Chronic granulocytic leukemia (CML) is a malignant stem cell disease with a clinical course divided into chronic (CP), accelerated (AP), and acute (BC) phases. Traditional therapeutic agents include hydroxyurea (HU), methylisatin, interferon (IFN), low-dose cytarabine (Ara-C), and hypertriglycerides (HHT). The success of IM has also put hematopoietic stem cell transplantation in a relatively “second-line” position among CML treatment options. The success of IM has also put HSCT in a relatively “second-line” position among CML treatment options. However, with the increasing clinical use of IM, drug resistance is becoming a prominent issue, and the monitoring of the efficacy of IM treatment, prognosis and new treatment options as well as new tyrosine kinase inhibitors (TKI) deserve attention. Meanwhile, advances in transplantation techniques and protocols have led to an expansion of the applicability of stem cell transplantation in the treatment of CML. CML is a more common malignant hematologic disease in elderly patients, and because of their advanced age, relatively poor general health and organ reserve capacity, and the increased likelihood of comorbidity with other diseases with increasing age, the drug treatment options and transplantation choices for elderly CML Therefore, the treatment of elderly CML needs more consideration in drug treatment options and transplantation choices. I. Traditional drug therapy (a) Hydroxyurea and methylisoindigo Hydroxyurea or methylisoindigo can control the symptoms of patients in the chronic phase and can lead to hematological remission in about 80%; of patients, with a 4-year survival rate of about 50%; and a 10-year survival rate of about 10%;. The combination of hydroxyurea, which has a rapid onset of action, and methotrexate, which is more effective in shrinking the spleen, may be more effective than monotherapy depending on the patient’s condition. Both hydroxyurea and methisoindigo do not allow patients to achieve complete genetic remission, fundamentally, nor do they stop or reverse the direction of disease progression, and are ineffective in patients in the accelerated and acute phases. (ii) Hypertrichophylline Hypertrichophylline is a plant base with myelosuppressive activity. 2.5 mg/m2?d applied continuously for 14 days to induce remission followed by 7 days of monthly maintenance can result in complete hematologic remission in 72%; of patients with advanced chronic phase, with major genetic remission in some patients (15%;) and even complete genetic remission in a few patients (7%;). HHT combined with low-dose Ara-C therapy can also be tried in patients with advanced chronic phase or accelerated phase who have failed interferon therapy; combined chemotherapy does not necessarily significantly improve hematologic or genetic remission rates, but has the potential to improve long-term patient survival. (iii) Interferon A study at the M.D. Anderson Cancer Center in the early 1990s showed that the application of recombinant IFN-a for CML induced a complete hematologic response (CHR) in 70% to 80% of patients and a major genetic response (MCyR) in 30% to 40% of patients, with 20% to 25% of patients achieving a complete genetic response (CcyR). genetic response (CcyR).In 1998 the Italian CML Treatment Collaborative Group reported the results of a group of 322 long-term prospective randomized controlled studies comparing the efficacy of interferon treatment (218 patients in the IFN-a group) with Hu or Bu treatment (104 patients in the chemotherapy group). The results showed that the median survival and 10-year survival rates were 104 months and 47% in the low-risk group and 64 months and 30% in the chemotherapy group, respectively; the median survival and 10-year survival rates were 69 months and 16% in the IFN group and 46 months and 5% in the chemotherapy group, respectively; and the MCyR rate was 28% in the IFN group and 0 in the chemotherapy group. The results showed that the IFN group was significantly better than the chemotherapy group, further confirming the efficacy of IFN in CML. Subsequent studies in other European countries also confirmed that IFN was significantly more effective than conventional chemotherapy and could prolong survival, especially in the low-risk group of patients who obtained CCR may achieve long-term survival. Studies have shown that there is no significant difference in genetic response rate and acquisition time between moderate doses of interferon 2.5 mU/m2?d and high doses of interferon 5.0 mU/m2?d, while high dose interferon therapy is less tolerable. Therefore, interferon therapy is usually used at moderate doses, and patients who are ineffective or cannot tolerate it may be considered for other treatments. Patients treated with interferon should continue interferon maintenance therapy after hematologic remission is achieved and should not be discontinued unless the hematologic response is lost or not tolerated. IFN can also be combined with Hu, low-dose Ara-C, and HHT depending on the patient’s condition with better efficacy than IFN alone; and among the various combination regimens, IFN combined with low-dose Ara-C + HHT may have better efficacy than IFN combined with HHT and others. In addition, most scholars have now agreed that the application of IFN before HSCT does not affect the transplantation outcome. Imatinib and new tyrosine kinase inhibitors (a) Imatinib Imatinib (IM) is a highly effective tyrosine kinase inhibitor, which can selectively inhibit BCR/ABL tyrosine kinase activity, and its introduction and clinical application is a milestone for CML treatment, making CML treatment enter the “Imatinib era”. The introduction and clinical application of IMATINIB is a milestone for CML treatment, bringing CML treatment into the “Imatinib era”. Foreign multicenter prospective trials have confirmed that the hematological remission rate and genetic remission rate of IM treatment for patients with primary CML in chronic phase are significantly better than those of interferon+Ara-C treatment group, with high quality of life and prolonged progression-free survival time of patients. The CyR rate at 18 months was 87%; and the CyR for IM as first-line treatment was 81%. In the IRIS trial, the 5-year MCyR was 66% and the CCyR was 55% for patients who were intolerant of IFN or failed IFN and started IM therapy in the “late chronic phase”. . This reflects the good “salvage” effect of IM in these “chronically advanced” patients, but also indicates that the long-term effect of “salvage” treatment is relatively poor compared with standard first-line IM treatment. The long-term effects of “salvage” therapy are relatively poor compared to standard first-line treatment for IM. Based on large series of clinical trials such as IRIS, imatinib has become the first-line treatment for CML in the NCCN and European LeukemiaNet guidelines. The observation of 95 patients with CML treated with imatinib in our center is closer to the data of IRIS, indicating that IM is more effective in treating the chronic phase of CML; also IM can improve patient survival to some extent in treating CML in the accelerated and acute phases. Our observations further suggest that IM as a first-line treatment, used in the chronic phase of CML, improves patient survival significantly better than as replacement therapy or used in the accelerated or acute change phase, and therefore IM should be clearly used as the first-line treatment of choice for patients in the chronic phase of CML. Early experiments have demonstrated that the intensity of IM exerting tyrosine kinase inhibitor effects is positively correlated with intracellular drug concentrations. To ensure that the intracellular drug concentration is higher than the required minimum concentration, a dose of IM below 300 mg/d is not recommended. In general, the recommended dose is 400 mg/d for patients in the chronic phase and 600 mg/d for patients at high risk; the recommended dose is 600-800 mg/d for patients in the accelerated or acute phase. If the previous discontinuation period is not more than 2 weeks, the original dose of IM will be restored; if the discontinuation period is more than 2 weeks, the dose will be reduced by 1/4 to 1/3 when IM is given again; hematocrit in patients in the accelerated or acute phase is often associated with the progression of the disease, so attention should be paid to supportive therapy while trying not to reduce the dose easily. ② Abnormal liver function: stop the drug when the liver function is abnormal at CTC grade 2 or above; IM reduce the dose and re-given when the liver function recovers to grade 1 or better. Patients who have obtained a complete molecular response (CMoR) may have their IM dose reduced to 300 mg/d maintenance therapy under the condition of regular microresidual leukemia (MRD) monitoring; conversely, if there is a loss of previously obtained molecular or genetic response during therapy or if there is a trend toward higher BCR-ABL transcripts in patients detected by quantitative PCR (RQ-PCR), both IM doses should be increased. With the widespread use of IM, the issues of IM efficacy monitoring, prognosis determination, and the determination of and response to drug resistance deserve attention. Patients with chronic-phase CML treated with IM should undergo a basic assessment before treatment, including bone marrow morphology, cytogenetics, and RQ-PCR for baseline BCR-ABL. Some foreign scholars have suggested that Sokal and Hasford prognostic score grouping can be used for basic clinical assessment, and additionally IC50imatinib, organic cation carrier-1 (OCT-1) mRNA levels and gene expression maps are baseline assessment tests that are to be further confirmed and may predict response. Currently, RQ-PCR and routine karyotyping are the most widely accepted tests for efficacy monitoring and prognosis. the IRIS trial observed that 40% of patients achieved MMoR at 12 months, and MMoR at 12 months was strongly correlated with 100% conversion-free survival at 60 months; long-term molecular monitoring found that approximately 25% to 30% of patients did not achieve MMoR after 60 months of treatment and that 10%; to 15%; of CML patients have disease progression. This suggests that early treatment response is important in assessing prognosis. RQ-PCR testing is recommended at least every 3 months after patients start IM therapy. This facilitates the early detection of patients who have responded poorly to IM but could benefit from increasing the IM dose or switching to other treatments, and facilitates the detection of patients with early acquired drug resistance. Patients with advanced chronic phase may be further screened for cytogenetic testing and BCR-ABL kinase structural domain (KD) mutations. Patients should undergo bone marrow cytogenetic testing at least every 6 months until they obtain a major molecular response (MMoR). Patients who obtain a CMoR may undergo RQ-PCR every 6 months. Once there is a loss of treatment response or a trend toward increased BCR-ABL transcripts, the interval between RQ-PCR and genetic testing should be shortened, and screening for KD mutations is desirable. IM drug resistance can be broadly classified into two categories: primary and secondary resistance. Primary resistance is defined as the inability to obtain a defined response; secondary resistance is defined as once obtained but later loss of relevant response, such as loss of genetic or hematologic response and progression of disease from chronic to progressive stage. The more accepted criteria are: failure to obtain a hematologic response at 3 months of IM therapy, failure to obtain a genetic response at 6 months, failure to obtain an MCyR at 12 months, and failure to obtain a CcyR at 18 months. the main causes of IM resistance include the presence of BCR-ABL kinase domain (KD) mutations and clonal evolution of leukemic clones. Some of these patients may be effective on high-dose IM therapy, while others may require second-generation ABL kinase inhibitors or allogeneic stem cell transplantation. Whatever second-line therapy is chosen should be selected before disease progression to AP or BC. Once the disease has progressed, second-line therapy is difficult to achieve long-term efficacy. (ii) New tyrosine kinase inhibitors 1. Nilotinib Nilotinib (NI) is an aminopyrimidine, which is an IM derivative. Like IM, NI binds to the structural domain of ABL kinase in the non-activated state, but binds more efficiently, has a lower binding requirement, and is 25 times more effective than IM. The drug is useful for multiple IM resistance mutations. myelosuppressive side effects were more pronounced with NI than with IM, with grade 3-4 hematologic toxicities observed in the trial; the most common grade 3-4 non-hematologic toxicities were rash and hyperbilirubinemia. The dose used in the phase II trial of nilotinib was 400 mg BID. 69% complete hematologic response (CHR); and 32% CCyR; in patients with IM refractory/intolerant chronic phase. 2. Dasatinib Dasatinib (DA) is a tranylcypromine, which binds to the structural domain of the activated state ABL kinase and also inhibits SRC family kinases. Preclinical studies have shown that this drug is 300 times more potent than IM. The drug is effective against the majority of IM resistance mutations, but like NI, neither drug is effective against T315I mutations.DA was first introduced into the clinic in November 2003.No dose-limiting toxic reactions were observed in phase I trials.The myelosuppressive side effects of DA were more pronounced than those of IM, with most patients experiencing grade 3-4 hematologic toxicity; the most common grade 3-4 non-hematologic toxic reaction was pleural effusion.DA was used in In phase II trials, the recommended dose is 70 mg BID. DA is effective in treating IM-refractory/intolerant patients with all stages of CML and Ph+ ALL, and is also effective in some NI-refractory patients. DA treats IM-refractory/intolerant patients with chronic stages CHR 90%;, CCyR 40%;; accelerated/acute change patients CHR, CCyR 30%; around; Ph+ ALL patients CHR 33%;, CCyR 44%;. The results of both NI and DA treatment in the chronic phase are encouraging, resulting in a sustained hematologic response in most patients and enabling MCyR, one-third CCyR in about half of the patients. the efficacy of salvage therapy with both drugs in the progressive phase is more limited, especially in Ph+ ALL, which often relapses early. 3. other MK-0457/VX-680 is a small molecule aurora kinase (AK) inhibitor, preclinical studies have demonstrated its significant anti-leukemic effects, and in vitro experiments have found that MK-0457/VX-680 can overcome a variety of BCR-ABL mutations, including T315I. first applied in clinical trials in 2006, three cases In 2006, MK-0457/VX-680 was first used in clinical trials, and three patients with CML or Ph+ ALL with T315I mutation achieved clinical efficacy without significant side effects. ON012380 is a non-ATP-competitive Bcr-Abl kinase inhibitor with Bcr-Abl T315I activity, and is one of the drugs of interest in overcoming T315I, but has not yet been reported for clinical use. III. Hematopoietic stem cell transplantation (a) Autologous hematopoietic stem cell transplantation Patients with autologous hematopoietic stem cell transplantation have a low cytogenetic response rate, cannot eliminate malignant clones, and have a high risk of relapse after transplantation. Even if imatinib is given first to obtain CCyR followed by autologous transplantation, it will only slightly improve the 3-5 year survival rate of patients undergoing autologous HSCT in the chronic phase to achieve an effect close to that of allogeneic HSCT, but longer-term follow-up will show a significantly lower survival curve for autologous HSCT due to late relapse. The efficacy of autologous transplantation for the progressive phase is poor. The application of stem cells harvested in the chronic phase for transplantation in the acute phase has a duration of only 4 months into the 2nd chronic phase and a 1-year survival rate of less than 30%;. (ii) Allogeneic hematopoietic stem cell transplantation Allogeneic stem cell transplantation (allo-SCT) can eradicate Ph chromosome-positive cell clones and become the only means to cure CML, and was the first-line treatment option for CML before IM was applied in the clinic. after IM was widely used in the clinic, allo-SCT was placed as the first-line treatment option for CML because the early and mid-stage efficacy of IM for primary CML was good enough. second- or even third-line treatment. The 5-year disease-free survival rate of conventional allogeneic HSCT for patients in the chronic phase, especially in the first chronic phase (CP1), is up to 80%; or more, compared to 40%; and less than 20%; for patients in the accelerated and acute phases, respectively. The main factor affecting post-transplant survival is post-transplant complications, followed by CML recurrence. Elderly patients undergoing allo-SCT also face problems of recipient age limitation and scarcity of suitable donor sources. Reduced dose pretreatment transplantation (RICT) is a transplantation modality that has received a lot of attention in recent years. the realization of RIC transplantation is attributed to an allogeneic immune response. the RICT relies more on the GVL effect than on the antitumor effect of chemotherapy for disease control. in 1998 RICT accounted for less than 1% of total transplantations in Europe, but this value increased to 31% in 2003-2004. Most of the data reported by RICT show that TRM reduces and brings the risk of transplantation to an acceptable range in older patients, and the patient age range is extended by 10-15 years, making it more suitable for older patients than conventional clearing transplantation. According to EBMT, the 3-year OS and DFS of RICT are comparable to those of conventional allo-SCT. In fact, the efficacy of RICT reported in recent years is generally better than that of concurrent clear marrow transplantation. 2007 M.D. Anderson Cancer Center reported the results of long-term follow-up (median 7 years) of RICT for 64 progressive CML (80%; for non-CP1 transplants) with 7-year OS and PFS of 33%; and 20%; and 5-year treatment-related mortality of 48%; respectively. . This long-term follow-up result was not weaker than conventional clear marrow transplantation, and no increased rate of late relapse after transplantation was observed. MRD testing after allogeneic transplantation is important. High-risk patients should be more closely monitored for changes in BCR-ABL transcript levels post-transplantation. Prompt intervention should be given to patients with signs of relapse. The current trend is that donor lymphocyte infusion (DLI) is still the “gold standard” of interventional therapy, but the rational use of IM allows for safer timing and dosing of DLI, thus improving overall patient survival. Treatment selection The treatment of elderly CML should be individualized according to all aspects of the patient’s condition. For patients of advanced age and poor economic status, hydroxyurea, methylisatin or interferon can be given, and patients in the progressive stage can be treated with intermittent application of low-dose chemotherapy such as low-dose HHT, Ara-C or combined with IFN. For these patients, it is not necessary to pursue remission rate unilaterally, but attention should be paid to improving patients’ symptoms and quality of life because of the heterogeneity of CML, and the duration of survival with tumor in some older patients is also close to natural life expectancy. Patients who are eligible should then be treated aggressively and standardized. After performing diagnosis and baseline evaluation, IM is given as first-line treatment, and if genetic remission is obtained, IM is given as maintenance treatment under the condition of regular MRD monitoring. For patients with ineffective IM or treatment failure, high-dose IM trial therapy is not recommended due to relatively poor tolerability in the elderly, and treatment with second-generation tyrosine kinase inhibitors (TKI) such as nilotinib and dasatinib is recommended instead. If results are achieved, the treatment is maintained. For patients with suitable donors who are eligible for transplantation, RICT may also be performed after failure of IM therapy, or second-generation TKI therapy. for patients who are not eligible for transplantation, if IM or second-generation TKI therapy fails, a trial of low-dose chemotherapy or other new drugs may be substituted.