Cumulative Incidence Of Leukemia Relapse Research Articles

Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant

ImportanceChronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD.ObjectiveTo determine whether repeated infusions of MSCs during the early stage after haplo-HSCT decreases the incidence of severe chronic GVHD.Design, Setting, and ParticipantsThis open-label, multicenter, parallel randomized clinical trial was conducted from April 2016 to January 2022. Eligibility criteria included a diagnosis of acute leukemia and having a haploidentical, suitable related donor for HSCT. The median (range) follow-up time was 39.0 (1.5-67.0) months.InterventionsThe enrolled patients with a haploidentical relative for HSCT received the modified busulfan/cyclophosphamide + antithymocyte globulin modified regimen and standard GVHD prophylaxis. Patients were randomly chosen to receive MSCs (the MSC group) (1 × 106 cells/kg, every 2 weeks, starting from 45 days after transplant, 4 times total) or regular prophylaxis (control group).Main Outcome and MeasureThe cumulative incidence of severe chronic GVHD.ResultsOf 158 patients, 58 (36.7%) were female individuals; the median (range) age for the MSC and control groups was 28 (18-60) years and 28 (18-56) years, respectively. A total of 158 patients were screened, and 148 patients were randomly assigned to the MSC group (n = 74) or control group (n = 74) 1 day before MSCs infusion. The estimated 2-year cumulative incidence of severe chronic GVHD was 5.4% (95% CI, 1.8%-14.0%) in the MSC group and 17.4% (95% CI, 10.1%-28.5%) in the control group (hazard ratio [HR], 0.29; 95% CI, 0.10-0.88; P = .03). There was no difference between the MSC and control groups in the cumulative incidence of leukemia relapse (HR, 1.17; 95% CI, 0.55-2.47; P = .68). The cumulative incidence of stage II to IV acute GVHD in the MSC group was significantly lower than that in the control group (HR, 0.25; 95% CI, 0.09-0.67; P = .01). The MSC group had better GVHD-free and relapse-free survival rates than the control group (HR, 0.62; 95% CI, 0.39-0.98; P = .04).Conclusions and RelevanceThe results of this randomized clinical trial show that early repeated infusions of MSCs decreased the incidence and severity of chronic GVHD, and the incidence and severity of acute GVHD manifested as a better GVHD-free and relapse-free survival rate for patients after haplo-HSCT.Trial RegistrationChinese Clinical Trial Registry: ChiCTR-IIR-16007806

Prognostic significance of SET-NUP214 fusion gene in acute leukemia after allogeneic hematopoietic stem cell transplantation.

The SET nuclear proto-oncogene (SET)-nucleoporin (NUP) 214 fusion gene (SET-NUP214) is a rare leukemia fusion gene. Due to the limited number of samples with SET-NUP214 fusion gene in previous studies, the significance of SET-NUP214 for measurable residual disease (MRD) monitoring in patients with acute leukemia (AL) is still unclear. Our study aimed to observe the dynamic changes in SET-NUP214 expression before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and analyzed whether SET-NUP214 could be used to evaluate MRD status. Our study included 24 AL patients who were newly diagnosed with SET-NUP214 fusion gene and they all received allo-HSCT. Their MRD was evaluated by monitoring SET-NUP214 fusion gene and leukemia-associated immunophenotype (LAIP). The median follow-up time was 501 days (56–2208 days). Of the enrolled patients, 6 (25%) patients died, including 3 (12.5%) patients died of leukemia relapse. Total 5 (20.8%) patients experienced hematological relapse at a median of 225 days (56–1057 days) post-transplantation. The SET-NUP214 median expression level at diagnosis was 405.1% (14.6%–1482.4%). SET-NUP214 gene expression generally became positive prior to flow cytometry results. In addition, the Kaplan-Meier survival curves analysis showed that those who had SET-NUP214 positive (SET-NUP214+) post-transplantation had a higher 2-year cumulative incidence of leukemia relapse (CIR) of 43.7 ± 18.8% (P < .05). However, there was no significant difference between SET-NUP214 positive and SET-NUP214 negative patients with regard to their 2-year overall survival (OS) (82.5 ± 11.3 vs 64.6 ± 17.5%, respectively, P = .271). ROC curve analysis turned out that the area under the ROC curve (AUC) was 0.916 (95% CI: 0.784–1.0; P = .005). In conclusion, SET-NUP214 fusion gene determined by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) could be used to evaluate MRD status after allo-HSCT. Patients with positive SET-NUP214 expression after transplantation will have a poor prognosis.

Tumorablative conditioning regimen for haploidentical stem cell transplantation in 102 children with hematologic malignancies: a single-center experience.

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) is widely carried out in China, and transplantation related complications decreased gradually with the transplant technology improving, and the overall survival(OS) increased year by year. However, relapse after transplantation is still one of the main causes of death in patients with hematological malignancy. In order to reduce the recurrence after HSCT, we set a tumorablative conditioning regimen (TAC ) regimen; the aim is as much as possible to eliminate the malignant clone to reduce the recurrence without increasing the conditioning toxicity. We retrospectively analyzed 102 cases of haplo-HSCT in our hospital from 2012 to 2017. Ninety-eight out of the 99 (99.0%) patients achieved primary engraftment. The 2-year OS and disease free survival (DFS) are 81.4% (83/102) and 77.45% (79/102). The cumulative incidence of leukemia relapse is 16.2% (16/99), Twenty-nine patients developed II-IV acute graft-versus-host disease (aGVHD) (29%) within 100 days and only nine patients have grade III-IV aGVHD (9%) in measurable 99 patients. The conditioning regimen was relatively well tolerated with limited regimen-related toxicity. The preliminary results show that TAC is safe and effective in haplo-HSCT of children with hematologic malignancies. This study will provide a clinical basis for the individualized conditioning regimen.

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

ABSTRACTLeukemia relapse and chronic graft-versus-host disease (cGVHD) are still major obstacles of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The numbers and activity of natural killer (NK) and T-regulatory cells can be increased post-transplantation by exposure to interleukin-2 (IL-2). We tested whether administering low-dose IL-2 would decrease leukemia relapse while reducing cGVHD after allotransplantation. This controlled, open-label randomized trial included 90 recipients of allotransplants. Subjects were randomized in a 1:1 ratio to either receive or not receive low-dose IL-2 during the early post-transplantation period. Patients in the IL-2 arm received a subcutaneous injection of low-dose IL-2 (1×106 U/d) on day 60 after allo-HSCT. IL-2 was administered daily for 14 d followed by a 14-d hiatus. The primary endpoint was the cumulative incidence of leukemia relapse (CIR). Three-year CIRs for the IL-2 arm and control arm were 23% (range 16–30%) and 11% (range 6–15%; p = 0.20), respectively. Minimal residual disease-positive (MRD+) tests were more common in the IL-2 arm compared to the control arm (36% [range 29–44%] vs. 15% [range 10–20%], p = 0.03). The cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was lower in the IL-2 arm compared to the control arm (33% [range 26–39%] vs. 57% [range 49–64%), p = 0.02). Therefore, the 3-y GVHD-free and GVHD progression-free survival (GPFS) rates were significantly higher in the IL-2 arm compared to the control arm (47% [range 39–55%] vs. 31% [range 25–38%], p = 0.048). Blood Tregs, NK cells, and NK-cell cytotoxicity were increased in subjects in the IL-2 arm between 3 mo and 6 mo post-transplantation. Administration of low-dose IL-2 during the immediate post-transplantation period was associated with a higher GPFS but did not decrease the CIR.

Wilms Tumor 1 Expression and Pre-emptive Immunotherapy in Patients with Acute Myeloid Leukemia Undergoing an Allogeneic Hemopoietic Stem Cell Transplantation

Minimal residual disease (MRD) was monitored by Wilms tumor 1 (WT1) expression in 207 patients with acute myeloid leukemia (AML) after an allogeneic hemopoietic stem cell transplantation (HSCT) as a trigger to initiate pre-emptive immunotherapy (IT) with cyclosporin discontinuation and/or donor lymphocyte infusion. The trigger for IT was WT1 ≥ 180 copies/104 Abelson cells in marrow cells in the first group of 122 patients (WT1-180) and ≥ 100 copies in a subsequent group of 85 patients (WT1-100). Forty patients received IT. The cumulative incidence (CI) of relapse was 76% in WT1-180 (n = 17) versus 29% in WT1-100 patients (n = 23) receiving IT (P = .006); the leukemia-free survival from MRD positivity was 23% versus 74%, respectively (P = .003). We then looked at the entire AML patient population (n = 207). WT1-180 and WT1-100 patients were comparable for disease phase and age. The overall 4-year CI of transplantation-related mortality was 13% in both groups; the CI of leukemia relapse was 38% in the WT1-180 and 28% in the WT1-100 patients (P = .05) and leukemia-free survival was 56% versus 48%, respectively (P = .07). In conclusion, we suggests that WT1-based pre-emptive immunotherapy is feasible in patients with undergoing an allogeneic HSCT. The protective effect on relapse is greater when IT is triggered at lower levels of WT1.

Efficacy, Safety and Long Term Results of Prophylactic and Preemptive Donor Lymphocyte Infusion after Allogeneic Stem Cell Transplantation for Acute Leukemia: A Registry-Based Evaluation on 343 Patients By the Acute Leukemia Working Party of EBMT

Background: Relapse is the most frequent cause of failure after alloSCT for acute leukemia (AL). Unlike in CML, infusion of donor lymphocytes (DLI) is of limited efficacy in overt hematological relapse. Hence, it may be preferable to give DLI in complete hematological remission (CHR) after alloSCT, to exploit the allogeneic graft-versus-leukemia (GvL) effect either as maintenance in high risk patients (prophylactic DLI, proDLI), or as early intervention to prevent hematological recurrence in case of decreasing donor chimerism or minimal residual disease (preemptive DLI, preDLI). However, no systematic analysis of this strategy is available so far, neither concerning the optimal way of application, nor with respect to safety and clinical efficacy. Here, the Acute Leukemia Working Party of the EBMT presents results from a registry-based survey on 343 patients with AML (n=266) or ALL (n=77), who received DLI in CHR after alloSCT. Patients: Median age was 48y, 64% of patients had received alloSCT from a matched sibling, 36% from an 8/8 matched unrelated donor. Disease status at time of alloSCT was CR1/CR2/advanced in 68%/14%/17% of cases, respectively. Patients had received standard/reduced intensity conditioning in 53%/47% of cases. Before alloSCT, 55% had received in vivo T-cell depletion (TCD), 16% ex vivo TCD, 10% in vivo plus ex vivo, and 19% no TCD. Reasons for preDLI were persisting mixed or decreasing donor cells chimerism (n=167, 49%) and persisting or recurrent minimal residual disease (MRD; n=32, 9%). ProDLI without any sign of leukemia was given to 144 patients (42%) with high risk disease Results: Median follow up from DLI1 was 6.5 years (range, 1.1-14.5). Median interval from alloSCT to first DLI (DLI1) was 180 days (range, 15-1178). Patients received a median of 2 infusions with the median CD3+ cell dose at DLI1 being 1x106/kg (range, 0.1-163). Reasons to discontinue DLI were: number of planned infusions reached (56%), GvHD (17%), disease progression (13%), and documented improvement of donor chimerism (6%). At 5y from DLI1, cumulative incidence of leukemia relapse was 43% and 28% in patients receiving preDLI for MRD and mixed chimerism, and 28% among recipients of proDLI given for maintenance in high risk disease. The corresponding 5y OS rates were 55%, 66% and 64%, 5y-LFS rates were 52%, 57% and 58%. Efficacy of preDLI could be directly demonstrated by decreasing MRD in 71% (15/21) and by improvement of donor chimerism in 68% (110/163) of informative patients. Furthermore, hematologic improvement was observed in 13 patients following proDLI. Cumulative incidences of acute GvHD grade II-IV and chronic GvHD after DLI were 13% and 32%, respectively. A multivariate model identified a history of aGvHD ≥grade II after alloSCT (p=0.009, HR 2.1, 95% CI 1.2-3.7), an interval from alloSCT to DLI &lt;6 months (p=0.003, HR 0.997, 95% CI 0.006-0.999), and a CD3+ cell count &gt;1 x 106/kg at DLI1 (p=0.024, HR 1.011, 95% CI 1.001-1.021) as risk factors for induction of GvHD after DLI in CHR. One hundred and thirty three patients (39%) had died at last follow-up, with relapse still being the most frequent cause of death (n=87). Sixteen patients (5% of the entire cohort) died from DLI-induced GvHD, and 29 patients died from other courses. In summary, in this large cohort of patients receiving DLI for AL in CHR after alloSCT, efficacy of preemptive DLI cells could be demonstrated in 69% of patients. About half of patients with MRD, and &gt;70% of patients with mixed chimerism did not experience hematological relapse during a follow up period of &gt;5 years, suggesting a clinically meaningful effect of preDLI in AL. GvHD was the most devastating complication, leading to death in 5% of patients. The identification of risk factors for GvHD may influence the selection of candidates for prophylactic and preemptive DLI in general, and may help to refine the use of DLI in this context with respect to cell dose and timing. Disclosures Schmid: Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Bug:Celgene, Novartis: Research Funding; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; TEVA Oncology, Astellas: Other: Travel Grant. Tischer:Sanofi-Aventis: Other: advisory board. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Autologous HSCT Followed By Immunotherapy and Maintenance Chemotherapy Compared with Allogeneic HSCT for Intermediate-Risk Molecules/Cytogenetics Acute Myeloblastic Leukemia in First Complete Remission

Background Autologous hematopoietic stem cell transplantation (auto-HSCT) is an alternative choice for acute myeloblastic leukemia (AML) with intermediate-risk molecules / cytogenetics (IR). Its disadvantage is high relapse rate, compared with allogeneic HSCT (allo-HSCT). To reduce leukemia relapse, we introduced a strategy of auto-HSCT followed by immunotherapy and maintenance chemotherapy for IR AML.Methods One hundred and seventy-six IR AML in first complete remission (CR1) undergoing HSCT between January 2001 and December 2010 at our single institute were enrolled in this study. The choice of auto-HSCT or HLA-matched sibling transplantation was based on the donor source and patients’ desire. The conditioning regimen included BuCY (busulfan 4 mg/kg/day P.O. or 3.2 mg/kg/day I.V. on days -7 to -4, and cyclophosphamide 60 mg/kg/day on days -3 and -2) and BuF (busulfan 4 mg/kg/day P.O. or 3.2 mg/kg/day I.V. on days -7 to -4, and fludarabine 30mg/m2/day on days −6 to −2). Cyclosporine A and methotrexate were administered for GVHD prophylaxis. For patients undergoing auto-HSCT, interleukin-2 (IL-2) was administered from day 0 at a dose of 3×106 U/day (three times a day) subcutaneously for 3 weeks. One or more subsequent cycles were given after a 30-day interval for up to 6 cycles unless the patient developed ≥ grade 3 toxicity. Standard chemotherapy was administered from three months post-transplantation. One or more subsequent cycles were given after a 90-day interval for up to 3 cycles. Survival, leukemia relapse and quality of life were compared between auto-HSCT and allo-HSCT.Results Of the 176 IR AML-CR1, 102 patients received auto-HSCT, and 74 received allo-HSCT. The 5-year overall survival (OS) and disease-free survival (DFS) post-transplantation were 73.8%±4.3% and 67.2%±4.7%, 69.1%±6.3% and 69.1%±6.3%, respectively, in auto-HSCT and allo-HSCT.There were no difference in OS and DFS between auto-HSCT and allo-HSCT (P=0.533, P=0.948). The 5-year cumulative incidence of leukemia relapse was 25.8%±4.6% and 13.5%±4.8%, respectively (P=0.171). The 5-year non-relapse mortality was 10.4%±3.1% and 19.9%±5.7%, respectively, in auto-HSCT and allo-HSCT (P=0.157). The performance status, measured using the Karnofsky performance score, was observed in 85 and 55 patients surviving 3 years in auto-HSCT and allo-HSCT. Of the auto-HSCT and allo-HSCT recipients, 98.8% and 89.1% had normal or near-normal activity scores (Karnofsky assessment 90–100%) in 3 years post-transplantation, and there was significant difference between the two groups (P=0.015).Conclusion Auto-HSCT followed by immunotherapy and maintenance chemotherapy might reduce relapse for IR AML-CR1 post-transplantation, and have similar survival compared with allo-HSCT. It is superior to allo-HSCT in quality of life. DisclosuresXuan:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding. Liu:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105); National Public Health Grand Research Foundation (201202017);: Research Funding; It was supported by Natural Science Foundation of Guangdong Province (S2012010009299); the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1);: Research Funding; It was supported by the Technology Plan of Guangdong Province of China (2012B031800403); the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027).: Research Funding.

Prophylactic Use of Sorafenib in Patients with FLT3-ITD-Positive Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations have been reported in 20%-30% of patients with acute myeloid leukemia (AML). FLT3-ITD-positive AML patients have an inferior survival, primarily due to lower complete remission (CR) rate and higher relapse rate. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) improves the outcomes of some FLT3-ITD-positive AML, a significant number will suffer disease recurrence after allo-HSCT. Sorafenib, an inhibitor of multiple kinases including FLT3, has shown promising activity in FLT3-ITD-positive AML. Recent studies have shown that sorafenib monotherapy or in combination with chemotherapy are effective in attaining CR, but they do not have significant improvement in relapse. Currently, prophylactic use of sorafenib after allo-HSCT has been rarely reported, and whether it can improve outcomes of FLT3-ITD-positive AML remains unclear.Methods A total of 18 patients with FLT3-ITD-positive AML undergoing allo-HSCT from January 2012 to March 2014 at our single institute were enrolled in this retrospective study. Seven patients were in first CR at the time of transplantation and all received standard conditioning: busulfan 4 mg/kg/d P.O. or 3.2 mg/kg/d I.V. (on days -7 to -4), cyclophosphamide 60 mg/kg/d (on days -3, -2). Eleven patients were not in CR (NR) at the time of transplantation and all received intensified conditioning: fludarabine 30 mg/m2/d (on days -10 to -6), cytarabine 2.0 g/m2/d (on days -10 to -6), total body irradiation 4.5 Gy/d (on days -5, -4), cyclophosphamide 60 mg/kg/d (on days -3, -2), etoposide 15 mg/kg/d (on days -3, -2). Sorafenib was used from day 30 to 180 post-transplantation. The initial dose of sorafenib was 400 mg orally twice daily and was adjusted in case of suspected toxicity or resistance (dose range, 200-800 mg daily).Results Of the 18 patients, 7 received prophylactic sorafenib, including 3 in CR and 4 in NR pre-transplantation; 11 did not receive prophylactic sorafenib, including 4 in CR and 7 in NR pre-transplantation. There were no significant differences in disease status pre-transplantation, HLA-typing and the source of donors between the two groups (all P>0.05). The eleven patients in NR at the time of transplantation all achieved CR and had complete chimerism by day +30 post-transplantation. With a median follow up of 433 (range, 124-765) days post-transplantation, 7 patients with prophylactic sorafenib all had no recurrence and survived. Of the 11 patients without prophylactic sorafenib, 5 experienced leukemia relapse at a median time of 92 (range, 49 to 335) days post-transplantation, including hematologic in 4 and central nervous system (CNS) in 1. The patient with CNS relapse achieved CR after radiotherapy and donor lymphocyte infusion (DLI), and was still alive now. Of the 4 patients with hematologic relapse, one abandoned treatment and 3 received treatment, including sorafenib combined with chemotherapy and DLI. Two of the three patients achieved short CR after treatment and finally all of them died of relapse within half a year. With a median follow up of 343 (range, 135-863) days post-transplantation, 6 patients survived and 5 died in the 11 patients without prophylactic sorafenib. Causes of death included leukemia relapse (n=4) and chronic graft-versus-host disease (n=1). The 1-year cumulative incidence of leukemia relapse was 0.0% and 50.9% in patients with and without prophylactic sorafenib (P=0.046). The 1-year overall and disease-free survival were 100.0% and 100.0% in patients with prophylactic sorafenib, compared with 49.9% and 42.4% in those without prophylactic sorafenib (P=0.066, P=0.028). The main side effect of sorafenib was rash, and none of patients experienced bone marrow suppression. Of the 10 patients with sorafenib treatment, 6 had hand-foot skin reaction and/or rash. Anti-allergy therapy was ineffective, and glucocorticoid was usually required. In 4 of the 6 patients, the skin rash covered gradually after reducing the dose of sorafenib and the use of glucocorticoid. Other two patients even required drug discontinuation, but sorafenib was tolerated after the reuse.Conclusions Early prophylactic use of sorafenib has an acceptable toxicity profile and could reduce relapse of FLT3-ITD-positive AML. DisclosuresLiu:It was supported by Natural Science Foundation of Guangdong Province (S2012010009299); the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105); National Public Health Grand Research Foundation (201202017): Research Funding; It was supported by the Technology Plan of Guangdong Province of China (2012B031800403); the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding. Xuan:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding.

Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia: Comparison of Outcomes Among HLA-Matched Sibling Donors, HLA-Matched Unrelated Donors and HLA-Mismatched Family Donors

AbstractPurpose: To compare the outcomes of acute leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched sibling donors (MSDs), HLA-matched unrelated donors (MUDs), and HLA-mismatched family donors (MFDs).Method: A total of 358 consecutive patients with acute leukemia undergoing allo-HSCT at our single institute between April 2008 to December 2013 were enrolled in this retrospective investigation. The outcomes including graft-versus-host disease (GVHD), transplantation related mortality (TRM), leukemia relapse and survival were analyzed.Results: Of the 358 patients, 158 patients received MSDs, 105 MUDs and 95 MFDs transplantation. Based on clinical and cytogenetic features, there were 50.6%, 67.6% and 81.5% of high-risk patients in the MSDs, MUDs and MFDs groups, respectively (P=0.002). All patients achieved full engraftment, except for 1 died from regimen related toxicity (RRT) and 3 from early infections. Hematopoietic engraftment was faster in the MSDs group than that in the MUDs and MFDs groups (p<0.001).The cumulative incidence of grade II to IV acute GVHD (aGVHD) were 23.4%±3.4%, 34.3%±4.6% and 41.3%±5.1% in the MSDs, MUDs and MFDs groups, respectively (P=0.003), while the cumulative incidence of grade III to IV severe grade aGVHD were not different among the three groups (8.2%±2.3%, 10.6%±3.2%, 12.1%±3.8%, respectively; P=0.858). The cumulative incidence of chronic GVHD (cGVHD)were 33.0%±3.9%, 37.1%±4.7% and 37.9%±5.0% in the MSDs, MUDs and MFDs groups, respectively (P=0.735). Median follow-up was 33.5 months, the 3-year cumulative incidence of leukemia relapse was 28.9%±4.3%, 31.7%±5.4% and 26.9±6.1%, in the three groups, respectively (P=0.698). The 5-year cumulative incidence of TRM in MSDs and MUDs groups were lower than that in MFDs group (23.5%±6.3% , 24.3%±4.5% and 34.1±6.3%, respectively; P=0.014).The 5-year overall survival (OS) post-transplantation were 56.8%±5.7%, 55.7%±5.1% and 50.5%±6.2% (P=0.138), and disease-free survival (DFS) were 54.7%±5.6%, 49.2%±5.3% and 46.3%±6.2% (P=0.070), which did not differ among the three groups. In the multivariate analysis, number of chemotherapy cycles before transplantation, donor age, aGVHD and cGVHD were significant factors affecting TRM, which was not relevant to donor types. And high-risk cytogenetics was the common risk factor for relapse and survival.Conclusions: Our results suggest that HLA-mismatched family donors are alternative choice for patients with acute leukemia undergoing HSCT when HLA-matched donors are not available. DisclosuresXuan:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding. Liu:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105); National Public Health Grand Research Foundation (201202017);: Research Funding; It was supported by Natural Science Foundation of Guangdong Province (S2012010009299); the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1);: Research Funding; It was supported by the Technology Plan of Guangdong Province of China (2012B031800403); the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027).: Research Funding.

Sequential Intensified Conditioning Followed By Tapering Of Prophylactic Immunosupressants and Donor Lymphocyte Infusions In Allogeneic Hematopoietic Stem Cell Transplantation For Refractory Leukemia

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is perceived as the only curative option for refractory acute leukemia. However, the relapse rate exceeds 50% in these patients undergoing allo-HSCT with standard myeloablative regimen. To improve outcomes of allo-HSCT for refractory leukemia, we previously introduced a strategy of sequential intensified conditioning and early rapid tapering of prophylactic immunosupressants for graft-versus-host disease (GVHD). The results indicated this strategy could improve outcomes of refractory leukemia, with 5-year overall survival (OS) and disease-free survival (DFS) of 44.6% ± 8.1% and 38.2% ± 7.7%. However, the 3-year cumulative incidence of leukemia relapse reached to 33.3%. To reduce the relapse rate but without increasing regimen-related toxicities (RRT), we increased the dose of etoposide (VP-16) in conditioning and infused donor lymphocytes (DLI). The aim of this prospective study was to assess the feasibility and efficacy of this modified strategy in patients with refractory acute leukemia. MethodsA total of 123 patients with refractory acute leukemia undergoing allo-HSCT from January 2009 to December 2012 were enrolled. Ninety-four patients received related (73 sibling and 21 family donors), 29 unrelated donor transplants; 73 were HLA locus matched, 50 mismatched. Modified sequential intensified conditioning regimen was: fludarabine (30 mg/m2/day, -10 to -6 days) + cytarabine (2.0 g/m2/day, -10 to -6 days) plus TBI (total body irradiation, 4.5 Gy/day, -5, -4 days) + cyclophosphamide (60 mg/kg/ day, -3, -2 days) + VP-16 (15 mg/kg/day, -3, -2 days). Cyclosporine A (CsA) was withdrawn rapidly in a stepwise fashion (total dose reduced by 20%/week) if patients who did not experience acute GVHD (aGVHD) by day +30 post-transplantation. Donor lymphocytes (1.0×108/kg, once a month, 4 doses totally) would be infused in patients without II° or more than II° aGVHD by day + 60 post-transplantation. ResultsAll patients achieved hematopoietic engraftment, except for two who died of infections and one who died of RRT during conditioning. All 120 evaluable patients achieved complete remission (CR) at the time of neutrophil engraftment and achieved complete donor chimerism by day +30 post-transplantation. The incidence of total RRT was 100%, and III-IV RRT was 22.0%. Within the first 100 days post-transplantation, 67 patients developed 95 episodes of infections. Twenty-one had bacterial infections, 7 had invasive fungal infections, 9 had viral infections except cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia, 24 had mixed infections and 6 had infections of unknown etiology. Moreover, 48 patients had CMV viremia, 3 developed CMV pneumonia; 41 had EBV viremia, 13 developed EBV-associated diseases. Of the 120 evaluable patients, aGVHD occurred in 31 cases by day +30. Of the 89 patients who did not develop GVHD by day +30, 28 developed aGVHD after CsA withdrawal. Of the 66 patients who received DLI by day +60, 20 developed aGVHD, and 43 developed chronic GVHD (cGVHD, including 13 migrating from aGVHD). cGVHD occurred in 65 of 102 patients who survived more than 100 days, including 43 after DLI. Twenty-three patients experienced leukemia relapse (hematologic in 16, genetic in 4, central nervous system in 2 and extramedullary in 1) at a median time of 165 (range, 28 to 479) days post-transplantation. The 3-year cumulative incidence of relapse was 25.3 ± 4.8%. Of the 23 patients who relapsed, 6 abandoned treatment and 17 received treatment, including 9 with chemotherapy and DLI, 6 only with chemotherapy, 1 only with DLI, and 1 with chemotherapy and radiotherapy. Only two of the 17 cases achieved CR after treatment, and the others all died of disease progress. With a median follow up of 316 (range, 7 to 1589) days post-transplantation, 75 patients survived and 48 died. Causes of death included leukemia relapse (n=21), infections (n=12), GVHD (n=8), EBV-associated diseases (n=5), cerebral hemorrhage (n=1) and secondary dyshematopoiesis (n=1). The 3-year OS and DFS was 58.8% ± 4.7% and 57.0% ± 4.8%. ConclusionsFor patients with refractory leukemia undergoing allo-HSCT, the modified strategy of sequential intensified conditioning followed by tapering of prophylactic immunosupressants and DLI not only improves OS and DFS, but also reduces leukemia relapse. Disclosures:Liu:It was supported by 863 Program (No. 2011AA020105).: Research Funding; It was supported by National Public Health Grand Research Foundation (Grant No. 201202017), National Natural Science Foundation of China (Grant No.81000231, No.81270647).: Research Funding; It was supported by Science and Technology Program of Guangzhou of China (11A72121174). : Research Funding.

Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study

ObjectiveWe conducted a prospective, randomized, open-label, multicenter study to compare busulfan plus fludarabine (BuFlu) with busulfan plus cyclophosphamide (BuCy) as the conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) in first complete remission (CR1).MethodsTotally 108 AML-CR1 patients undergoing allo-HSCT were randomized into BuCy (busulfan 1.6 mg/kg, q12 hours, -7 ~ -4d; cyclophosphamide 60 mg/kg.d, -3 ~ -2d) or BuFlu (busulfan 1.6 mg/kg, q12 hours, -5 ~ -2d; fludarabine 30 mg/m2.d, -6 ~ -2d) group. Hematopoietic engraftment, regimen-related toxicity (RRT), graft-versus-host disease (GVHD), transplant related mortality (TRM), and overall survival were compared between the two groups.ResultsAll patients achieved hematopoietic reconstitution except for two patients who died of RRT during conditioning. All patients obtained complete donor chimerism by day +30 post-transplantation. The incidence of total and III-IV RRT were 94.4% and 81.5% (P = 0.038), and 16.7% and 0.0% (P = 0.002), respectively, in BuCy and BuFlu group. With a median follow up of 609 (range, 3–2130) days after transplantation, the 5-year cumulative incidence of TRM were 18.8 ± 6.9% and 9.9 ± 6.3% (P = 0.104); the 5-year cumulative incidence of leukemia relapse were 16.5 ± 5.8% and 16.2 ± 5.3% (P = 0.943); the 5-year disease-free survival and overall survival were 67.4 ± 7.6% and 75.3 ± 7.2% (P = 0.315), and 72.3 ± 7.5% and 81.9 ± 7.0% (P = 0.177), respectively in BuCy and BuFlu group.ConclusionCompared with BuCy, BuFlu as a myeloablative condition regimen was associated with lower toxicities and comparable anti-leukemic activity in AML-CR1 patients undergoing allo-HSCT.

Sequential Intensified Conditioning and Tapering of Prophylactic Immunosuppressants for Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation for Refractory Leukemia

For patients with advanced leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), a major obstacle to success, especially in those with a high leukemia cell burden, is relapse of the underlying disease. To improve the outcome of allo-HSCT for refractory leukemia, we investigated the strategy of sequential intensified conditioning and early rapid tapering of prophylactic immunosuppressants therapy for graft-versus-host disease (GVHD) during the early stage after transplantation. A total of 51 patients with refractory leukemia (median age, 30.0 years; unfavorable karyotypes, 49%) received fludarabine (Flu) 30 mg/m(2)/day and cytarabine 2 g/m(2)/day (on days -10 to -6), 4.5 Gy total body irradiation (TBI)/day (on days -5 and -4), and cyclophosphamide (Cy) 60 mg/kg/day and etoposide 600 mg/day (on days -3 and -2) for conditioning. Cyclosporine A (CsA) was withdrawn rapidly in a stepwise fashion to avoid overwhelming GVHD reactions if acute GVHD (aGVHD) did not develop at day +30. All 51 patients developed regimen-related toxicities (13 with grade III-IV); 93.9% of them achieved complete remission by day +30. Median follow-up was 41 months (range, 6.6 to 92.2 months); 5-year overall survival (OS) and disease-free survival (DFS) were 44.6% +/- 8.1% and 38.2% +/- 7.7%, respectively. Thirteen patients relapsed; the 3-year cumulative incidence of leukemia relapse was 33.3%. On multivariate analysis, cytogenetic status was the only significant pretransplantation factor. Survival was better in patients with grade I or II aGVHD than in those without aGVHD. Our data indicate that the sequential strategy of cytoreductive chemotherapy followed immediately by intensified myeloablative (MA) conditioning for allo-HSCT and rapid tapering of prophylactic immunosuppressants for GVHD in the early stage after transplantation has an acceptable toxicity profile and may be a better approach to treating refractory leukemia.

Hematopoietic Stem Cell Transplantation (HSCT) from Alternative Donors for Acute Leukemia at High-Risk of Relapse. The Haploidentical Option.

Despite advances in chemotherapy for acute leukemia, survival is poor when patients have unfavourable prognostic features at diagnosis, when they do not achieve CR after the first induction cycle and when they are in second or later remission. In these circumstances an allogeneic HSCT is preferred. The chance of finding a matched unrelated donor depends on the HLA diversity and although molecular analysis achieves closer matches it reduces the probability of finding a donor. Furthermore, many patients relapse while waiting for transplant. Transplantation of HSCs from a one-haplotype mismatched family member offers an immediate source of HSCs to almost all leukemia patients who urgently need an allogeneic transplantation because of the high-risk of leukemia relapse and who do not have a matched, either related or unrelated, avaible donor. Over the past decade, our group has shown the two major obstacles to mismatched transplants, that is severe acute GVHD in T-cell-replete transplants and graft rejection in T-cell-depleted transplants, can be overcome by infusing a megadose of extensively T-cell-depleted HSCs after an immuno-myelo-ablative conditioning regimen. Since our first reports (Aversa et al. Blood 1994 and NEJM 1998), the main modifications to our original approach were: a) in October 1995, fludarabine was substituted for cyclophosphamide in our TBI-based conditioning regimen; b) peripheral blood cells were positively selected by using initially the Ceprate device and then, since January 1999, the Clinimacs instrument which ensures a 4.5 log T-cell depletion in a one-step procedure with no E-rosetting; c) in the 138 patients transplanted since January 1999 post-transplant G-CSF administration was stopped so as to improve immune recovery.The patient population included 90 AML and 48 ALL, median age 28 years (range 9–62), 40 (29%) in bad-risk CR I, 43 (31%) in second or later CR and 55 (40%) in relapse at transplant. Primary full-donor engraftment was achieved in 125/134 evaluable patients (93%); 8 patients engrafted after second transplants. Overall engraftment was achieved in 133 patients (96%). Without any post-transplant immunosuppressive prophylaxis, grade II-IV acute GvHD occurred in 7/133 evaluable patients and 5/106 developed chronic GvHD. Cumulative incidence (C.I. 95%) of non-leukemia mortality was 36% (19%–53%) and 40% (19%–66%) for patients who were respectively in CR or in relapse at transplant. 38/51 deaths were infection-related. Disease status was the major risk factor for relapse and EFS. Cumulative incidence of leukemia relapse was 27% (12%–45%) and 60% (30%–80%), p=0.006, for ALL patients in CR and relapse respectively; 17% (8%–29%) and 46% (29%–61%), p=0.0001, for AML in CR and relapse respectively. ALL and AML patients transplanted in relapse have, respectively, a 6% and 13% probability of surviving event-free. For those transplanted in remission, EFS is respectively 38% and 50% for ALL and AML patients in any CR at transplant. These results indicate the mismatched transplant should be offered to high-risk acute leukemia patients without a HLA-identical donor not as a last resort, but as a viable option in the early stages of the disease.