4.2 Understanding of Chronic Myelogenous Leukemia in Modern Medicine

4.2 Understanding of Chronic Myelogenous Leukemia in Modern Medicine

Chronic myelogenous leukemia is a malignant clonal disease characterized by chronic proliferation of granulocytic lineage cells, caused by malignant transformation of hematopoietic stem cells. Leukemic cells exhibit the characteristic t(9;22)(q34;q11) chromosomal translocation (Ph chromosome) and the resulting bcr-abl fusion gene abnormality. In recent years, diagnosis and treatment of chronic myelogenous leukemia have made significant progress compared with the past.

4.2.1 Causes and Pathogenesis of Chronic Myelogenous Leukemia

4.2.1.1 Cytogenetics

The cytogenetic hallmark of chronic myelogenous leukemia is the Ph chromosome, where the c-abl proto-oncogene on chromosome 9 translocates to the bcr region on chromosome 22, forming the bcr-abl fusion gene. This gene is transcribed and translated into the bcr/abl fusion protein (P210) activated by high tyrosine kinase activity, and the pathogenesis of chronic myelogenous leukemia is closely linked to the high tyrosine kinase activity of the P210 protein.[4] 90%–95% of CML patients exhibit bcr-abl rearrangement.[5] Research has found that the break site within the bcr gene varies among different CML patients, but most are located within approximately 5.8 kb of the bcr gene, a region known as the Major Breakpoint Cluster Region.[6] Although the number of Ph chromosomes can decrease after treatment, they are difficult to eradicate, making relapse common.

4.2.1.2 G6PD Isoenzyme

The clonal nature of chronic myelogenous leukemia has been further confirmed by studies on G6PD isoenzymes. Currently, the gene encoding G6PD is located on the X chromosome, and among the two G6PD regulatory factors in female somatic cells, only one is active. Studies have shown that among heterozygous female CML patients carrying G6PD isoenzymes, their granulocytes, monocytes, red blood cells, and lymphocytes all express either type A or type B G6PD isoenzymes, further suggesting that the pathology of chronic myelogenous leukemia originates at the pluripotent stem cell level.[7]

4.2.1.3 Cellular Dynamics

Clinical experiments have gradually confirmed that normal hematopoietic stem cells in CML patients usually coexist with pathological hematopoietic stem cells. The total number of granulocytes in CML patients increases, but this increase is not due to rapid division and proliferation of leukemic cells, nor is it caused by maturation disorders; rather, leukemic cells expand through proliferation pools and prolonged presence in the bloodstream, while normal hematopoietic stem cell pools shrink, leading to massive cell accumulation. Even after clinical remission, blood counts can return to normal, but abnormal cell lines still persist.[8]

4.2.1.4 Spleen Factors

The role of the spleen in the pathogenesis of chronic myelogenous leukemia remains unclear. However, numerous experiments and clinical observations indicate that the spleen facilitates the migration, proliferation, and blast transformation of leukemic cells.[9] The spleen gathers large numbers of leukemic cells, providing a favorable environment for their proliferation and metastasis, increasing the cyclical movement of leukemic cells between peripheral blood, bone marrow, and spleen, thereby disrupting the normal regulatory processes of cell release.[10]

4.2.2 Treatment of CML

4.2.2.1 Conventional Drug Therapy

4.2.2.1.1 Hydroxyurea

A drug that specifically inhibits DNA synthesis during the cell cycle, once recommended as the first-line monotherapy for CML, but with poor efficacy in the accelerated phase and virtually no effect in the blast phase.[11]

4.2.2.1.2 Mustard Gas

An alkylating agent, non-specific to the cell cycle, highly effective for most CML patients in the chronic phase, but with obvious adverse reactions such as bone marrow suppression, rash, and pulmonary interstitial fibrosis.[12]

4.2.2.1.3 Interferon

Has been used to treat CML for nearly 20 years, once serving as the first-line treatment for Ph chromosome-positive CML patients who could not undergo allogeneic stem cell transplantation.[13] In the 2006 edition of the NCCN guidelines for chronic myelogenous leukemia treatment, it was downgraded to a second-line drug.[14]

4.2.2.2 Molecular Targeted Therapy

4.2.2.2.1 Imatinib

A synthetically produced, specific tyrosine kinase inhibitor (trade name Gleevec), a derivative of 2-phenylaminopyrimidine, capable of inhibiting the proliferation and anti-apoptotic effects of Ph chromosome-positive leukemic clones, and the first successful targeted drug for treating Ph chromosome-positive CML patients.[15] Recent studies show that it can enhance the antigen-presenting function of antigen-presenting cells and remove T-cell immune tolerance toward tumors.[16] Imatinib achieves remarkably high major cytogenetic responses and complete cytogenetic responses, so many researchers propose using Imatinib as the first-line drug for early-stage treatment of CML.[17]

4.2.2.2.2 Dasatinib It is structurally unrelated to imatinib; it binds to Abl in its active conformation, thereby inhibiting not only Abl kinase but also Src family kinases. It exhibits strong inhibitory activity against most mutant forms of BCR-ABL kinase except T315I, with an inhibitory potency more than 300 times that of imatinib [18]. Moreover, it demonstrates high efficacy and good tolerability in chronic myeloid leukemia patients resistant to imatinib as well as in Ph chromosome-positive acute lymphoblastic leukemia [19].

4.2.2.3 Bone Marrow Transplantation

4.2.2.3.1 Allogeneic Bone Marrow Transplantation (Allo-BMT)

Currently, this remains the only proven curative approach for chronic myeloid leukemia [20]. Most experts recommend allogeneic bone marrow transplantation for patients under 25 years of age regardless of clinical presentation; for those over 25, decisions should be made based on clinical features and the presence of high-risk factors [21]. These high-risk factors include patient gender, age, disease duration, donor source, time from diagnosis to transplantation, pre-transplant treatment, and conditioning regimen [22]. The interval between diagnosis and transplantation is generally recommended to be no more than one to two years. Survival rates are higher in the chronic phase compared to the accelerated or blast phases, with lower relapse rates. The 5-year survival rate for chronic-phase patients undergoing allogeneic bone marrow transplantation exceeds 70% [23].

4.2.2.3.2 Autologous Bone Marrow Transplantation (ABMT)

For patients diagnosed with chronic myeloid leukemia, early mobilization of hematopoietic stem cells followed by autologous transplantation is recommended. These stem cells possess the ability to reconstitute hematopoiesis post-transplantation and exhibit a lower risk of graft-versus-host reaction compared to allogeneic bone marrow transplantation [24].