A Study Of The Effect Of Allogeneic Hematopoietic Stem Cell Transplantation On Acute Lymphocytic Leukemia

Background and purposeAcute lymphoblastic leukemia (ALL) is a hematological malignancy of hematopoietic stem cells. ALL is a heterogeneous disease, children and adults ALL outcomes vary widely. The reasons for the distinct different in children and adults ALL outcomes include:1. Differences between the cytogenetics. ALL characterized by the presence of the TEL/AML1fusion gene and super diploid is more frequently observed among children compared with adults, and is associated with a favorable prognosis. ALL characterized by the BCR/ABL fusion gene carries a poor prognosis and is much more common among adults than children ALL.2. Age. Older age is a poor prognosis in ALL.3. Leukemic cell clearance. About60%to75%children ALL experienced clearance of minimal residual disease (MRD) at the end of induction therapy, adult patients seem to have a slower rate of leukemic cell clearance compared with children, with30%to50%of adult patients having MRD negativity after initial induction. Aforementioned factors make the adult ALL poor prognosis, with the overall survival (OS) rate less than10%. After the1990s, with using the experience of the children ALL chemotherapy regimens and allogeneic hematopoietic stem cell transplantation (allo-HSCT), OS rate increased to30-40%. For adult ALL patients with high risk factors [Philadelphia chromosome positive (Ph), white blood cell count (WBC) more than50×109/L, or associated with central nervous system leukemia (CNSL)], and failed to achieve CR after two standard induction chemotherapy, their outcomes were very poor. For aforementioned patients, allo-HSCT should be considered as the front line therpy, but it remains poor prognosis for Ph+ALL patients. At the beginning of this century, tyrosine kinase inhibitors (TKI) were used for treatment for Ph+ALL. TKI combined with chemotherapy pre-transplant had increased disease-free survival significantly. TKI combined with chemotherapy has been recommended as the first-line treatment of patients with Ph+ALL by the national comprehensive cancer network (NCCN). MRD monitoring has an important role in prediction of recurrence in patients with ALL, as well as, in choice of the intensity of therapy follow-up. But after conditioning regimens and new hematopoietic stem cell implantation, the original host immune system with Ph is damaged, if TKI could have benefit to patients remain uncertain. TKI could inhibit the activity of tyrosine kinase, induces Ph+cells apoptosis. Meanwhile, tyrosine kinase is in normal cells, such as dendritic cells, T cells, etc., long-term TKI therapy must affect immune function of our body. Considering the above two points, it is uncertain that TKI therapy was used in consolidate or maintain course post-transplant. With intensitied chemotherapy, TKI and allo-HSCT, the prognosis of ALL patients has been improved dramatically, but still with high recurrence rate. ALL patients still had a high relapse rate after standard conditioning regimens allo-HSCT, increasing the intensity of conditioning regimens to reduce the recurrence rate after transplantation had been considered by many groups, such as adding high dose of etoposide, cytarabine, etc. to the standard total body irradiation+cyclophosphamide conditioning regimens. Compared with standard conditioning regimens, intensitied conditioning regimens have certain advantages. Our group had reported the good effect of intensitied conditioning regimens (fludarabine+cytarabine+irradiation+cyclophosphamide) in refractory leukemia. This paper retrospective analysis the long-term survival and risk factor for prognosis of205cases ALL patients, optimized strategy for ALL patients before and after the transplantationMethodsTwo hundred and five patients with ALL, who underwent allo-HSCT from May1995to June2011at Nanfang hospital, Southern Medical University, were enrolled in this analysis. A number of factors were analyzed, including age, immunophenotyping, BCR/ABL fusion gene, disease state, HLA typing, conditioning regimens, cell source, graft versus host disease (GVHD), therapy post-transplant (TKI, donor lymphocyte infusion) and so on, The hematopoietic reconstruction, GVHD, recurrence and death, long-term survival, etc. were analyzed between standard conditioning regimens (total body irradiation+cyclophosphamide, modified busulfan+cyclophosphamide) and intensitied conditioning regimens (total body irradiation+cyclophosphamide+etoposide or teniposide, fludarabine+cytarabine+irradiation+cyclophosphamide). Seventy-five cases of Ph+ALL in205cases of ALL were divided into four groups: imatinib therapy pre-transplant, post-transplant, both pre-and post-transplant, neither pre-nor post-transplant. The efficacy of imatinib administration pre-and/or post-HSCT for patients with Ph+ALL was evaluated. From June2011, TKIs were used under the monitor of MRD detection in15cases of Ph+ALL (MRD group). The survival, relapse, and mortality were analyzed between these15cases and23cases Ph+ALL with experiential imatinib treatment (none MRD group). Statistical analysis: SPSS17.0statistical package was used for processing, the data were showed as mean ±standard deviation(x±s). The data before and after mobilization, between two independent groups were compared with independent sample or paired sample t test. The ranked data were compared with Chi-square test. Differences between characteristics were assessed by Kruskal-Wallis test. Repeated measures were used to analyze peripheral blood lymphocyte subsets. The survival and univariate analysis were described according to the Kaplan-Meier method. Differences between survival curves were assessed by the log rank test. Cox regression model was used for multivariate analysis. Statistical significance was defined at the P less than or equal to0.05level.Results1.1Totally,205ALL patients,131were male,74were female. The median age was24years old (range from11to61years old). One hundred and sixty-five of205cases achieved CR after induction chemotherapy (CR rate was80.5%).132cases were at the first time remission,23were at more than the second time remission,8were at partial response and42were at none remission at time of transplnat. The neutrophils and platelets reconstruction time were both not statistically significant between standard and intensitied group (P=0.094and0.145, respectively). The incidences of regimens related toxicity (RRT) were100%in both groups, the degrees of RRT were not statistically significant. There were52and64cases of degree0to I acute GVHD in standard and intensitied group, respectively. There were45and44cases of degree II to IV acute GVHD in standard and intensitied group, respectively. There were27and30cases of limit chornic GVHD in standard and intensitied group, respectively. There were21and20cases of intensive chornic GVHD in standard and intensitied group, respectively. The difference in acute GVHD and chornic GVHD between two groups were all not significant.1.2With followed up until December31,2012,57cases experienced relapse, the relapse rate was27.8%.84cases died, the mortality rate was41.0%. The univariate and multivariate analysis both showed that none CR status at transplant was the risk factor for relapse and overall survival (P=0.042and <0.001, respectively). The odds ratio of relapse in patients with none CR status at transplant was1.927times of that in patients with CR status at transplant (95%CI:1.060-3.506). The odds ratio of death in patients with none CR status at transplant was2.303times of that in patients with CR status at transplant (95%CI:1.419-3.739).1.3The relapse and mortality rate in standard group were higher than that in intensitied group. In patients with CR, the mortality in standard group was significant higher than that in intensitied group (P<0.001). The5-year overall survival (OS) were44.1±5.6%and46.8±7.8%, the5-year disease-free survival (DFS) were36.5±6.9%and44.9±7.5%in standard and intensitied group, respectively. The5-year OS and DFS in intensitied group were higher than that in standard group, the difference were both not significant (P=0.831and0.652, respectively). In patients with CR, the5-year OS were48.7±5.8%and68.0±9.9%, the5-year DFS were40.1±7.4%and68.0±9.1%in standard and intensitied group, respectively. The5-year OS and DFS in intensitied group were higher than that in standard group, the difference were both not significant (P=0.071and0.091, respectively). In patients with none CR, the5-year OS were11.1±10.5%and15.2±8.8%, the5-year OS in intensitied group were higher than that in standard group, the difference were not significant (P=0.463). the5-year DFS were11.1±10.5%and9.5±8.0%in standard and intensitied group, respectively. The5-year DFS in intensitied group were lower than that in standard group, the difference were not significant (P=0.290).1.4Of75Ph+ALL patients,48patients received imatinib therapy, including25patients received imatinib pre-transplant,10post-transplant,13both pre-and post-transplant, and27did not accepted imatinib therapy. Of38patients who received imatinib pre-transplant,30patients accepted imatinib therapy during the time of initiate induction chemotherapy (28achieved CR), and3during the time of consolidation therapy,5patients accepted imatinib therapy during the time of refractory and relapse (4achieved CR). The time of imatinib therapy pre-transplant was at a median of98days (range33-256days). Of23patients who received imatinib post-transplant, the imatinib therapy was initiated at a median of67days (range60-89days) post-transplant and the time of imatinib therapy was at a median of108days (range34-278days). The difference of incidence of aGVHD and cGVHD were both not significant (P=0.914and0.218, respectively). With a median follow-up time of395days post-transplant,38patients were alive and37death. Twenty-nine patients have relapsed (38.7%) after transplantation. Univariate and multivariate analysis both showed that none CR status at transplant was significantly associated with worse OS, DFS and relapse. The odds ratio of relapse in patients with none CR status at transplant was4.035times of that in patients with CR status at transplant (95%CI:1.663-9.791). The odds ratio of death in patients with none CR status at transplant was2.078times of that in patients with CR status at transplant (95%CI:1.041-4.150).1.5The estimated3-year OS was47.5±13.6%,42.0±17.6%,45.1±15.6%and29.3±10.1%, respectively (P=0.402), and3-year DFS were43.3±13.4%,28.0±16.4%,26.9±20.7%and23.0±11.7%, respectively (P=0.732) in the patients with imatinib therapy pre-transplant, post-transplant, both pre-and post-transplant, neither pre-nor post-transplant. Regardless of imatinib pre-transplant,3-year OS and DFS were40.9±12.5%and27.5±12.7%for patients received imatinib post-transplant (n=23), respectively, compared with34.9±9.0%and28.3±10.5%for patients without imatinib therapy post-transplant (n=52)(P=0.284and0.467, respectively). The incidence of relapse at3-year was28.0%,60.0%,46.2%and37.0%in the patients with imatinib therapy pre-transplant, post-transplant, both pre-and post-transplant, neither pre-nor post-transplant, respectively. Regardless of imatinib therapy pre-transplant, the incidence of relapse at3-year for patients with imatinib therapy post-transplant (n=23) was52.2%, comparing with32.6%(P=0.036) in patients without imatinib therapy (n=52) post-transplant.1.6In post-transplant, flow cytometry was performed to detect lymphocyte subsets in peripheral blood in patients at the time point of pre-imatinib (before using imatinib),30days and60days (different time points were defined as within-subjects) after imatinib therapy (n=20) and patients without imatinib therapy at the same period (n=25)(two groups were defined as between-subjects). Repeated measures of general linear model showed that between-subjects had not significant differences in the ratio of blood CD3+ T cells (P=0.168), CD3+CD4+T cells (P=0.088), CD3+CD8+ T cells (P=0.209), and CD19+ B cells (P=0.142). The ratio of CD4+CD25+Foxp3+ T cells (Tregs) were significantly higher at30and60days after imatinib therapy than that in pre-imatinib (within-subjects, P all<0.001). Compared with patients who did not received imatinib therapy at the same period, the ratio of Tregs cells at30days and60days after imatinib therapy post-transplant were significantly increased (between-subjects, P<0.001).1.7From June2011, TKIs were used under the monitor of MRD detection in15cases of Ph+ALL (MRD group). The survival and mortality were analyzed between these15cases and23cases Ph+ALL with experiential imatinib treatment (none MRD group). The molecular biology recurrence rate in MRD group was46.7%and the hematology recurrence rate in none MRD group was39.1%. The difference between the mortality of MRD group and none MRD group (20.0%vs34.8%) were not significant (P=0.215). The600-day DFS in two groups were45.0±16.1%and53.8±11.9%, respectively. The difference between the600-day OS of MRD group and none MRD group (68.1±16.1%vs57.3±10.9%), were not significant (P=0.327).Conclusion1The tolerance of intensitied conditioning regimen, which was on the basis of TBI+CY conditioning regimen, is well. The intensitied conditioning regimen can reduce the relapse and mortality rate of ALL patients after transplantation, and improve OS and DFS.2Imatinib therapy before transplantation could bring benefit to patients with Ph+ALL. Whether administration of imatinib regardless of the molecular status of the disease post-transplant could bring benefit to patients with Ph+ALL is a worthy goal for further study.3The immune inhibition of imatinib may have some relationship with that imatinib treatment post-transplant may increase the relapse rate.