and <10% in BM, the diagnosis is CMML? 1. Peripheral blood blast cells 5% to 19% or bone marrow 10% to 19%, or peripheral blood or bone marrow blast cells <20% and Auer body positive, diagnosed as CMML? 2; (6) meet the above diagnostic criteria and peripheral blood Eosinophils 1.5 × 109 / L were diagnosed as CMML? 1 or CMML? 2 with eosinophilia. (In the diagnosis of CMML, blasts include blasts, blasts, and naive monocytes.) Reposted in China Paper Download Center

3 Differential diagnosis of chronic myelomonocytic leukemia 3

6.1 Myelodysplastic Syndrome (MDS) CMML has been used as one of the classifications of MDS. The clinical manifestations and laboratory results of the two are similar, but the peripheral blood mononuclear cells of CMML increase> 1 × 109 / L.

6.2 Chronic myelogenous leukemia (CML) CML is also one of myeloproliferative diseases. It has the characteristics of bone marrow proliferative diseases, and the degree of bone marrow hyperplasia is mostly active to extremely active, mainly the granulocytes, and the other lines are inhibited. Specific Ph chromosome is positive.

6.3 Atypical chronic myelogenous leukemia (aCML) The so-called atypical CML refers to CML with Ph (-) without bcr? Abl translocation. Peripheral blood leukocytes were normal or decreased, and naive granulocytes increased in blood slices (> 0.15), but no basophils increased. Bone marrow showed active hyperplasia or extreme hyperactivity, with multi-line pathological hematopoiesis, mainly granulocyte hyperplasia, the ratio of grain to red was often <10: 1, eosinophils were normal or increased, but basophils did not increase. It is known that this type of tyrosine kinase inhibitor (STI571, glivec, Gleevec) is ineffective.

6.4 Juvenile granulocytic mononuclear leukemia (JMML) This type is a rare infancy and is more common in infants and young children under 2 years of age. It is a mixed type myeloid cell tumor with dual characteristics of MDS / MPD. Children often have skin manifestations (such as eczema and xanthomatosis). JMML is characterized by marked pathological hematopoiesis of myeloid cells, increased mononuclear cells, and elevated anti-alkaline hemoglobin (HbF). Patients with Ph (-) and no bcr? Abl rearrangement, intramedullary naive and abnormal monocytes, as well as erythroid precursor cell proliferation and erythrocyte production abnormalities are manifested in elevated HbF (0.15 to 0.50), and red blood cells I antigen expression is reduced.

6 Treatment and prognosis of chronic myelomonocytic leukemia 6

All experts agree that the proportion of primitive cells is closely related to the prognosis, the higher the primitive cells, the worse the prognosis. The survival time of this disease is 10 to 60 months, with a median survival period of 20 months. So far, there is no better treatment method that can make patients relieve. For newly diagnosed CMML patients, exploring more meaningful experimental treatment options requires us all to work hard.

7.1 Supportive care In the absence of a better treatment, supportive care is the key treatment of CMML. Most CMML patients are older and often accompanied by other diseases, and supportive care is particularly important. Patients with hemoglobin <10 g / L are regularly infused with concentrated red blood cells based on the symptoms of anemia. When platelets <20 × 109 / L with bleeding symptoms, platelet transfusion is performed, and when platelets <10 × 109 / L, preventive platelet transfusion is performed. Other anti-infection and nutritional support should be used selectively.

7.2 Chemotherapy CMML has obvious pathological hematopoiesis, and most of the hematopoiesis is poor. Most patients cannot tolerate intense chemotherapy, and low-dose chemotherapy may have some effect. Commonly used single-drug treatment programs are: low-dose cytarabine, 5? Azacytidine, homoharringtonine, etoposide, etc. all have certain effects.

Patients with high white blood cells can use hydroxyurea. The dosage of hydroxyurea is 1 to 4 g / d, so that the white blood cells are maintained at a level of (5 to 10) × 109 / L.

It has been reported that the use of topoisomerase I inhibitor topotecan to treat CMML has achieved certain effects. In clinical trials, 25 patients with CMML received topotecan, 2 mg / (m2 · d), continuous intravenous drip for 5 days, and 28% of patients achieved complete remission (CR) with a median remission period of 8 months [6].

7.3 Demethylation treatment Demethylation drugs such as decitabine (decitabine, 5? Azacytosine deoxycytidine, 5? Aza? 2 '? Deoxycytidine) is currently the strongest known DNA A Glycation-specific inhibitors can re-transcribe tumor suppressor genes inactivated by methylation in vivo and induce their expression. Compared with intensive chemotherapy, these drugs usually do not cause serious adverse reactions. Aribi reported [7] that the 19 patients with CMML were treated with the demethylated drug decitabine, 11 patients had a complete response and 2 patients had a partial response, with a total effective rate of 69%. And there were no serious complications. Wijermans et al [8] analyzed the results of three clinical trials. A total of 31 CMML patients participated in the treatment, with an average age of 70.2 years, 71% were male patients, and 8/28 (29%) cases had white blood cell counts> 2 at the time of consultation. 000 / L, 39% of bone marrow blasts> 5% (11/28). The total effective rate was 25% (14% CR + 11% PR), 11% had advanced hematology, and 39% had stable disease.

7.4 Hematopoietic stem cell transplantation can be used in patients <50 years of age with matching donors. Hematopoietic stem cell transplantation is theoretically a possible cure for CMML. However, restrictions such as age limit the number of patients who can be transplanted.

7.5 Other clinical trials of inhibitors of deacetylated histones, such as sodium valproate, have shown satisfactory results. Siitonen et al. [9] reported the use of valproic acid, retinoic acid, and 1,25 dihydroxyvitamin D3. 19 Of the patients with MDS or CMML, 3 were effective and 9 patients stopped treatment within 16 weeks due to side effects.

The response was stopped at 100-200 mg / d and taken orally. About 20% of patients reduced blood transfusion or increased hemoglobin.

In some patients, translocations occur on chromosomes 5 and 12, leading to the appearance of the platelet-derived growth factor receptor gene beta (PDGFR? B) and the TEL gene. The protein expressed by this gene can be inhibited by tyrosine kinase inhibitors such as Gleevec. It has been reported that one patient with CMML and PDGFR? B? TEL gene translocation recurred after hematopoietic stem cell transplantation, and Gleevec was effective. It is suggested that some patients with CMML can be successfully treated with this drug.

But in terms of current medical technology, I am afraid that only bone marrow transplantation can completely cure the disease, which is also the status quo that we need to work hard to change.