Leukemias are a group of highly heterogeneous malignant hematologic diseases that consist of multiple independent disease entities. The disease originates from genetic mutations and clonal proliferation of hematopoietic stem cells, in which the leukemic cells in the clone lose the ability to further differentiate and mature and stagnate at different stages of cell development. Leukemia cells accumulate in the bone marrow and other hematopoietic tissues in large numbers, resulting in the suppression of the growth of normal blood cells of all three lineages and infiltrating all organs and tissues in the body, causing a series of symptoms. The development of leukemia, like other tumors, is a multifactorial, multigene, multistep, multistage and very complex biological phenomenon. Acute leukemia is the result of the accumulation of genetic mutations in hematopoietic stem and progenitor cells under the blow of multiple pathogenic factors, and the stem and progenitor cells eventually change malignantly into leukemic stem cells with self-renewal ability and proliferation and survival advantages. The cytogenetic and epigenetic studies of leukemia have made great progress in recent years, and some molecular markers have provided us with new differential diagnosis methods and basis for prognostic judgment. In the new WHO (2008) classification scheme for tumors of hematopoietic and lymphoid tissues, more reproducible cytogenetic abnormalities have been classified as separate leukemia types. A series of new drugs targeting certain genetic abnormalities have also emerged, opening up new avenues of treatment for leukemia. With advances in molecular genetics, leukemia treatment collaborative groups around the world have provided new guidelines for the diagnosis and treatment of leukemia, and these guidelines provide strong evidence for the clinical treatment and prognosis of leukemia.
MICM (morphology, immunology, genetics and molecular biology) of leukemia remains the main tool to improve the accuracy and consistency of leukemia diagnosis. Blood cell morphology and histochemical staining are the basis of leukemia diagnosis; therefore, FAB typing remains the most basic and commonly used diagnostic method to diagnose acute leukemia. Immunotyping of leukemia is an important supplement and further deepening of morphological typing, which is of great significance for the diagnosis of leukemia. The most recent WHO classification scheme classifies leukemias according to cytogenetic or molecular genetic abnormalities and has become an important component of the overall clinicopathogenetics of leukemia. AML). The survival of patients with a primitive cell ratio of 0.20 to 0.30 has been shown to be very similar to that of those with a primitive cell ratio of ≥0.30, indicating that the disease is already acute in nature and that the prognosis may be better if the disease is treated as early as possible. Other differences include separate classification of several types of AML with recurrent cytogenetic translocations in the WHO protocol; separate classification of AML with multilineage proliferation abnormalities; separate typing of treatment-related AML; WHO also follows the FAB typing criteria for AML into a separate category (AML non-specific types), in which only the M0, M1, M2, M4, M5, M6, and M7 are listed The WHO classification of these unique cytogenetic abnormalities in leukemia is important for understanding the nature of the disease, developing treatment plans and determining the prognosis. The NCCN guidelines have risk stratification to guide treatment and prognosis. The new WHO classification for acute lymphoblastic leukemia (ALL) eliminates the morphological criteria of FAB and explicitly includes lymphoblastic lymphoma (LBL) and ALL in the same disease diagnosis, i.e. LBL/ALL, with LBL and ALL considered as different manifestations of the same disease. B lymphoblastic leukemia/lymphoma is subdivided into those with recurrent genetic abnormalities and those with non-specific types. Immunological typing is of great significance in guiding treatment. Immunological typing can truly reflect the stage attributes of leukemic cell differentiation and development in ALL patients, and is also meaningful for prognosis determination.
Complete remission (CR) rates, disease-free survival (DFS) and overall survival (OS) rates in acute leukemia have been significantly improved in the last four decades due to the adoption of differentiation-inducing agents in the treatment of acute promyelocytic leukemia (APL), improved remission-inducing regimens, high-dose combination chemotherapy and hematopoietic stem cell transplantation for post-remission treatment, and enhanced supportive therapies. However, some patients still fail to achieve CR in both AML and ALL, many patients still relapse in CR cases, and relapsed and refractory cases do not remain in remission for long even if they obtain remission, and even patients who undergo HSCT are at risk of relapse. All these reveal to us the necessity of further improving the therapeutic effect of acute leukemia. The treatment of APL with vincristine and arsenic is a major innovation in the history of AML treatment, changing the previous concept of relying solely on chemotherapy to try to “completely kill” the leukemia cells, and now the CR rate of APL has reached over 90%, and the 5-year OS rate of alternate maintenance treatment with vincristine, arsenic and chemotherapy has reached over 80%. The treatment of acute leukemia is a systemic project, and in addition to anti-leukemic therapy, supportive therapy and management of complications are important to achieve the desired outcome. Effective prevention and treatment of hyperleukocytic leukemia, central nervous system leukemia, acute tumor lysis syndrome, and retinoic acid treatment-related syndrome are also extremely important factors affecting the prognosis of leukemia. The choice of induction remission regimen differs between non-APL and APL. At this stage, the treatment of non-APL acute leukemia is still based on combination chemotherapy, which is individualized, standardized and empirical based on evidence-based medicine. In recent years, it is believed that desoxorubicin (IDA) + ara-C and VDLP (vincristine, erythromycin, levomeperidine, prednisone) are one of the best regimens for induction of remission in AML and ALL, respectively, and treatment response is an important prognostic factor, according to which the treatment regimen must be dynamically adjusted. For induction chemotherapy in adults with ALL, more emphasis is placed on the use of MICM staging to develop a stratified treatment plan. Combination, high dose and early intensification are the basic principles of treatment after remission. It is currently considered appropriate to consolidate either AML or ALL with medium or high dose Ara-C or methotrexate (MTX), HyperCCVAD/MA (hyper-segmented CTX, VCR, ADR, DXM/ HDMTX, Ara-C) for Burkitt’s lymphoma/leukemia and mature B- ALL, and high-dose Ara-C, high-dose MTX and high-dose CTX greatly improved the prognosis of T-ALL. Imatinib + VDLP resulted in a high CR rate in adults with Ph+ ALL. CAG (arabinosin, Ara-C, G-CSF) prestimulation regimens are suitable for older age or secondary AML. microscopic residual disease (MRD) monitoring during CR can predict relapse early and is an important guide to determine the intensity of therapy and treatment approach after remission. Relapsed, refractory leukemia has a low remission rate and an extremely poor prognosis, with primary and secondary drug resistance being the main causes. High-dose Ara-C combination chemotherapy, FLAG±IDA (fludarabine, Ara-C and G-CSF±IDA) has been used for relapsed, refractory leukemia treatment with some efficacy. Resistance reversal agents, modulators of chromosomal remodeling, cell signaling inhibitors, anti-angiogenic therapy, immunotherapy and leukemia-targeted therapy are being investigated for the treatment of refractory, relapsed leukemia. Important progress has been made in the treatment of chronic granulocytic leukemia (CML), and the application of imatinib has opened up a new era in the treatment of CML. Imatinib is a targeted therapy drug specifically targeting BCR-ABL tyrosine kinase and was approved by the FDA in 2001 for the treatment of patients with Ph+ chronic phase CML resistant to interferon or in accelerated or acute phase. However, some patients develop primary or secondary resistance to imatinib, and there are already second-generation dasatinib, nilotinib and third-generation small molecule tyrosine kinases that have entered clinical trials and can be expected to bring hope to patients with imatinib resistance. For chronic lymphocytic leukemia (CLL) requiring treatment, chemotherapy can improve signs and symptoms but does not prolong survival or cure the disease. The drugs commonly used are nitrogen mustard phenylbutyrate and fludarabine, in combination with or without rituximab. Fludarabine in combination with cyclophosphamide is currently an effective regimen for the treatment of relapsed refractory CLL.
Over the past decades, as research on hematopoietic stem cell transplantation (HSCT) has intensified, people have gained a more rational understanding of its principles, and HSCT has made important and profound developments in many aspects, including the source of hematopoietic stem cells, the scope of transplantation applications, transplantation strategies and methods, detection systems and immunotherapy. Currently, allo-HSCT should be performed as early as possible for high-risk AML. For APL, most scholars advocate that allo-HSCT should be considered only for those with CR2 stage and positive MRD test. It should be clear that allo-HSCT is still the only method to cure CML, and the efficacy of allo-HSCT is optimal within 1 year of diagnosis, while the efficacy of transplantation decreases significantly when it progresses to accelerated and acute stages. Nearly 85% of allo-HSCTs performed to date are allogeneic transplants, which is the most used and most mature allogeneic transplantation modality. For patients without HLA-allogeneic siblings, HLA-allogeneic non-blood donor HSCT (URD-HSCT) is also a major option, especially with the rapid expansion and effective operation of the bone marrow donor registry in recent years, and advances in HLA high-resolution genetic matching technology, making URD-HSCT increasingly another important transplantation option, with the maturation of the URD-HSCT technology in recent years. system has matured, URD-HSCT has also achieved efficacy close to that of sibling allogeneic HSCT. In addition, another potential advantage of URD-HSCT is that it may have a stronger GVL effect than related URD-HSCT with a low recurrence rate after transplantation. Haploidentical HSCT is currently a highly promising direction for allogeneic transplantation. The higher incidence of severe GVHD and graft rejection rates and lower OS rates relative to sibling allogeneic donor transplantation have been the main factors affecting the success of haploidentical HSCT, and G-CSF mobilized bone marrow + peripheral blood stem cell transplantation alleviates the incidence of severe GVHD and improves the success rate of haploidentical HSCT . Non-cleared marrow HSCT has reduced non-relapse mortality after transplantation due to its reduced hematologic toxicity and expanded the target population and indications for allogeneic transplantation, but its relative advantages are partially offset by reduced pretreatment intensity and post-transplantation immunosuppressive applications for leukemic relapse and high infection mortality, so there are still several aspects of non-cleared marrow HSCT that need improvement and refinement. Umbilical cord blood stem cell transplantation (UCBT) is characterized by lower incidence and severity of GVHD and low HLA matching requirements (1-2 or even 3 antigenic loci can be implanted), but it is also noted that it contains a lower number of nucleated cells, and in adult, large-weight patients UCBT leads to low implantation rates and partially limits its clinical application. The success of UCBT in large-weight adults with double cord blood in recent years foresees that the continuous optimization of UCBT efficacy will make it a transplantation direction with a wide scope for development.