| Objectives1. To explore the clinical and moleculargenetic characteristics, and factors affecting outcome of adult Philadelphia-positive acute lymphoblastic leukemia(Ph+ ALL).2. To explore factors affecting minimal residual disease(MRD) and its prognostic value in adult Ph+ ALL patients who received allogeneic hematopoietic stem cell transplantation(allo-HSCT).3. To clarify the clinical, cytogenetic and molecular characteristics and prognosis of adult Ph+ ALL patients with ABL kinase domain mutations(ABL-KDMs), and to evaluate the role of allo-HSCT in the treatment options.4. To investigate on the role of xbp1 gene in pathogenesis of adult Ph+ ALL.Methods1. A database review was undertaken of the diagnostic characteristics of 217 Ph+ ALL patients in our center from January 2006 to December 2014. Effects of tyrosine kinase inhibitors(TKIs) in induction therapy and the role of allo-HSCT in outcome were evaluated.2. MRD was monitored post-CR and pre-allo-HSCT by detecting BCR-ABL fusion gene in 82 Ph+ ALL patients. Factors influencing MRD and the prognostic value of MRD were evaluated.3. A database review was undertaken of the results of Ph+ ALL patients with ABL-KDMs performed in our center from February 2010 to August 2014, including clinical and cyto-molecular genetic characteristics at the outset of diagnosis, type and frequency of mutation, and prognosis. Statistical analysis on the role of treatment regimen of allo-HSCT combined with TKIs was also conducted.4. Expression level of xbp1 gene was detected. The association between xbp1 gene and diagnostic characteristics, treatment response and prognosis were evaluated. We firstlydiscovered that xbp1 gene deletion existed in a relatively high proportion of Ph+ ALL.Results1. The basic characteristics of Ph+ ALL included: 1) gender: male 125, female 92; 2)extramedullary infiltration: 92/217(42.4%); 3) median WBC count 44(1-650)×109/L. The bone marrow characteristics included: 1) bone marrow blast cells: 84.5(26.0-99.0)%; 2)immunophenotyping: B-lymphoid expression 166/210(79.0%), accompanied by myeloid expression 44/210(21.9%), accompanied by CD34 expression 146/168(86.9%); 3) subtype of BCR-ABL fusion protein: P190 124/207(59.9%), P210 78/207(37.7%), negative5/207(2.4%); 4) cytogenetic analysis: normal 28/171(16.4%), t(9;22) 56/171(32.7%),additional chromosomal abnormality 87/171(50.9%). 110 patients received traditional chemotherapy as induction regimen, with 7 patients died of treatment-related toxicity.82/103(79.6%) acquired complete remission(CR), and 2/55(3.6%) acquired major molecular response(MMR). 107 patients received a combined induction regimen of chemotherapy with TKIs(101 imatinib, 3 nilotnib, 3 dasatinib), with 1 patient died of reatment-related toxicity. 99/106(93.4%) patients acquired CR, and 20/78(25.6%) acquired MMR, both results significantly higher than that of patients receiving chemotherapy alone.We further divided TKIs incorporation into two groups, i.e., early usage( the 1st to the 14 th day of induction therapy) and late usage(the 15 th day to the time of bone marrow examination after induction). Results showed that CR rate and MMR rate in the early usage group was 4/78(94.9%) and 18/56(32.1%) respectively, higher than that of late usage group(25/28 89.3% and 2/22, 9.1%). Among the 181 CR patients, 102(82.0%) relapsed within 8 months. 2-year CIR, OS and EFS of all patients were 54.3%, 48.2% and 66.7%,respectively; and 64.5%, 43.3%, 41.6% in the allo-HSCT group, remarkably better than that of chemotherapy group(30.9%, 22.7%, 69.2%). For allo-HSCT patients, donar type affected neither survival nor relapse, with OS, EFS, CIR and NRM in the fully-matched sibling group, unrelated group and haploidentical group 61.7%vs.63.5%vs.63.4%,36.5%vs.45.2%vs.47.0%, 54.5%vs.34.9%vs.32.9%, and 13.4%vs.26.6%vs.24.9%.2. When all the patients achieved morphologically CR in BM, only 16(19.5%)patients acquired MRD negativity. 1/16 patient(4.0%) acquired MRD negativity in patients receiving chemotherapy alone, significantly lower than that of patients receiving combined therapy of chemotherapy with imatinib(26.3%). Earlier usage of imatinib was capable of further increasing MRD negativity, yet not reaching statistical significance.Marrow examination was performed on all patients at a median time of 15(range, 9~34)days before transplantation. Results showed that 38 patients(46.3%) achieved MRD negativity. Only imatinib integration in induction therapy was marginally associated with MRD negativity, as 30/57 patients(52.6%) achieved MRD negativity compared to that of32.0%. The 2-year CIR after transplantation in the post-CR MRD-neg group was 0%,significantly lower than that of 32.2% in the MRD-pos group, although post-CR MRD did not affect OS and EFS. The 2-year CIR after transplantation in the pre-HSCT MRD-neg group was 15.2%, significantly lower than that of 35.3% in the MRD-pos group. 1/6patient(16.6%) relapsed within one year after transplantation in the MRD-neg group,remarkably lower than that of 75% in the MRD-pos group. Patients in the MRD-neg group featured better OS and EFS than MRD-pos group(77.3%vs.55.9% and 67.9%vs.50.1%).3. 42 patients were detected to show positive results among all the patients, with median time from diagnosis to mutation occurrence of 8 months.The median age of mutation group was 40-year-old, older than non-mutation group(32.5-year-old). The incidence of additional chromosomatic abnormality of mutation group was higher than non-mutation group, with alternations in 7, 5 chromosome and +Ph more frequently observed. 21 types of mutation at 18 locations were observed, with T315 I mutating ranking the top followed by E255K/V, Y253H/F and E459 K. Mutation group featured no significant difference in CR rate in contrast to non-mutation group, but was remarkably lower in MMR rate than non-mutation group. The 2 year and 5 year overall survival rate of mutation group was 45.4% and 35.0% respectively, much shorter than the non-mutation group(67.8% and 63.3%). The median survival of patients with T315 I and E255K/V was19 and 10 months, significantly shorter than patients with other mutations. Among the 42 patients with mutations, 14 were performed with allo-HSCT, and the median survival was29 months, longer than patients received chemotherapy alone(17 months). 14 allo-HSCT patients were given nilotinib or dasatinib at the time of mutation occurrence, and there was no significant difference in the overall survival in contrast to patients who continue to take imatinib.4. The expression level of xbp1 gene and downstream genes increases in Ph+ ALL patients. Two groups were formed according to expression levels, i.e., high/low xbp1 gene expression group. High expression group featured higher rate of extramedullary infiltration rate, high WBC and platelet count, and higher incidence of additional chromosomaticabnormality. xbp1 expression level did not affect CR rate in Ph+ ALL patients who treated with combined induction regimen of chemotherapy with TKIs, but high expression group had remarkably lower CR rate(64.7%) than low expression group(93.3%) in patients receiving chemotherapy alone. xbp1 expression level did not affect relapse in all the patients, but high expression group had significantly higher relapse rate within 6 months(62.5%) than low expression group(23.1%). 2-year OS and EFS rate were 46.0% and37.9%in high expression group, worse than those of 66.4% and 46.8% in the low expression group. Whether patients receiving allo-HSCT or chemotherapy as the maintenance therapy,high expression group had worse survival than low expression group.Conclusions1. Adult Ph+ ALL feature low CR rate and poor prognosis, with older and high WBC count as unfavorable factors. Chemotherapy combined with TKIs is capable of increasing CR rate, and early usage would further increase MMR rate. Allo-HSCT in CR could alter the poor outcome of Ph+ ALL patients, but the type of donor does affect prognosis.2. Chemotherapy combined with TKIs is capable of increasing MRD negativity in induction therapy of adult Ph+ ALL. Pre-allo-HSCT MRD negativity yields less relapse and better outcome, among which who also have post-CR MRD negativity feature the best result.3. We find that adult Ph+ ALL patients with ABL-KDMs were relatively older, with higher frequency of developing additional chromosomatic abnormality. Mutation features diversity and complexity, remarkably affecting outcome. T315 I and E255 K mutations account for more than half of all cases, characterized by a less favorable prognosis.Currently, allo-HSCT is the only method that has the potential of elongating life expectancy, but the utility of second-generation TKIs during relapse dose not necessarily have an edge on survival over imatinib.4. The expression level of xbp1 gene and downstream genes increases in adult Ph+ALL patients, affecting diagnostic characteristics, treatment response and prognosis. |
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