Risk Stratification And Treatment Goals Of Chronic Myeloid Leukemia

Objectives: Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm characterized by abnormal proliferation of mature myeloid cells.Since the introduction of tyrosine kinase inhibitors(TKI),the prognosis of CML has been dramatically improved.Most CML patients now enjoy durable remission and near normal survival.However,there are several concerns remaining in the management of CML.First,while more than 90% has the Philadelphia chromosome as the sole cytogenetic abnormality at initial presentation,a small proportion of patients has cytogenetic abnormality other than the Phladelphia chromosome,namely additional cytogenetic aberrations(ACAs).Despite numerous studies looking into the prognostic value of ACAs,it remains controversial regarding the classification of ACAs and their impact on CML disease course.Second,there are several subtypes of the BCR-ABL1 transcript,of which the phenotypic and prognostic impact is yet unclear,especially for those rare subtypes.At last,while complete cytogenetic response is believed to be sufficient for optimal outcome in CML chronic phase,the goal of treatment in blast phase remains controversial.Methods: The study utilized the following inclusion criteria: 1.Diagnosed as chronic myeloid leukemia by bone marrow pathology,and received at least one type of tyrosine kinase inhibitor treatment,including imatinib,dasatinib,nilotinib,bosutinib and ponatinib;2.Age at diagnosis > 18 years;3.The translocation t(9;22)is confirmed by conventional karyotyping.Exclusion criteria included: 1.CML patients with cryptic Ph;2.Myeloid sarcoma as the sole presentation of progression to blast phase.The criteria is made based on such considerations that 1.The first clinical trial involving TKIs were started at the year 1998;2.Adolescent CML patients have different characteristics and management strategy compared to adults;3.The prognostic impact of crypyic Ph is controversial and it is not possible to determine whether cytogenetic aberrations are present in Ph positive or negative cells;4 CML patients with myeloid sarcoma have different disease course and karyotype analysis is seldomly done in solid tissue;5.Treatment is vastly different in pediatric CML patients.Furthermore,as FISH assessment is not readily available in 1998,patients diagnosed in 1998 were not included in the comparison of variant Ph and standard Ph.Results: According to the described criteria,a total of 2326 patients were included.First,we found that CML karyotype can be stratified to 4 groups based on the presence,type and complexity of ACAs: the high risk group includes karyotypes with high risk single ACAs [-7/del(7q),i(17)(q10),3q26.2 rearrangements] and complex ACAs with high risk component;the intermediate-2 risk group includes karyotypes with complex ACAs without high-risk component;the intermediate-1 risk group included karyotypes with single non-high-risk ACAs;and the standard risk group included karyotypes without ACAs.The stratification successfully predicted the risk of progression to blast phase and correlates well with patients survival.Second,the rare e1a2 BCR-ABL1 transcript has a significant impact on the phenotype and prognosis of CML patients.Compared to patients with typical transcripts,those with e1a2 transcript are more likely to have monocytosis during chronic phase,more likely to progress to BP,more likely to have lymphoid or mixed phenotype in BP,and their blasts in myeloid BP are more likely to express monocytic markers in myeloid BP.At last,in CML BP,prognosis is still highly associated with treatment response,however,the detail pattern is quite different from such association in chronic phase.Patients who achieved only complete cytogenetic response do not have more favorable response than those with only hematological response.Patients who acehived major molecular response have a significantly better response than those who did not,and patients who have molecularly undetectable leukemia have a good prognosis with a median survival over 10 years.Conclusion: Complex variant Ph indicates poor prognosis.High risk ACA carriers have an extremely poor outcome.e1a2 transcript have a high impact on CML phenotype and prognosis.The treatment goal in CML BP should be to achieve MUL.