allogeneic sct for cml, tki failure after tki failure

Conditions: Chronic Myeloid Leukemia

Summary: the investigators will evaluate the outcomes of allogeneic stem cell transplantation which is the only curative treatment modality in the patients with chronic myeloid leukemia after failing tyrosine kinase inhibitor therapy. however, any update was not reported on the transplant outcomes in the patients failed tki therapy, thus necessitating update of this data. also, the european group for blood and marrow transplantation (ebmt) risk score is still of value, but insufficient numbers of patients have been transplanted in recent years and after tki therapy to allow a robust reanalysis. our study hypothesis is that allogeneic sct treatment modality can rescue cml patients who failed tki therapy due to resistance or to intolerance with improved survival and long-term outcomes. also, another hypothesis will be examined if the ebmt risk score proposed pre-imatinib era can reproduce similar prognostic risk stratification of long-term outcomes in the patients treated with tki.

allogeneic stem cell transplantation (sct) remains the only currently available treatment that can render patients durably molecularly negative, but the associated procedural-related morbidity and mortality remain a major deterrent. currently the followings are accepted as reasonable indication for allogeneic sct for cml: failure to 2nd generation tyrosine kinase inhibitor (2gtki) after imatinib failure, 2gtki frontline failure, or any patients meeting the criteria of failure such as development of additional cytogenetic abnormality (aca), clonal evolution in ph neg clone, development of mutation and loss of ccyr as well as any advanced disease stage including accelerated or blastic phase. however, insufficient numbers of patients have been transplanted in recent years and after tki therapy, thus necessitating update of this data. the ebmt risk score has been used for a decade for the decision making of transplantation in the pre-imatinib era. however, it has never been re-evaluated in a larger cohort of cml patients treated with tkis prior to sct then received allosct, thus requiring to be reanalysed for its prognostic implication on long-term survival. as mentioned above, any update was not reported on the transplant outcomes in the patients failed tki therapy, thus necessitating update of this data. also, the ebmt risk score2 is still of value, but insufficient numbers of patients have been transplanted in recent years and after tki therapy to allow a robust reanalysis. this is retrospective study. the medical records will be reviewed retrospectively. the treatment outcomes such as complete cytogenetic response (ccyr), major molecular response (mmr), molecular response at 4.5 log reduction (mr4.5), treatment failure (tf), progression free survival (pfs) and overall survival (os) will be estimated using kaplan-meier method. the ccr will be defined as 0% of ph+ metaphase cells in the marrow or less than 1% by international scale using bcr-abl1 transcript polymerase chain reaction (pcr) test. the mmr is defined as lower than or equal to a 0.1%is of bcr-abl1 fusion gene transcripts, and mr4.5 is defined as 0.0032%is bcr-abl1 transcript level, equivalent to a 4.5 log reduction of bcr-abl1 transcript level. time to treatment failure (ttf) is defined as the interval between allogeneic sct and the occurrence of events that indicated that cml has relapsed including primary hematologic resistance, cytogenetic resistance, loss of ccyr, development of abl tyrosine kinase domain mutation, clonal evolution and progression to accelerated phase (ap) or blastic crisis (bc). death is considered as censored for ttf. time to pfs is defined as the interval between transplantation and confirmation of progression to ap or bc or death from any cause, while os was calculated from transplantation until the date of death from any cause or of latest follow-up. pre-transplant characteristics and transplant procedure data will be also collected including the age, disease stage, diagnosis/transplant date, donor type and gender match. summary of treatment outcomes following previous tki therapies will be also collected. post-transplant events such as graft-versus-host disease (gvhd) and progression of cml will be also collected. no study intervention. assessment of efficacy: cytogenetic responses were categorized as complete (0% ph+ cells in marrow by conventional cytogenetics), partial (1% to 34% ph+ cells in marrow), or minor (35% to 90% ph+ cells in marrow). a major cytogenetic response (mcyr) was defined as the sum of ccyr and partial cytogenetic response (i.e. 0% - 35% ph+ cells in marrow). major molecular response (mmr) was defined as lower than or equal to a 0.1%is of bcr-abl1 fusion gene transcripts, and molecular response 4.5 (mr4.5) was defined as 0.0032%is bcr-abl1 transcript level, equivalent to a 4.5 log reduction of bcr-abl1 transcript level. time to treatment failure (ttf) is defined as the interval between allogeneic sct and the occurrence of events that indicated that cml has relapsed including primary hematologic resistance, cytogenetic resistance, loss of ccyr, development of abl tyrosine kinase domain mutation, clonal evolution and progression to accelerated phase (ap) or blastic crisis (bc). death is considered as censored for ttf. time to pfs is defined as the interval between transplantation and confirmation of progression to ap or bc or death from any cause, while os was calculated from transplantation until the date of death from any cause or of latest follow-up. statistical analysis: the list of cml patients will be utilized for this retrospective study. study id, gender, disease characteristics at the time of diagnosis, details of treatment, detailed response to treatment, resistance or intolerance and long-term outcomes will be retrospectively reviewed. study endpoints will be analyzed with respect to complete cytogenetic response (ccr), major/complete molecular response (mmr/cmr), loss of response, resistance, progression to advance disease and death. the cumulative incidence of ccr, mmr and cmr will be estimated and compared using the approach proposed by gray (gray, 1988). overall survival will be analyzed using the kaplan-meier method and compared using the log-rank test. loss of response, resistance and failure-free survival will be analyzed using the test for cumulative incidence to account for competing risk events. baseline characteristics, including sokal score, age, gender, disease stage, will be adopted as surrogates for further response, progression free and overall survival following transplantation. for the ebmt risk score, age of the patient, stage of the disease at transplant, time from diagnosis (\ 12months), donor type, and donor recipient gender combination will be used for the calculation. the transplant outcomes will be compared according to the ebmt risk score. p-values of less than 0.05 will be considered statistically significant. hazard ratios (hr) and 95% confidence intervals (ci) will be estimated with a predetermined reference risk of 1.0. the ezr software will be used for the statistical analyses.

Eligibility criteria:
inclusion criteria: * patients treated with allogeneic stem cell transplantation (sct) since 2000 till 2013 for any of tyrosine kinase inhibitor (tki) failure due to resistance or intolerance during chronic myeloid leukemia (cml) management with tyrosine kinase inhibitor exclusion criteria: * any cml patients not previously treated with tki therapy prior to allogeneic stem cell treatment.

Keywords: chronic myeloid leukemia allogeneic hematopoietic cell transplantation tyrosine kinase inhibitor tki failure