Search

Unmanipulated haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) has been an established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of treatment failure for patients with relapsed/refractory disease or with very high-risk gene mutations such as TP53, TET2, and DNMT3a. In this study, we aimed to establish the tolerance and efficacy of prophylactic donor lymphocyte infusion (DLI) with G-CSF-primed peripheral blood progenitors for prevention of relapse in these very high-risk patients after haplo-PBSCT. The prophylactic DLI was given at a median of 77 days after transplantation in 31 of 45 consecutive patients with very high-risk leukemia/lymphoma. The median dose of CD3 + cells for infusion was 1.8 × 10 7 /kg. The 100-day incidences of acute graft-versus-host disease (GVHD) grades 2-4 and 3-4 after DLI were 55.3% and 10.2%. The 2-year incidences of chronic GVHD and severe chronic GVHD were 52.0% and 18.2%. The 2-year incidences of non-relapse mortality and relapse were 33.1% and 32.5%. The 2-year probabilities of overall survival and relapse-free survival were 40.1% and 31.9%. Poor-risk gene mutations (p = 0.029), disease in non-remission status prior to transplantation (p = 0.005), and donors older than 40 years of age (p = 0.043) were associated with relapse after DLI. In multivariate analysis, disease in non-remission status prior to transplantation was an independent risk factor of relapse (hazard ratio = 4.079; p = 0.035). These data showed the feasibility of the prophylactic DLI in the haplo-PBSCT setting and the anti-leukemic efficacy in very high-risk leukemia/lymphoma.

Both European Group for blood and marrow transplantation risk score (EBMT score modified model) and hematopoietic cell transplantation comorbidity index (HCT-CI) are suitable for evaluating patients undergoing unmanipulated haploidentical blood and marrow transplantation (HBMT), while the predictive capacity of the combined model following haploidentical transplantation is still unknown. In this study, we calculated and validated 322 consecutive unmanipulated HBMT patients. Patients in groups with HCT-CI scores of 0 or 1-2 exhibited similar overall survival (OS), non-relapse mortality (NRM), and relapse rates, independent of their EBMT score modified model. In the group in which patients' HCT-CI scores were ≥3, patients with high EBMT score modified model showed lower OS (p = 0.003) and higher NRM (p = 0.001) than did patients with low EBMT score. In conclusion, this combined model can be used to predict outcomes and may improve the stratification of high-risk patients following unmanipulated HBMT.

This retrospective study compared the transplantation outcomes of 98 consecutive patients with acute leukemia. Allogeneic hematopoietic stem cell transplantation was performed using G-CSF-mobilized bone marrow and blood (G-BM&PB) or G-CSF-mobilized peripheral blood (G-PB) from HLA-identical sibling donors. The G-BM&PB and G-PB groups displayed significantly different neutrophil recovery rates (medians of 15 vs. 14 d, respectively; p = 0.009) but similar platelet recovery rates. The cumulative incidences of grades II-IV acute graft-versus-host disease (aGVHD) in the G-BM&PB and G-PB cohorts were similar (16.2 ± 4.7% vs. 21.8 ± 7.4%, respectively; p = 0.676), but the incidences of grades III-IV aGVHD were significantly different (5.5 ± 3.1% vs. 18.9 ± 7.1%, respectively; p = 0.042). The G-BM&PB and G-PB cohorts displayed similar cumulative incidences of chronic GVHD (cGVHD, 49.1 ± 5.7% vs. 42.7 ± 6.8%, respectively; p = 0.465), one-yr cumulative incidences of treatment-related mortality (16.5 ± 3.5% vs. 24.4 ± 4.1%, respectively; p = 0.220), and five-yr cumulative incidences of relapse (13.9 ± 4.8% vs. 26.8 ± 7.2%, respectively; p = 0.113). The five-yr probability of leukemia-free survival (LFS) was significantly higher in the G-BM&PB group than in the G-PB group (77.8 ± 5.2% vs. 57.6 ± 8.6%, respectively; p = 0.023). Multivariate analysis identified G-PB as an independent risk factor for grades III-IV aGVHD and LFS. Our results suggest that HLA-identical transplantation with G-BM&PB results in superior clinical outcomes compared with G-PB for patients with acute leukemia., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Either WT1 or leukemia-associated aberrant immune phenotypes (LAIPs) was one of the minimal residual disease (MRD) parameters used to predict leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We first evaluated the clinical value of various positive MRD standards for accurately indicating relapse based on WT1 and FCM data in adult patients with acute leukemia (AL). In total, 824 AL patients treated with allo-HSCT were enrolled in this study. We compared the sensitivity and specificity of diverse, multiple-criteria MRD prognostic standards based on WT1 and FCM assays. Higher sensitivity was achieved without a loss of specificity when MRDco+, which was defined as two consecutive WT10.6+ or FCM+ or both WT10.6+ and FCM+ in the same sample within a year posttransplantation, was used as the positive MRD standard. Similar results were observed, even in 484 patients who had both abnormal WT1 and LAIPs values before transplant. A multivariate analysis showed that MRDco+ was an independent risk factor for leukemia relapse after transplant in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The combined use of FCM and WT1 monitoring could distinguish between patients with low and high risks of relapse. Various positive MRD standards were useful for guiding intervention.

Background: Many patients who require allogeneic hematopoietic stem cell transplantation (allo-HSCT) lack a human leukocyte antigen (HLA)-matched donor. Recently, a new strategy was developed for HLA-mismatched/haploidentical transplantation from family donors without in vitro T cell depletion (TCD)., Methods: Over the past 9 years, 756 patients underwent haploidentical transplantation using a protocol developed by the authors, which combines granulocyte-colony stimulating factor-primed bone marrow (G-BM) and peripheral blood stem cells without in vitro TCD. The long-term outcome with this treatment modality was reported, and a risk-factor analysis was provided., Results: Of these patients, 752 (99%) achieved sustained, full donor chimerism. The incidence of grades 2 through 4 acute graft-versus-host disease (GVHD) was 43%, and the 2-year cumulative incidence of total chronic GVHD was 53%. The 3-year cumulative incidence of nonrelapse mortality was 18%. The 2-year cumulative incidences of relapse were 15% and 26% in the standard-risk and high-risk groups, respectively. Of the 756 patients, 480 survived throughout the follow-up period of 1154 days (range: 335-3511 days) with the 3-year leukemia-free survival rates of 68% and 49% in the standard-risk and high-risk groups, respectively. Lower leukemia-free survival was associated with high-risk disease status (P = .001), chronic myelogenous leukemia disease type (P = .004), neutrophil engraftment beyond 13 days after transplant (P = .012), and the occurrence of grades 2 through 4 acute GVHD (P = .019)., Conclusions: The results from the authors' 9-year experience showed that G-BM combined with peripheral blood stem cells from haploidentical donors, without in vitro TCD, is a reliable source of stem cells for transplantation by using the protocol developed by the authors., (Copyright © 2012 American Cancer Society.)

Objective: To explore the outcome of human leukocyte antigen (HLA)-mismatched/haploidentical hematopoietic stem cell transplantation (HSCT) for refractory/relapsed acute leukemia (AL) patients and its related risk factors., Methods: 96 refractory/relapsed AL patients who received HLA-mismatched/haploidentical HSCT following conditioning regimen comprised of modified busulfan/cyclophosphamide (BU/CY) plus thymoglobulin (ATG) from Jan 2003 to Jun 2011 were analyzed retrospectively., Results: Of the 96 patients, 61 suffered from acute myeloid leukemia (AML), and 35 acute lymphoid leukemia (ALL), all of them in non-remission (NR) or relapse before transplantation. With a median follow-up of 373 (34 - 3157) d, 33 cases (34%) survived, 31 survived without leukemia, and 35 relapsed. The estimated 3-year overall survival (OS) and disease-free survival (DFS) rate was 30.2% and 29.0%, respectively. The 3-year OS rate was significantly higher for AML patients (39.2%) than for ALL patients (15.4%) (P = 0.005). The estimated 3-year OS probabilities for patients with and without prophylactic donor lymphocyte infusion (DLI) were 38.0% and 11.8%, respectively (P = 0.001). Sex, age, conditioning regimen (BU/CY or not, dosage of ATG), the number of HLA mismatches between the donor and recipient, and the number of infused mononuclear cells were not independent factors affecting OS, DFS and relapse. Multivariate analysis showed that DFS rate was significantly higher in patients receiving prophylactic DLI (P = 0.003), in patients with AML (vs with ALL) (P = 0.037) and with chronic GVHD (P = 0.006)., Conclusions: Haploidentical HSCT may prolong DFS in part refractory/relapsed AL patients and even cure them. Prophylactic DLI may reduce relapse and increase survival; for patients with refractory/relapsed ALL, other therapy for prevention and treatment of post-transplant relapse should be explored.

Background: Chimerism analysis is an important tool for the surveillance of post-transplant engraftment. It offers the possibility of identifying impending graft rejection and recurrence of underlying malignant or non-malignant disease. Here we investigated the quantitative chimerism kinetics of 21 relapsed leukemia patients after allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: A panel of 29 selected sequence polymorphism (SP) markers was screened by real-time polymerase chain reaction (RT-PCR) to obtain the informative marker for every leukemia patient. Quantitative chimerism analysis of bone marrow (BM) samples of 21 relapsed patients and 20 patients in stable remission was performed longitudinally. The chimerisms of BM and peripheral blood (PB) samples of 14 patients at relapse were compared., Results: Twenty-one patients experienced leukemia relapse at a median of 135 days (range, 30 - 720 days) after transplantation. High recipient chimerism in BM was found in all patients at relapse, and increased recipient chimerism in BM samples was observed in 90% (19/21) of patients before relapse. With 0.5% recipient DNA as the cut-off, median time between the detection of increased recipient chimerism and relapse was 45 days (range, 0 - 120 days), with 76% of patients showing increased recipient chimerism at least 1 month prior to relapse. Median percentage of recipient DNA in 20 stable remission patients was 0.28%, 0.04%, 0.05%, 0.05%, 0.08%, and 0.05% at 1, 2, 3, 6, 9, and 12 months, respectively, after transplantation. This was concordant with other specific fusion transcripts and fluorescent in situ hybridization examination. The recipient chimerisms in BM were significantly higher than those in PB at relapse (P = 0.001)., Conclusions: This SP-based RT-PCR assay is a reliable method for chimerism analysis. Chimerism kinetics in BM can be used as a marker of impending leukemia relapse, especially when no other specific marker is available. Based on our findings, we recommend examining not only PB samples but also BM samples in HSCT patients.

We studied the impact of risk stratification-directed interventions for minimal residual disease (MRD) on relapse and disease-free survival (DFS) prospectively in 814 subjects with standard-risk acute leukemia receiving allotransplantation in first or second complete remission. A total of 709 subjects were MRD(-) after transplantation (Group A); 105 subjects were MRD(+), 49 received low-dose IL-2 (Group B), and 56 received modified donor lymphocyte infusion (DLI) with or without low-dose IL-2 (Group C). Posttransplantation immune suppression for GVHD was also modified based on MRD state. The cumulative risk of relapse was significantly less and DFS was significantly better in subjects in Group C than in subjects in Group B (P = .001 and P = .002, respectively), but was not different from subjects in Group A (P = .269 and P = .688, respectively). Multivariate analyses confirmed that MRD state and modified DLI were significantly correlated with relapse (P = .000, odds ratio [OR] = 0.255 and P = .000, OR = 0.269) and DFS (P = .001, OR = 0.511 and P = .006, OR = 0.436, respectively). These data suggest that risk stratification-directed interventions with modified DLI in patients with standard-risk acute leukemia who are MRD(+) after transplantation may improve transplantation outcomes.

The outcomes of an historic comparison of 117 consecutive, high-risk, acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) from HLA-mismatched/haploidentical donors (HID, n = 81) or HLA-identical sibling donors (ISD, n = 36) without the use of in vitro T cell depletion (TCD), between the period of January 2005 and April 2009 were compared. Full engraftment was achieved in 98% of patients in the HID group and 97% in the ISD group. The cumulative incidences of grades II-IV acute graft-versus-host disease (aGVHD) in the HID and ISD cohorts were 49% and 24%, respectively (P = .014) with a relative risk (RR) of 2.99 (1.25-7.21) (P = .014). The incidence of chronic GVHD (cGVHD) did not differ significantly between the 2 cohorts. The 2-year cumulative incidence of relapse was significantly lower in HID (26%) than in ISD patients (49%) (P = .008). The 2-year cumulative incidence of nonrelapse mortality (NRM) was comparable in recipients of HID (34%) and ISD grafts (38%) (P = .85). The 3-year probability of overall survival (OS) was higher in HID patients (42%) than in ISD (20%) (P = .048) patients. Our comparisons suggest that HID transplants can achieve a stronger graft-versus-leukemia (GVL) effect than ISD for high-risk acute leukemia patients., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the safety and efficacy of second allogeneic hematopoietic stem cell transplantation for the relapsed hematologic malignancies., Methods: The data of 25 relapsed patients received the second allogeneic transplantation as a salvage therapy in Institute of Hematology Peking University between October 1999 and March 2010 were analyzed retrospectively. Twenty-four patients relapsed at 8.8 (1 - 55) months after the first transplantation, except one received the second transplantation as prophylaxis therapy. They received the second transplantation after 3 (0.3 - 20) months' therapy. The median time between the 2 transplants was 10.6 (0.6 - 59.0) months., Results: Most of the patients were given the conditioning regimen including total body irradiation (TBI, 700 - 779 cGy) or modified busulfan and cyclophosphamide (BUCY, BU 12 mg). All patients survived more than 30 days and achieved sustained white blood cell engraftment. Sinus obstructive syndrome, irradiation dermatitis and acute myocardial infraction were occurred in 3 patients and recoverable. Until January 31 in 2011, with a median observation period of 9.1 (2.0 - 131.1) months, 8 patients had been living with a overall survival (OS) of 30.9%. Twelve patients relapsed at a median 4.4 months and 10 died of it. The other 7 patients died of transplant related complications. The non-relapsed mortality was 35.1%. The disease status at the 2nd transplantation was the only factor which effected the OS (P = 0.009)., Conclusions: The second allogeneic transplantation is a viable option for patients relapsing after the first transplantation. Reduced intensive conditioning regimen ensures the graft engraftment and reduces transplant related toxicity.

Objective: To investigate the efficacy and safety of secondary anti-fungal prophylaxis (SAP) in haematopoietic stem cell recipients who had a history of antecedent invasive fungal infection (IFI)., Methods: The patients with hematological diseases, who were scheduled to undergo haematopoietic stem cell transplantation (HSCT) in our unit from April 2005 to July 2008, received our routine conditioning regimen. Patients, who had a history of antecedent IFI, were given SAP from the start of conditioning chemotherapy until the end of the at-risk period. We chose the effective antifungal drug that was used for antecedent IFI as the secondary prophylaxis drug., Results: There were 26 patients at entry. Six patients had probably adverse events (AEs) related to the secondary prophylaxis drug during the prophylactic process and the secondary prophylaxis terminated in two patients because of AEs. The remaining patients received SAP for a medium of 75 days (range 10 - 212 days). Relapsing IFI occurred in four patients during SAP and in one after SAP. The rate of relapsing IFI was 19.2% (5/26). The median time of relapsing IFI was day 42 (range, 1 - 146). The mortality rate among relapsed patients was 60.0% (3/5). No risk factors that might be associated with IFI was identified by logistic regression model., Conclusion: Prior IFI is not an absolute contraindication for HSCT. Secondary antifungal prophylaxis can reduce the risk of recurrent infection in patients with prior IFI, but its schedule and time of therapy need further study.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the best therapeutic options to cure acute leukemia (AL). However, many patients have no human leukocyte antigen (HLA)-matched donor. Recently, we developed a new method for HLA-mismatched/haploidentical transplantation without in vitro T cell depletion (TCD). This method combined granulocyte-colony stimulating factor (G-CSF)-primed bone marrow and peripheral blood with intensive immunosuppression. We analyzed the outcome of 250 consecutive patients with AL who underwent HLA-mismatched/haploidentical transplantation with 1-3 mismatched loci of HLA-A, B, and DR from family donors via our new transplant protocol. Two hundred forty-nine patients achieved sustained, full donor chimerism. The incidence of grade 2-4 acute graft-versus-host disease (aGVHD) was 45.8%, and that of grades 3 and 4 was 13.4%, which was not associated with the extent of HLA disparity. The cumulative incidence of total chronic GVHD (cGVHD) was 53.9% and that of extensive cGVHD was 22.6% in 217 evaluable patients. One hundred forty-one of the 250 patients survived free of disease recurrence at a median of 1092 days (range: 442-2437 days) of follow-up. Seventeen patients received DLI as a treatment for relapse after transplantation and 7 patients achieved leukemia-free survival (LFS). The 3-year probability of LFS for acute myelogenous leukemia (AML) was 70.7% and 55.9%, and for acute lymphoblastic leukemia (ALL) it was 59.7% and 24.8% in standard-risk and high-risk groups, respectively. Lower LFS were associated with diagnosis of acute leukemia in the high-risk group (P= .001, relative risk [RR], 95% confidence interval [CI]: 2.94[1.535-5.631]) and the occurrence of aGVHD of grades 3 and 4 (P= .004). HLA-mismatched/haploidentical HSCT was feasible with unmanipulated blood and bone marrow harvest.

Purpose: We retrospectively evaluated the feasibility and safety of a modified prophylactic donor lymphocytes infusion (DLI) approach in advanced leukemia., Materials and Methods: Thirty-three patients with advanced leukemia received modified prophylactic DLI; that is, granulocyte colony-stimulating factor-primed peripheral blood progenitor cells instead of steady-donor lymphocyte harvests were used, and a short-term immunosuppressive agent (cyclosporine A or methotrexate 10 mg once per week for 2 to 4 weeks) was used for prevention of DLI-associated graft versus host disease (GVHD) after human leukocyte antigen-identical sibling hematopoietic stem cell transplantation., Results: Thirty-nine infusions were performed in 33 patients. The mononuclear cells and median CD3+ cells infused for DLI were 1-2 x 10(8) and 0.93 x 10(6) per kilogram, respectively. Six patients experienced II-IV-grade acute GVHD. Twenty patients developed chronic GVHD. No GVHD-related death or transfusion-related pancytopenia was observed. With an 18-month median follow-up, 16 patients were in disease-free survival, and overall survival at 1 and 1.5 years was 69.0% and 50.2%, respectively., Conclusion: The modified prophylactic DLI strategy might represent a step forward in the treatment of advanced leukemia.

Objective: This study aimed to confirm localized residual leukaemia in the abnormal expanded peripheral bone marrow (e-PBM) of the extremities using Tc-sulfur colloid imaging and bone marrow aspirations., Methods: Whole-body bone marrow scintigraphy was performed in 420 adult and 48 childhood leukaemia patients using Tc-sulfur colloid (370 MBq). Central bone marrow (CBM) from the iliac crest and e-PBM from the proximal epiphyseal line of the tibia were aspirated at the time of routine examination and compared., Results: The expansion rate of the PBM in the non-remission stage of acute leukaemia was 73.1%, and it decreased to 38.4% in the complete remission stage. The most common site of PBM expansion was the epiphysis of the knee joint (74.5%). Cytological examination of the e-PBM at the complete remission stage revealed 30.9% localized residual leukaemia. The complete remission period (69+/-23 days) of PBM expansion was significantly greater than that of CBM depletion (43+/-31 days) (P<0.01). Localized residual leukaemia of the e-PBM could not be detected in the childhood acute leukaemia patients and in the patients without e-PBM. The difference in the relapse rate and time was statistically significant between patients with e-PBM (29.1%) and without e-PBM (3.5%) (P<0.01)., Conclusion: These findings suggest that induction chemotherapy does not always have a synchronous and parallel effect on CBM and PBM. The e-PBM is less sensitive to chemotherapy and can easily exist in localized residual leukaemia. The detection of residual leukaemia in the e-PBM by bone marrow scintigraphy is very important in the treatment of leukaemia.

Objective: To explore the incidence and risk factors of hepatic events and overall survival among HBsAg positive leukemia patients after allo-hematopoietic stem cell transplantation (allo-HSCT)., Methods: A retrospective clinical study was conducted at the bone marrow transplant unit in our hospital between March 2001 and November 2006. A total of 26 HBsAg positive leukemia patients were included in the study. 18 patients received HLA-identical sibling allo-HSCT, 7 patients received HLA-mismatched related and 1 patient received HLA-identical unrelated. All the patients were free from hepatitis C infection before and after allo-HSCT. HBV serologic markers, including HBsAg, HBeAg, HBsAb, HBeAb and HBcAb were tested. 2 patients were positive for HBV-DNA before allo-HSCT., Results: The cumulative incidence for acute graft vs host disease (aGVHD) grades I -IV was 50.0%. The cumulative incidence for chronic GVHD was 25.0%. 15 (57.7%) of all the patients had abnormalities of liver function after allo-HSCT. The types of hepatic disease were reactivation of HBV and hepatic GVHD. The cumulative incidence in 5 years for hepatitis B reactivation was 33.4%, the median day of hepatitis B reactivation was 82th (65th-159th) day. The virologic and clinical outcomes were compared between two groups; one received lamivudine as prophylactic (group 1) and the other did not receive lamivudine (group 2). After transplantation, 1 patient in group 1 and 7 patients in group 2 had hepatitis due to reactivation of HBV. The cumulative incidence for hepatitis B reactivation was statistically different between the two groups (P= 0.006). None in group 1 but 4 in group 2 died of HBV-related hepatic failure. 10 of the 26 patients died after transplantation. The overall survival (OS) in 5 years was 59.0%. The causes of death included hepatic failure (5 cases), lung infection (3 cases) and relapse of leukemia (2 cases). By multivariate Cox analysis, development of hepatic failure was a significant predictor of mortality (P = 0.000)., Conclusion: HBsAg positive leukemia patients often suffered from hepatic injury after allo-HSCT. The principal cause of hepatic damage was the reactivation of HBV. Hepatic failure caused by HBV was the principal reason of death. Prophylaxis with lamivudine in HBsAg positive leukemia recipients can reduce the reactivation of HBV.

Objective: To observe the efficacy and safety of donor lymphocyte infusion (DLI) for treatment of leukemia relapse after HLA-mismatched hematopoietic stem cell transplantation (HSCT)., Methods: Patients received DLI were studied for the occurrence of graft-versus-host disease (GVHD) , remission of leukemia and long-term survival after granulocyte colony-stimulating factor (G-CSF). G-CSF-primed DLI and GVHD prophylaxis (some received chemotherapy)., Results: Acute grade III - IV GVHD was observed in 8 of 24 patients relapsed after HSCT and GVHD prophylaxis reduced the incidence (P = 0.013). Eight patients developed chronic GVHD and myelosuppression in three patients. Sixteen of twenty-four patients achieved complete remission. Nine of them survived leukemia-free for a median of 1310 (961 - 1914) days after HSCT. The 1-year and 2-year probability of leukemia-free survival was 60% and 40%, respectively. The number of blasts influenced on remission and survival. Occurrence of extensive chronic GVHD was related to higher remission rate (P = 0.046). All three patients with Ph-positive acute lymphoblastic leukemia died of relapse., Conclusion: The G-CSF-primed DLI with GVHD prophylaxis(some combined with chemotherapy) is a potentially effective therapeutic option for patients with relapsed leukemia after HLA-mismatched HSCT.

Objective: To retrospectively analyze the results of a consecutive series of 90 refractory/relapsed acute leukemia (AL) patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) in our center., Methods: Of the 90 refractory/relapsed AL patients, 56 were male and 34 female, with a median age of 37 (13 - 59) years. Among them, 73 patients suffered from AL including 11 Ph+ acute lymphoid leukemia in first complete remission, 23 in second or greater complete remission, 39 in non-remission or relapse and 17 patients suffered from myelodysplastic syndrome (MDS-RAEB or RAEB-T) before transplant. Allo-HSCT from HLA identical siblings was performed for all the patients, of whom 27 received bone marrow transplantation (BMT), 30 peripheral blood stem cell transplantation (PBSCT) and 33 BMT + PBSCT. Eleven patients underwent allo-HSCT with conditioning regimen of CY/TBI and 79 with BU/CY. CsA + MTX regimen was use for prophylaxis of graft-versus-host disease (GVHD). The average follow-up was 15 months., Results: At the last follow-up, 56/90 (62.2%) survived, 50/90 (55.5%) survived without leukemia and 28/90 (31.1%) relapsed. The estimated 4-year overall survival (OS) and disease-free survival (DFS) of the 90 cases was 45.5% and 34.9%. The 4-year OS and DFS were significantly higher for patients in CR (54.0%) or MDS (70.1%) than in non-remission and relapsed (28.2%) patients before allo-HSCT (P = 0.027). The outcome of grade 0-I acute GVHD was better than that of II-IV GVHD (57.6% vs 26.7%, P = 0.015). Sex, age, central nervous system leukemia, conditioning regimen and the source of stem cell were not the factors affecting OS, DFS, cumulative incidences of relapse rate and treatment related mortality. Multivariate analysis showed the most significant factor associated with high DFS was the disease state., Conclusions: allo-HSCT can cure a significant proportion of refractory/relapsed AL patients, especially for those in CR. Early allo-HSCT is recommended for MDS patients.

Objective: To study the safety and effect of G-CSF mobilized donor hematopoietic stem cells infusion (GPBSCI) as the therapy for the failure of platelet recovery after allogeneic hematopoietic stem cell transplantation., Methods: The clinical data of 15 patients with acute or chronic leukemia undergoing GPBSCI 16 times, 9 males and 6 females, aged 33 (14 approximately 48), were retrospectively analyzed., Results: The median number of mononuclear cells (MNC) from bone marrow was (4.21 +/- 1.91) x 10(8)/kg (1.50 x 10(8)/kg approximately 7.46 x 10(8)/kg). The median number of MNCs from peripheral blood was (3.27 +/- 1.40) x 10(8)/kg (1.13 x 10(8)/kg approximately 5.90 x 10(8)/kg). The median CD34+ count was (2.13 +/- 1.69) x 10(6)/kg (0.24 x 10(6)/kg approximately 5.67 x 10(6)/kg). All the patients had achieved white cell engraftment. 8 patients with primary failure of platelet recovery and 7 patients with secondary failure of platelet recovery received donor peripheral stem cells infusion. The median day of infusion was +113 days (43 approximately 384 days). The median number of infused mononuclear cells was (3.09 +/- 1.54) x 10(8)/kg (1.35 approximately 5.99) x 10(8)/kg. Only 1 patient had transfusion related GVHD. Clinical efficacy was seen in 9 patients (56.3%). The efficacy of infusion within 100 day after transplantation was 87.50%, significantly higher than that conducted 100 days after the transplantation (25.00%, P = 0.012)., Conclusion: With minimal side effect, GPBSCI may be an effective strategy for the therapy of failure of platelet recovery.

In this study, we tested the efficacy and safety of donor lymphocyte infusion (DLI) with granulocyte colony-stimulating factor (G-CSF) priming in patients who relapsed after haploidentical hematopoietic stem cell transplantation (HSCT). Twenty patients received DLI at a median of 177 days after HSCT. Eight patients survived in complete remission for a median of 1118 days. The 2-year probability of leukemia-free survival was 40%. Acute graft-versus-host disease (GVHD) grade 3-4 occurred in six patients after DLI. GVHD prophylaxis reduced the incidence of acute GVHD. Our primary data showed that G-CSF-primed DLI with GVHD prophylaxis was a potentially effective therapeutic option for patients who relapsed after haploidentical HSCT.

Objective: To compare the outcomes in hematological patients receiving unrelated peripheral blood stem cell transplants (UPBSCT) with those receiving unrelated bone marrow transplants (UBMT) in a retrospective analysis., Methods: Sixty-three patients with hematological diseases with HLA-matched (65%) or mismatched (35%) unrelated donors were receiving UPBSCT (n = 33) or UBMT (n = 30) between May 2001 and June 2005 in our institute. They all received standard conditioning regimens with Bu/Cy (n = 53) or TBI/Cy (n = 10) with the addition of ATG for 3 - 4 days (n = 58) or CD3 antibody (n = 5). There were more patients receiving rabbit ATG in the UPBSCT group than UBMT (21/33 vs 8/25, P = 0.02) and the remaining patients received pig ATG. Graft versus host disease (GVHD) prophylaxis consisting of cyclosporine, methotrexate and mycophenolate mofetil were the same., Results: The two groups were matched for the following factors: gender, diagnosis, HLA-compatibility and conditioning regimens. The median age in the UPBSCT group was 29.5 (10 - 47) years and in the UBMT 21.5 (7 - 42) years (P < 0.05). The UPBSCT group consisted of 10 females and 23 males and the UBMT group 7 females and 23 males. Eleven patients in the UPBSCT and 8 patients in the UBMT group were diagnosed with as chronic myeloid leukemia (CML); 9 and 12 as acute myelocytic leukemia (AML); 11 and 10 as acute lymphatic leukemia (ALL); 2 and 0 as severe aplastic anemia (SAA). There were more patients in aggressive stage (>CR1) in the UBMT group than in the UPBSCT group (9/30 vs 3/33, P = 0.06). Median follow-up was 12 months after UPBSCT and 20 months after UBMT (P < 0.05). UPBSCT group had a higher number of infused MNC as comparison with UBMT group (6.16 x 10(8)/kg vs 2.80 x 10(8)/kg, P < 0.05). Both neutrophil and platelet recovery were faster after UPBSCT (11 days vs 17 days, 14 days vs 27.5 days, P < 0.01). Although the cumulative incidence of grades II - IV acute GVHD and severe aGVHD in the UPBSCT group were less than in the UBMT group (33.04% vs 66.69%, 7.26% vs 34.52%, P < 0.05), there was no difference after the source of ATG was counted. The incidence of chronic GVHD did not differ between the two groups (18/25 vs 14/22). Relapse including molecular relapse occurred in 6 of the 31 patients after UPBSCT and in 4 of the 30 patients after UBMT (P > 0.05). Finally, fifteen of the 30 patients died after UBMT, as compared with 8 of the 33 patients after UPBSCT. The cumulative overall survival was 62.45% after UPBSCT and 47.22% after UBMT (P = 0.114)., Conclusion: Our results indicate that UPBSCT led to significantly faster leukocyte and platelet engraftment without increasing the incidence of aGVHD and the overall survival was comparable between the two methods of therapy.

The outcomes of 293 patients with leukemia undergoing HLA-identical sibling (n = 158) or related HLA-mismatched (n = 135) hematopoietic cell transplantation (HCT) performed during the same time period were compared. Patients received BUCY2 in HLA-identical sibling HCT or BUCY2 + ATG in mismatched HCT as conditioning regimens, followed by unmanipulated marrow and/or peripheral blood (PB) transplantation. All patients achieved full engraftment. The cumulative incidences of grades II to IV acute graft-versus-host disease (aGVHD) in the matched and mismatched cohorts were 32% (CI, 25%-39%) versus 40% (CI, 32%-48%, P = .13), respectively, with the relative risk (RR) = 0.64 (95% CI, 0.43-0.94), P = .02. The incidence of chronic GVHD did not differ significantly between the cohorts (P = .97). Two-year incidences of treatment-related mortality and relapse for matched versus mismatched were 14% (range, 9%-20%) versus 22% (range, 15%-29%) with P = .10 and 13% (range, 8%-19%) versus 18% (range, 10%-27%) with P = .40, respectively. Two-year adjusted leukemia-free survival (LFS) and overall survival were 71% (range, 63%-78%) versus 64% (range, 54%-73%) with P = .27 and 72% (range, 64%-79%) versus 71% (range, 62%-77%) with P = .72, respectively. Multivariate analyses showed that only advanced disease stage and a diagnosis of acute leukemia had increased risk of relapse, treatment failure, and overall mortality. In summary, HCT performed with related HLA-mismatched donors is a feasible approach with acceptable outcomes.

Objective: To study the effect of growth factor-primed donor hematopoietic stem cells infusion (GPBSCI) as an early adoptive immunotherapy., Methods: Twelve patients with high-risk leukemia received prophylactic GPBSCI after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Out of the 12 patients, two were Ph(+) ALL in CR(1), one ALL in CR(2), one refractory ALL, three AML (one in relapse, one refractory disease, one in CR(3)), four CML in advanced stage and one myelodysplastic syndrome-refractory anemia with excess blast (MDS-RAEB)., Results: Sixteen infusions were performed in the 12 patients, including 5 infusions were performed within +90 days post-SCT. The median mononuclear cells (MNC) and CD3(+) cells infused for GPBSCI before +90 d were 1.00 (0.95 - 1.24) x 10(8)/kg and 0.53 (0.39 - 0.63) x 10(8)/kg, and after +90 d were 2.27 (1.00 - 4.30) x 10(8)/kg and 1.15 (0.55 - 2.10) x 10(8)/kg, respectively. Four patients developed grade I - II acute GVHD, and one grade III acute GVHD. Seven patients developed chronic GVHD, of which four cases were extensive. Two patients had no transfusion related GVHD. No transfusion related pancytopenia was observed. Ten patients survived disease-freely at 563 (415 - 728) days of follow-up. Two patients died of leukemia relapse after GPBSCI., Conclusion: Allo-HSCT with prophylactic GPBSCI could maximize graft-versus-leukemia effect with few fatal complications and might be a potentially curative strategy for hematological malignancy patients with high risk of relapse.

This study was aimed to investigate various factors influening erythrocyte recovery following ABO-incompatible allogeneic HSCT. 157 patients following ABO-incompatible allogeneic HSCT were selected for the investigation. Cox regression analysis were used to identify the statistically significant factors including sex, age, schemes of transplantation, HLA-matched, mismathed, conditioning regimens, preventive measures for GVHD, occurrence of grade I-II GVHD, CMV infections and types of incompatible blood group. The results showed that minor ABO-incompatible, number of mononuclear cells infused, age of patients and unrelated BMT were four important main factors influening the erythrocyte recovery. In conclusion, the erythrocyte recovery is more quick in patients with minor ABO-incompatible and more number of mononuclear cells infused, while it is slow in patents with old age and unrelated BMT.

Objective: To investigate the new methods of human leukocyte antigen (HLA) mismatched transplantation in patients with hematologic malignancies., Methods: In this pilot study, 58 patients, 33 with high-risk or advanced leukemia, were transplanted with cells from an HLA-haploidentical family donor with at least 1 of 6 loci mismatched. After conditioning, patients received non ex vivo, T cell-depleted grafts of G-CSF-primed bone marrow plus G-CSF-mobilized peripheral blood stem cells, as well as graft-versus-host-disease (GVHD) prophylaxis., Results: All patients achieved sustained, full donor type engraftment. The incidence of grades II-IV acute GVHD was 37.9% (22 of 58), and grades III and IV aGVHD developed in only 2 and 1 patients, respectively. Furthermore, there was no statistically significant association between the extents of HLA mismatching and the degree of aGVHD. Twenty six of 42 (61.9%) evaluable patients had developed chronic GVHD (cGVHD) with limited cGVHD in 15. Nine patients relapsed, all but one with advanced or refractory leukemia. Fourteen patients died (24.1%), of whom 7 died of recurrent diseases and 7 of transplant-related complications (TRM): main causes of TRM were infection(2), intestinal pneumonia(2), CMV encephalitis(1), hepatitis(1) and aGVHD (1). Forty-four of the 58 patients (75.9%) survived and 42 (72.4%) were disease free with a median follow-up of 10 months (range, 2 to 37.5 months). The 2-year probabilities of disease-free survival for patients with standard and high risks were 77.6% and 63.2% respectively, which showed that high-risk disease status at transplantation was associated with worse disease-free survival (P=0.04). The degree of HLA mismatching between the donor and the recipient was not related to event-free survival (P=0.57), nor was cell number infused and aGVHD (P=0.78, 0.94 respectively)., Conclusion: (1)HLA mismatched transplantation can be per formed without ex vivo T cell depletion. (2)Using G CSF mobilized PBSCs as a source of stem cells may be possible and safe even in HLA mismatched transplantation.

A total of 123 consecutive patients with advanced-stage, acute leukemia undergoing HSCT from HLA-identical sibling donors were analyzed. A G- CSF-primed DLI was planned within day 60 post-transplantation before hematologic relapse was diagnosed. Fifty of the 123 individuals received prophylactic DLI, and 73 individuals received no prophylactic treatment. The incidence of grades II- IV acute graft-versus-host disease ( GVHD) was 17% for patients receiving DLI and 23% for patients not receiving DLI (p = 0.35). The incidence of chronic GVHD was 38% for patients receiving DLI and 17% for patients not receiving DLI (p = 0.021). The two-yr cumulative incidence of relapse was significantly lower in patients who received prophylactic DLI (46%) compared with patients who did not receive prophylactic DLI (66%) (p = 0.02). The three-yr probability of overall survival was higher in patients who received prophylactic DLI (36%) than in patients who did not receive prophylactic DLI (11%) (p = 0.001). The leukemia-free survival was also higher in patients who received prophylactic DLI (29%) than in patients who did not receive prophylactic DLI (9%) (p = 0.001). Our comparisons suggest that the prophylactic use of DLI can significantly increase survival of patients with advanced-stage, acute leukemia who receive HLA-identical sibling HSCT. [ABSTRACT FROM AUTHOR]

In this study, we prospectively investigated the immune reconstitution in patients with hematological malignancies after human leukocyte antigen (HLA)-mismatched/unmanipulated haploidentical transplantation (50 cases) and HLA-matched transplant (25 cases). Transplant-related mortality, relapse, leukemia-free survival, and overall survival were similar between the two transplant strategies, although the cumulative incidence of CMV antigenemia was significantly higher in haploidentical recipients than in HLA-matched recipients (49.9 ± 7.2% versus 13 ± 7%, P = 0.007). Compared with HLA-matched recipients, T-cell subset and dendritic cell subgroup cell counts in the first 90 days after grafting were lower in haploidentical recipients. The difference was most striking for CD4 and CD4 naïve T cells. Reconstitution of B cells and monocytes was comparable between groups. T cells appeared equally functional in both groups among patients without graft-versus-host disease. Our results suggest that the clinical outcomes were not compromised by the early delayed immune reconstitution following haploidentical transplantation. [ABSTRACT FROM AUTHOR]

This study evaluated the prognostic value of minimal residual disease (MRD) monitoring by four-color flow cytometry (FCM) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). MRD was examined with four-color FCM at different time points in 139 patients (including pediatric and adult patients) with ALL after allo-HSCT. Real-time quantitative polymerase chain reaction (RQ-PCR) was applied to evaluate the MRD of Philadelphia chromosome-positive ALL (Ph+ ALL) patients. Patients who were FCM-positive (FCM+) after transplantation had a lower event-free survival (EFS) of 0.54 and a higher cumulative incidence of relapse (CIR) of 0.54 compared to an EFS of 0.80 and a CIR of 0.08 in FCM-negative (FCM−) patients (EFS, p < 0.001; CIR, p < 0.001). Similar results were obtained in high-risk patients and Ph+ ALL patients. Moreover, a FCM+ status after the second month post-HSCT (defined as MRD positive) proved to be a predictor of leukemia relapse. Multivariate analysis for EFS, OS and CIR showed that MRD status after transplantation was an independent prognostic factor ( p < 0.001, p = 0.013, and p < 0.001, respectively). A good correlation was found between the MRD results of FCM and RQ-PCR ( n = 126 pairs, Spearman r = 0.8139, p < 0.001). MRD monitoring by four-color FCM post-transplantation is an important tool for relapse prediction in ALL patients. Prompt and appropriate pre-emptive anti-leukemia treatment could be considered based on the status of MRD after HSCT. [ABSTRACT FROM AUTHOR]

Abstract: To evaluate the prognostic value of the expression of the mixed lineage leukemia (MLL) gene for predicting the relapse of patients with MLL-rearranged acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the levels of MLL transcripts in bone marrow (BM) specimens were monitored serially by real-time quantitative polymerase chain reaction (RQ-PCR) at predetermined time points in 40 patients with MLL-rearranged AL who were treated with allo-HSCT. These patients were followed for a median of 24.5 months (range, 8 to 60 months). A total of 236 BM samples were collected and analyzed. Of these, 230 were monitored concurrently for minimal residual disease (MRD) by flow cytometry (FCM) for leukemia-associated aberrant immune phenotypes and by RQ-PCR for the expression of the Wilms tumor (WT1) gene. The 3-year cumulative incidence of relapse in patients who experienced MLL-positive patients (MLL > .0000%) (n = 9) after HSCT was 93.5% (95% confidence interval [CI], 87% to 100%) compared with 12.5% (95% CI, 5.6% to 19.4%) for MLL-negative patients (n = 31) (P < .001). For these 2 patient groups, the 3-year overall survival (OS) was 12.5% (95% CI, .8% to 24.2%) and 77.8% (95% CI, 68.4% to 87.2%) (P < .001), respectively, and the 3-year leukemia-free survival (LFS) was 0% and 72.2% (95% CI, 61.1% to 83.3%), respectively (P < .001). MLL positivity was associated with a higher rate of relapse (hazard ratio [HR], 18.643; 95% CI, 3.449 to 57.025; P = .001), lower LFS (HR, 7.267; 95% CI, 2.038 to 25.916; P = .002), and lower OS (HR, 8.259; 95% CI, 2.109 to 32.336; P = .002), as determined by Cox multivariate analysis. The expression of the MLL gene had a higher specificity and sensitivity than WT1 or MRD monitored by FCM for predicting the relapse of the patients with MLL + AL. Our results suggest that monitoring the expression of the MLL gene may help to identify patients with MLL + AL who are at high risk of relapse after allo-HSCT and may provide a guide for suitable intervention. [Copyright &y& Elsevier]