Disease Introduction
Chronic myelogenous leukemia (CML) is a clonal disease characterized by an increase in peripheral blood neutrophils with various stages of naïve granulocytes, increased basophils and splenomegaly, and originates from pluripotent hematopoietic stem cells. The disease begins with a long-lasting chronic phase (CP), progresses to a short accelerated phase (AP), and eventually evolves to an acute phase (BP). Leukemic cells have a characteristic t(9;22)(q34;q11) chromosome translocation to form the Ph chromosome. The annual incidence of CML is about 1/100,000 of the population and accounts for about 15% to 20% of adult leukemias, with a male:female ratio of about 1.4:1. The pathogenesis of CML is based on the t(9;22)(q34;q11) chromosome translocation resulting in the formation of a BCR fusion between the ABL gene located in the 9q34 break region and the BCR gene in the 22q11 break region. The formation of a BCR-ABL fusion gene, the latter with extremely high protein tyrosine kinase activity, activates a variety of signaling pathways by altering the phosphorylation status of some key regulatory proteins, such as increasing the number of progenitor cells and reducing the stem cell pool by activating the Ras signaling pathway involved in the regulation of cell proliferation and differentiation, and stem cells become part of the proliferating pool, resulting in the continuous expansion of immature granulocytes.
Another mechanism of action of BCR-ABL is to cause defective cell adhesion function of CML cells by interfering with the function of β1 integrin, causing immature cells to release into the peripheral blood and migrate to extramedullary sites. In addition, BCR-ABL can lead to continuous expansion of myeloid cells by inhibiting apoptosis. Approximately 20% to 40% of patients with CML are diagnosed asymptomatic and are detected by routine blood tests. Common manifestations include fatigue, decreased work force, abdominal discomfort and stomach fullness, weight loss, and excessive sweating. The general condition deteriorates significantly after the acute phase, with symptoms associated with severe anemia, thrombocytopenia and significant splenomegaly. With advances in treatment, the median survival of patients with this disease is now 5 to 7 years. Qiu Huiying, Department of Hematology, The First Hospital of Soochow University
Diagnostic points]
The diagnosis of chronic phase of CML is not difficult. The diagnosis can be established based on clinical manifestations, where there is an unexplained persistent increase in white blood cell count, typical blood and bone marrow picture changes, reduced or negative neutrophil alkaline phosphatase score, splenomegaly, and positive bone marrow cells with Ph chromosome and/or BCR/ABL fusion gene. The diagnosis should be followed by accurate staging. Prognosis and choice of treatment options are closely related to the stage of disease.
The entire course of chronic leukemia is divided into three phases: chronic phase, accelerated phase and acute phase. The key points of diagnosis for each stage are as follows.
(i) Chronic phase.
1. Splenomegaly, which may be accompanied by fever, malaise, anorexia, weight loss, etc.
2. Blood picture: significant increase in white blood cells (>30×109/L), mainly medium- and late-stage granulocytes and rod-shaped granulocytes, primitive cells <10%, increased acidophilic and basophilic granulocytes, and a small number of nucleated red blood cells can be seen.
Bone marrow picture: bone marrow proliferation is obvious to extremely active, mainly granulocytosis, with an increase in medium- and late-stage granulocytes and rod-shaped nuclei, and primitive cells <10%.
4.Neutrophil NAP score is significantly reduced or negative.
5, Positive Ph chromosome and/or positive BCR/ABL fusion gene.
6, Significant increase in CFU-GM colonies or clusters.
(ii) Diagnostic points of accelerated phase: Diagnosis can be made with one or more of the following
1, 10-19% of primitive cells in peripheral blood or bone marrow.
2.Periodic blood basophils ≥20%.
3, Persistent thrombocytopenia (<100×109/L or persistent thrombocytosis (>1000×109/L) that is not related to treatment.
4. Progressive splenomegaly and leukocytosis with ineffective treatment.
5. Cytogenetic evidence of clonal evolution (i.e., presence of additional genetic abnormalities not present at the time of initial diagnosis in the chronic phase of CML).
6. Patches and clusters of megakaryocyte proliferation with significant reticulocyte sclerosis or collagen fibrosis, and/or significant granulocyte developmental abnormalities should be considered suggestive of accelerated CML. These manifestations have not been analyzed in large series of clinical studies, and thus it is not clear whether they are independent diagnostic criteria for accelerated CML, but they are often seen in conjunction with one or more of the features listed above.
(C) Acute phase: Acute phase can be considered when one of the following is present
1. Primitive cells in peripheral blood or bone marrow >20%.
2. Extramedullary primitive cell infiltration.
3.Bone marrow biopsy shows large foci or clusters of primitive cells.
Treatment]
The efficacy of CML is judged by hematological remission, cytogenetic remission (i.e., disappearance rate of Ph+ cells) and molecular biological remission (i.e., rate of BCR-ABL fusion gene conversion) (Table 4-1-1). Since these three different levels of remission are significantly correlated with the survival of CML patients, the main objective of modern CML treatment is how to improve the remission rate of the latter two and strive for long-term patient disease-free survival.
Table 4-1-1 Criteria for determining the efficacy of CML
Efficacy level Definition
Complete hematologic remission Blood cell count is completely normal, and white blood cell <10×109/L, platelet <450×109/L, white blood cell classification count is normal, no extramedullary leukemia manifestation
Partial hematological remission Except ① peripheral blood leukocyte classification count can be seen naive cells, ② platelets >450×109/L but decreased by 50% compared with before treatment, ③ there is still splenomegaly but decreased by 50% compared with before treatment, the rest is the same as complete hematological remission
Microcytogenetic remission Ph-positive cells 35%-90%
Partial cytogenetic remission Ph-positive cells 1%-34%
Complete cytogenetic remission (CCR) Ph-positive cells 0%
Significant cytogenetic remission (MCR) Ph-positive cells 0% to 35%
Significant molecular remission (MMR) BCR-ABL mRNA levels reduced by ≥3 logarithmic steps
Complete molecular remission (CMR) BCR-ABL negative by RT-PCR
1. conventional treatment CML is often hyperuricemic at the time of presentation or relapse; therefore, allopurinol (allopurinol), 300 mg/d, should be given orally before treatment and adequate rehydration to maintain urine output; if the patient has risk factors for massive cytolysis, the amount and frequency of allopurinol administration should be increased and the urine output should be maintained at 150 ml/h. Since allopurinol can develop Because allopurinol can cause allergic dermatitis, it should be discontinued after the white blood cell count has decreased to normal, splenomegaly has decreased significantly, and there is no significant hyperuricemia.
Gleevec, also known as STI-571 (Signal transduction inhibitor-571), is a competitive inhibitor of the BCR-ABL fusion gene tyrosine kinase. A total of 83 patients with chronic phase I CML who had failed interferon therapy were treated in 14 dose groups ranging from 25-1000 mg/d. The results confirmed that the lowest dose for maximum clinical efficacy was 300 mg/d. Of the 54 patients who received 300 mg/d or more, 53 (98%) achieved complete hematologic remission (CHR) and 31% achieved significant cytogenetic remission (MCR). Encouraged by these results, 58 patients with slow-onset acute or Ph+ acute leukemia were treated with doses of 300 mg-1000 mg/d, and 55% (21/38 patients) of patients with CML acute and 70% (14/20 patients) of patients with Ph+ ALL achieved hematologic efficacy.
The results of pharmacokinetic studies showed that the in vivo potent drug concentration (1 μM) was achieved at a dose of 300 mg, and the steady-state peak concentration was 4.6 μM at a dose of 400 mg, followed by a maintenance concentration of 2.13 μM and a half-life of 19.3 hours, suggesting that once-daily dosing is sufficient. Subsequently, 454 patients with CP CML, 181 patients with AP CML and 229 patients with BP CML entered phase II clinical trials with complete hematologic remission rates of 91%, 69% and 29%, respectively, and significant cytogenetic remission rates of 55%, 24% and 16%, respectively. the drug was approved for marketing by the US FDA on May 10, 2001.
The results of the Phase III International Randomized Study (IRIS) of interferon and STI571 showed that STI571 as first-line treatment for newly diagnosed CML CP patients was better than interferon + low-dose cytarabine in terms of hematologic and cytogenetic efficacy, treatment tolerability, and potential conversion to AP and BC, with follow-up to 42 months. Patients treated with STI571 as first choice had a CHR of 98%, MCR of 91%, complete cytogenetic remission (CCR) of 84%, and progression-free survival (PFS) of 94%. The latest follow-up results suggest that.
(i) Imatinib is well tolerated and effective for long-term treatment of primary CML;
(ii) The best cumulative MCR and CCR at 54 months of treatment were 92% and 86%, respectively;
(iii) 97% of patients with CCR at 12 months of treatment did not progress to the accelerated/acute phase within 54 months;
(iv) 100% of patients who achieved BCR-ABL ≥ 3-log reduction within 12 months of treatment did not progress to the accelerated/acute phase within 54 months;
⑤ <1% of patients who received Gleevec initially progressed to AP/BC at year 4, a lower rate of progression than in each of the previous 3 years;
⑥At month 54, more than 90% of patients subsequently assigned to the imatinib arm survived, and patients who achieved CCR with imatinib had a long-term benefit, even those in the high-risk group with Sokal scores;
STI571 has now replaced interferon as the standard drug of choice for treatment of patients with all stages of CML. 2009 edition of the NCCN CML treatment guidelines for initial treatment of CML are only available for Gleevec and clinical trials.
The recommended dose of Gleevec in the chronic phase of CML is 400 mg/d. Complete blood counts and leukocyte sorting, cytogenetics, and quantitative RT-PCR monitoring should be performed periodically during Gleevec treatment (Table 4-1-2), and dose increases from 400 mg/d to 600 mg/d or from 600 mg/d to 800 mg/d should be considered for the following conditions.
① Disease progression;
② Complete hematologic remission has not been achieved after 3 months;
③ No major cytogenetic remission at 6 months;
④ Complete cytogenetic remission not achieved at 12 months;
⑤ Loss of previously achieved hematologic or cytogenetic remission. The main prognostic factors affecting the efficacy of Gleevec were the pre-treatment patient Sokal score and cytogenetic outcome. Hasford et al. found that patients in the low-risk group who achieved MCR at 21 Gleevec treatments had a 74% (CI 63%-85%) chance of 10-year survival; patients in the low-risk group who did not achieve MCR at 21 Gleevec treatments had a 20% (CI 10%-31%) chance of 10-year survival (CI 10%-31%); the likelihood of 10-year survival for patients in the intermediate-risk group with MCR at 21 Gleevec treatments was 60% (CI 45%-75%); the likelihood of 10-year survival for patients in the intermediate-risk group without MCR at 21 Gleevec treatments was 12% (CI 5%-19%); the likelihood of 10-year survival for patients in the high-risk group with MCR at 21 Gleevec treatments was 0 (CI 0); and the likelihood of 10-year survival for patients in the high-risk group with MCR at 21 Gleevec treatments was 0 (CI 0). The likelihood of 10-year survival was 0 (CI 0-0) for patients in the high-risk group who did not achieve MCR at 21 Gleevec treatments, and 11% (CI 1-20%) for patients in the high-risk group who did not achieve MCR at 21 Gleevec treatments.
Table 4-1-2 Recommendations for disease monitoring during Gleevec therapy
Complete blood count and Cytogenetics Quantitative RT-PCR
Leukocyte sorting (bone marrow) (peripheral blood)
Diagnosis Weekly until blood counts are stable Pre-treatment Pre-treatment
Complete hematologic remission Every 2 to 4 weeks Every 3 to 6 months Every 3 months
Complete cytogenetic remission Every 4 to 6 weeks Every 12 to 18 months Every 3 months
Significant molecular biological remission Every 6 weeks Every 12-18 months Every 3 months
Complete molecular biological remission Every 6 weeks Every 12 to 18 months Every 3 months
The duration of Gleevec treatment for chronic phase CML remains an unanswered question, and there is limited information in this regard. Only 6 case reports are available in which patients who obtained CCR after Gleevec treatment (and had at least 1 negative PCR before discontinuation) developed Ph+ cells again after discontinuation, and 3 of these cases were effective after re-dosing. The experience of these patients suggests that after obtaining CCR with Gleevec therapy, treatment should be continued and the BCR-ABL should be monitored in the correct way to prevent relapse. Another problem with Gleevec therapy is drug resistance (Table 4-1-3).
The incidence of primary hematologic resistance is approximately 5%, and cytogenetic resistance is more common in patients with chronic-phase CML, with an incidence of approximately 15%. The main mechanisms of resistance to Gleevec are BCR-ABL-dependent resistance (so-called “secondary resistance”, mainly mutations in the BCR-ABL kinase region, accounting for about 50%-90% of patients with resistance, followed by BCR-ABL overexpression, accounting for about 10% of patients with resistance) and BCR-ABL non-dependent resistance ( This is known as “primary resistance”, which occurs in about 5% of patients in the chronic phase and 30%-50% of patients in the acute phase). The main strategies to overcome Gleevec resistance are: increasing the dose of Gleevec (800 mg/d), using new ABL inhibitors (Nilotinib, 400 mg, po, bid; Dasatinib, 70 mg, po, bid), using drugs that downregulate BCR-ABL protein (e.g., Geldanamycin, 17-AAG), and combination with other signal transduction inhibitors (e.g., farnesyl inhibitors).
Table 4-1-3 Clinical definitions of Gleevec resistance
Primary drug resistance Acquired drug resistance
Initial treatment dose ≥300 mg/d, within 3 months Loss of hematologic efficacy
No hematologic efficacy
Loss of complete cytogenetic remission
Treatment dose ≥400mg/d after 3 months of treatment
No mild cytogenetic remission More than 3 months between tests Ph-positive bone marrow cell count increased by ≥ 30%
New cytogenetic abnormalities in Ph-positive clones after 6 months of treatment at doses ≥400 mg/d
No significant cytogenetic remission achieved
Serial monitoring of BCR-ABL to internal control gene ratio increased by ≥1
Treatment dose ≥ 400 mg/d, after 12 months of treatment Logarithmic grade
No complete cytogenetic remission achieved
The major side effects of Gleevec treatment were myelosuppression, nausea, muscle cramps, bone pain, arthralgia, rash, diarrhea, edema, fluid retention, and impaired liver function (Table 4-1-4).
Table 4-1-4 Management of Adverse Reactions to Gleevec
Hematologic adverse reactions
Grade 3-4 neutropenia (neutrophil count <1.0 × 109/L)
Add growth factors to maintain neutrophil counts above 1.0 x 109/L, or
Continue until grade 2 or better, maintain dose if grade 2 is reached within 2 weeks, reduce dose by 25%-33% (not less than 300 mg) if grade 3-4 lasts longer than 2 weeks
Grade 3-4 thrombocytopenia (platelet count <50×109/L)
Continue medication until grade 2 or better, if grade 2 is reached within 2 weeks then maintain the original dose, if grade 3-4 lasts longer than 2 weeks then reduce the dose by 25%-33% (not less than 300mg)
Grade 3-4 anemia
Addition of erythropoietin (EPO)
During the accelerated phase, patients may experience disease-related hematocrit without discontinuing the drug
Special emergency measures
Diarrhea: supportive therapy
Edema: diuresis, supportive therapy
Fluid retention: diuresis, supportive therapy, drug dose reduction, intermittent dosing or discontinuation
Gastrointestinal discomfort: take medication with food and drink a large glass of water
muscle spasms: calcium supplementation.
Rash: local or systemic glucocorticoids, dose reduction, intermittent dosing or discontinuation
Non-hematological adverse reactions
Grade 3: treated according to the above special emergency measures, or grade 4 if symptomatic treatment is ineffective
Grade 4: Continue medication to grade 1 or better, then consider dose reduction of 25%-33% (not less than 300mg)
3.Allogeneic hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a promising means of curing CML. Factors affecting the efficacy include patient age, disease stage and time from diagnosis to transplantation, pre-transplantation treatment, and pretreatment protocols. Patients with unrelated donor Allo-HSCT older than 50 years have a short survival, while age has relatively little effect on HLA-matched sibling donor Allo-HSCT. The survival rate of CP transplantation was better than that of AP or BP, and the recurrence rate was lower. 5-year survival rates after transplantation of HLA-matched sibling donor Allo-HSCT were 75%, 40%, and 10% for CP, AP, and BP, respectively. patients treated with leucovorin before BMT had a worse outcome than hydroxyurea. the effect of IFN-α treatment on The effect of IFN-α therapy on the efficacy of BMT treatment is controversial. The effect of pre-transplantation Gleevec on transplantation mortality and risk of recurrence is unclear. Previous studies have suggested that pre-transplantation Gleevec may increase transplantation-related toxicity, particularly liver toxicity, but more recent studies have confirmed that pre-transplantation Gleevec has no effect on transplantation outcomes.
The pretreatment regimen Cy+TBI and BUS+Cy both have similar efficacy, and the 5-year survival rate of patients receiving HLA-matched sibling donor Allo-HSCT during CP is above 70%. the major cause of transplant-related death in Allo-BMT is GVHD. while de-T-cell Allo-BMT reduces the incidence of GVHD, the relapse rate is significantly higher, suggesting that graft-versus Leukemia (GVL) effect is an important factor in the efficacy of Allo-BMT for CML. Despite the satisfactory results of Allo-BMT for CML, only 20-25% of patients have HLA-matched sibling donors. In recent years, with the use of molecular biology for HLA high-resolution matching and the clinical application of new immunosuppressive agents, the efficacy of Allo-HSCT with unrelated donors (including umbilical cord blood stem cells) for the treatment of CML has been significantly improved. There is no longer any difference in the efficacy of HLA-matched sibling donor transplants.
To better guide clinical selection of appropriate patients for allogeneic HSCT, the European Peripheral Blood and Marrow Transplantation Group has proposed a prognostic determination score system based on data from 3142 patients (Table 4-1-5). According to this point system, patients with points 0, 1, 2, 3, 4, 5, and 6 had 5-year disease-free survival rates of 72%, 70%, 62%, 48%, 40%, 18%, and 22%, respectively, and transplant-related mortality rates of 20%, 23%, 31%, 46%, 51%, 71%, and 73%.
Table 4-1-5 Allogeneic hematopoietic stem cell transplantation prognostic point system
Parameter Score
A. Donor type
HLA-matched sibling donor 0
Unrelated/HLA-mismatched sibling donor 1
B. Disease stage
Chronic phase 0
Accelerated phase 1
Acute phase 2
C. Age
<20 years 0
20-40 years old 1
>40 years old 2
D. Donor/recipient gender
Other 0
Female donor/male recipient 1
E. Time from diagnosis to transplantation
≤12 months 0
>12 months 1
4. Other treatments
(1) Interferon: Before the introduction of Gleevec, interferon was the treatment of choice for chronic-phase CML, but it was adjusted to second-line use starting with the 2006 edition of the NCCN CML treatment guidelines, and interferon was chosen only for those patients who could not tolerate Gleevec, Dasatinib, and Nilotinib.IFN has achieved some consensus for the treatment of CML.
The starting dose of IFN should be 3MU-5MU/m2/d, and the dose should be increased to 9MU-12MU/d after 2-3 weeks, or the maximum tolerated dose that achieves significant hematologic efficacy (i.e., WBC count 2-4×109/L and platelet count close to 50×109/L) and the need to reduce the patient’s toxic symptoms. The shortest time to expect cytogenetic remission is 6 months, generally until disease progression or intolerable drug toxicity occurs;
(ii) Results from several large series of randomized controlled clinical trials and “meta-analyses” of IFN for CML have confirmed that INF significantly prolongs the survival of patients with chronic CML compared to conventional chemotherapeutic agents such as maricylan and hydroxyurea;
(3) IFN combined with other chemotherapeutic drugs, such as low-dose cytarabine (20 mg/m2/d), is more effective than IFN alone.
(2) Maryland: It was the first chemotherapeutic drug widely used in the treatment of CML, and its efficacy was confirmed by randomized comparison in 1968. The commonly used dose is 4mg-6mg/d orally. Since the drug has significant after-effects, the dose should be reduced or discontinued when the white blood cell count drops to about 30×109/L. Most patients require maintenance therapy, and the maintenance dose can be reduced to 2 mg orally twice/week. About 95% of patients in the chronic phase are effective, with a decrease in white blood cell count, a decrease in spleen size, an increase in red blood cell pressure product, and a return to normal general condition. Maryland treatment often does not result in the disappearance of Ph chromosomes, and the aim of Maryland treatment is to control the chronic phase and reduce mortality. The main adverse effects of this drug are severe bone marrow suppression, skin pigmentation, gynecomastia similar to adrenocortical insufficiency syndrome and pulmonary fibrosis.
(3) Hydroxyurea: A randomized controlled series in 1993 confirmed the superiority of hydroxyurea (HU) over marilyn (BUS), with median survival significantly better in the HU group than in the BUS group (58 and 45 months, respectively) and 5-year survival rates of 44% and 32%, respectively. Depending on the white blood cell count, the starting dose is 1g-4g/d orally; when the white blood cell drops to 20×109/L it is changed to 1g-2g/d and the maintenance dose is 0.5g-2.0g/d; when the white blood cell count drops to 5×109/L it should be suspended. Adverse effects of hydroxyurea are mild and may include rash, myeloid macrocytosis, macrocytosis, increased menstrual flow, and baldness, but there is little bone marrow suppression and no cases of pulmonary fibrosis. The rate of Ph chromosome positivity may be reduced in some patients.
(4) Indocyanine and its derivative methylisatin: Indocyanine and methylisatin are new drugs first created for the treatment of CML by the Institute of Hematology, Chinese Academy of Medical Sciences after more than 20 years of research. The total effective rate is 95.8% with 100mg~300mg/d of indocyanine alone, divided into 3-4 oral doses. The overall remission rate was 80.6% with methisoindigo 75mg~150mg/d in 3 oral doses alone. The effect of spleen reduction was significantly better compared with BUS and HU. Recently, our study confirmed that the long-term efficacy of methisoindigo is similar to that of HU, and methisoindigo combined with HU can significantly prolong the chronic phase and reduce the 5-year acute change rate of patients. Some patients may have a reduced rate of Ph chromosome positivity.
5.Treatment of acute transformation period
Patients with acute myeloid transformation have a CR rate of 20%-30% with AML treatment regimens (e.g., high-dose AraC-based regimen FLAG-Ida, etc.) and a complete remission period of only a few weeks or months. About 25-35% of patients with acute changes are acute lytic or biphenotypic leukemic changes, and although about 60% of patients with Hyper-CVAD regimens achieve CR, their overall survival is only 4-6 months. Gleevec (800 mg/d) results in complete hematologic remission in 50-70% of patients, but median survival is only 7-10 months. Hematopoietic stem cell transplantation can achieve a 3-year DFS of 15%-20%.
6. Treatment strategy selection
The NCCN 2009 version of CML treatment guideline is: patients with confirmed chronic phase CML should choose Gleevec at 400 mg/d for initial treatment.
If hematologic remission is achieved, continue treatment with the original dose of Gleevec; if hematologic remission is not achieved or relapses after achieving hematologic remission, then Nilotinib, Dasatinib, hematopoietic stem cell transplantation (HSCT), interferon ± Ara-C or enter clinical trials may be used.
Evaluation including cytogenetics after 6 months of Gleevec: if complete cytogenetic remission is achieved, maintain the original dose of Gleevec; if partial or minimal cytogenetic remission is achieved, continue with the original dose of Gleevec or increase the dose of Gleevec to 800 mg/d if tolerated by the patient; if no cytogenetic efficacy is achieved, Nilotinib may be used, Dasatinib ,hematopoietic stem cell transplantation (HSCT), interferon ± Ara-C or enter clinical trials.
Evaluation including cytogenetics after 12 months of Gleevec use: complete cytogenetic remission, continue treatment with the original dose of Gleevec; partial cytogenetic remission, continue treatment with the original dose of Gleevec or increase the dose of Gleevec to 800 mg/d if tolerated by the patient; mild cytogenetic remission or no cytogenetic efficacy, then Gleevec can be used Nilotinib , Dasatinib , hematopoietic stem cell transplantation (HSCT), interferon ± Ara-C or enter clinical trials.
Evaluation including cytogenetics after 18 months of Gleevec use: complete cytogenetic remission, continue Gleevec treatment at the original dose; partial cytogenetic remission, Nilotinib, Dasatinib, increase Gleevec dose to 800 mg/d if tolerated, HSCT, interferon ± Ara-C or enter clinical trials. Ara-C or enter clinical trials; for mild cytogenetic remission or no cytogenetic efficacy, Nilotinib, Dasatinib, HSCT, interferon ± Ara-C or enter clinical trials.