Probability Of Leukemia-free Survival Research Articles

The Impact of Center Experience on Results of Reduced Intensity – Allogeneic Hematopoietic Stem Cell Transplantation. A Survey From the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT)

AbstractAbstract 3517Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning (RIC-HSCT) is increasingly applied for the treatment of patients with acute myeloid leukemia. However, the procedure is heterogeneous with no standards based on randomized trials being elaborated so far. Hence, particular therapeutic decisions are in major part based on individual experience.The goal of this study was to evaluate the impact of center experience on outcome of RIC-HSCT. Based on the registry of ALWP of the EBMT, we analyzed results of 1413 HLA-matched related (n=1058) or unrelated (n=355) transplantations performed in 203 European centers between 2001 and 2007. Only patients with AML in first complete remission were included. Median recipient age was 55 years (range, 18–77 y.). Centers were categorized by quintiles according to the number of RIC-HSCT procedures in a study period.The 2 years probability of leukemia-free survival (LFS) after RIC-HSCT performed in centers with the lowest activity (1st quintile, ≤ 15 procedures/7 years) equaled 43% compared to 55% in the remaining ones (p<0.001). The incidence of non-relapse mortality (NRM) was 24% and 15%, respectively (p=0.004). In a multivariate model adjusted for other potential prognostic factors low RIC-HSCT activity was associated with decreased chance of LFS (HR=0.69, p<0.001) as well as increased risk of NRM (HR=1.69, p=0.001) and relapse (HR=1.37, p=0.01). No significant differences were found between centers belonging to the 2nd -5th quintile.We conclude that center experience is a strong predictor of outcome and should be considered for future analyses evaluating results of RIC-HSCT. Disclosures:Off Label Use: Dasatinib as first line therapy in Ph ALL.

The Prophylactic Use of G-CSF During Induction and Consolidation of Adults with Acute Lymphoblastic Leukemia Is Associated with Reduced Risk of Relapse and Improved Leukemia-Free Survival. A Joint Analysis of Five Randomized Trials on Behalf of the European Working Group for Adult ALL (EWALL)

AbstractAbstract 2130The use of granulocyte colony stimulating factor (G-CSF), either filgrastim or lenograstim, along with induction and consolidation of adults with acute lymphoblastic leukemia (ALL) was a subject of several trials documenting significant shortening of neutropenia, reduced rate of infections and better adherence to chemotherapy protocol. The above studies, however, were not powered to detect differences with regard to long-term outcome.We performed a joint analysis of follow-up data from five multicenter prospective, randomized trials performed in France, Poland, Sweden, Austria and Australia. Among 347 adults with ALL (median age 33 years), 185 were assigned to receive prophylactically G-CSF while 162 patients were treated without G-CSF support. G-CSF was administered either in parallel to chemotherapy or in a sequential mode.With the median follow-up of 3.2 years, the remission duration was significantly longer for patients receiving G-CSF compared to controls (33 vs. 17 months, p=0.007). The difference was particularly pronounced for T-ALL (median not reached vs. 13 m., p=0.01) and a trend was observed for B-ALL (22 vs. 17 m., p=0.11). The 5-years probability of leukemia-free survival (LFS) was 38% for patients assigned to the G-CSF arm and 23% for the remaining subjects (p=0.01). There was also a tendency to increased overall survival (OS) rate in favor of patients receiving G-CSF (45% vs. 39%, p=0.17), which reached statistical significance in a subgroup of T-ALL (54% vs. 33%, p=0.03). In a multivariate analysis adjusted to age, initial WBC and the presence of Ph chromosome the prophylactic use of G-CSF was associated with reduced risk of relapse (HR=0.65, p=0.01) and treatment failure (HR=0.7, p=0.02). The differences remained significant when the observations were censored at the time of alloHSCT.We conclude that the prophylactic use of G-CSF during induction and consolidation of adults with ALL is associated with reduced risk of relapse and improved LFS. The possible explanation could be better adherence to chemotherapy schedules, as demonstrated in previous studies. Patients with T-ALL appear to particularly benefit from the use of G-CSF. Disclosures:No relevant conflicts of interest to declare.

Outcome of Adults with Acute Lymphoblastic Leukemia Treated with a Pediatric-Inspired Therapy: A Single Institution Experience

AbstractAbstract 4337The results of treatment of adults with ALL remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. Eighty adult ALL patients were prospectively treated in a single institution in a 16-year period with a schedule based on the St. Jude's TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intratecal therapy. Median age was 31 years (range 18 – 86); 92% were B-cell malignancies and 14% were Ph1 (+). Ten patients did not complete the first course of chemotherapy and 4 exited early. 44 of 66 patents (67%) achieved a complete remission; relapses presented in 57%. The median probability of overall survival (OS) was 28 months, whereas the 144-month OS was 27%. The median probability of leukemia-free survival (LFS) was 28 months, and the 144-month LFS 35%. Ph1 (+) patients did worse than Ph1-negative and T-cell leukemias did better than B-cell ones. Concerning toxicity, eight patients had toxic deaths (12%), two developed acute pancreatitis and one secondary diabetes. This pediatric-inspired therapy rendered better results than those obtained in similar socioeconomic circumstances using adult-oriented treatments; tolerance was acceptable and costs were low since it employs affordable drugs and can be delivered as outpatients. Disclosures:No relevant conflicts of interest to declare.

Association of Human Development Index with rates and outcomes of hematopoietic stem cell transplantation for patients with acute leukemia

AbstractHuman Development Index (HDI) is used by the United Nations Organization to measure socioeconomic achievements of countries. We evaluated the association of HDI with rates and outcomes of hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia. For the analysis of HSCT rates, all adults with acute leukemia (n = 16 403) treated in 30 European countries, between 2001 and 2005, were included. Association of HDI with the outcome was analyzed for 2015 patients with acute myeloid leukemia treated with myeloablative allotransplantation. Countries were classified according to HDI quintiles. Highly significant correlation was found for HDI and the total number of HSCT per population (R = 0.78; P < .001), as well as separately for sibling HSCT (R = 0.84; P < .001), unrelated HSCT (R = 0.66; P < .001), and autologous HSCT (R = 0.43; P = .02). The probabilities of leukemia-free survival for 5 consecutive groups of countries with increasing HDI were: 56%, 59%, 63%, 58%, and 68% (P = .01). In a multivariate analysis, transplantations performed in countries belonging to the upper HDI category were associated with higher leukemia-free survival compared with the remaining ones (HR = 1.36, P = .008), which resulted mainly from reduced risk of relapse (HR = 0.72, P = .04). We conclude that, in Europe, the HDI is associated with both rates and results of HSCT for acute leukemia.

HLA-mismatched hematopoietic SCT without in vitro T-cell depletion for myelodysplastic syndrome

Allogeneic hematopoietic SCT (HSCT) is currently the only curative treatment for myelodysplastic syndrome (MDS). However, many patients cannot find an HLA-matched donor. We have developed a new protocol for HLA-mismatched (including haploidentical) HSCT using G-CSF-primed BM plus G-CSF-mobilized PBSCs without in vitro T-cell depletion. A total of 36 patients diagnosed with high-risk MDS (RAEB (refractory anemia with excess blasts) or RAEBt (RAEB in transformation)) underwent transplantation from HLA-mismatched family donors. All patients achieved sustained myeloid engraftment. The cumulative incidence of grades II-IV acute GVHD (aGVHD) was 60% and that of grades III and IV aGVHD was 15%. The 2-year cumulative incidence of chronic GVHD was 56%. After a median follow-up of 17 months, 4 patients had relapsed and died and 25 patients were still alive. The 2-year probability of leukemia-free survival (LFS) was 65%. Patients transplanted within 7 months of diagnosis had better LFS (89 vs 43% ). Severe aGVHD decreased the LFS significantly by increasing non-relapse mortality (NRM). This study confirms that HLA-mismatched HSCT is a treatment option for MDS. Patients with high-risk MDS benefit from receiving HSCT early in the course of the disease.

Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.

Abstract 2321Poster Board II-298The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT.Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases.With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009).CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL. Disclosures:No relevant conflicts of interest to declare.

12 Years Experience in Peru with Related Allogeneic Stem Cell Transplantation (allo-sct) in Children with High Risk ALL.

Abstract 3356Poster Board III-244 Background:ALL accounts for approximately 70-83% of all childhood leukemia. High risk ALL is a big problem in our country and allogeneic related HSCT has proven to be a curative treatment for high risk patients with ALL. Patients and Methods:We analyzed the clinical data of 51 children (27 boys and 24 girls) with ALL undergoing related BMT/PSCT from Edgardo Rebagliati Hospital between 1996 and 2008. Survival probabilities were analyzed by Kaplan and Meier method. Outcome of different subgroups was compared by the log-rank test. Results:The recipients median age at transplantation was 10.7 years (range, 1 - 18 years). The disease status at conditioning were 1st CR (n=33), 2nd CR or more (n=18). The median interval from diagnosis to BMT was 14 months (range, 4 - 93 months). We have used two conditioning regimen: TBI/CTX/VP16 (TBI-1200Gy/CTX-120 mg/kg/ VP16-40mg/kg) in 34 patients (66.7%) or TBI/CTX 16 (31.4%) and 1 patient (2%) standard BuCy conditioning regimen. Graft-versus-host disease (GVHD) prophylaxis was methotrexate and cyclosporin. The median infused CD34 cell number was 6.21×106/kg (range 1.61-14.9×106/kg). The resource of hematopoietic cell was bone marrow 33.3% (17 patients), peripheral blood, 64.7% (33 patients) and both 2% (1 patient). Acute GVHD occurred in 10 (19.6%) patients, and chronic GVHD occurred in 15 (29.4%) patients.Twelve year overall survival (OS) is 59.8% ± 8.7% (n= 51) and leukemia-free survival probabilities (DFS) were 62.9% ± 8.2%. Patients with 1st CR and 2nd CR had a 5 year EFS of 60.1% and 67.3% (log-rank test, P 0.92), respectively.The mortality non related to transplant was 29.5%; 10 patients (19.6%) due to progressive disease and five patients (9.9%) by sepsis. Conclusions:Allo-SCT is well tolerated in high risk ALL children with prolonged OS and DFS. Not found statistical significance on OS and DFS between the conditioning regimen used, between status pre-transplant (1st CR vs 2nd CR) and we found statistical significance in favor to PB as a source of SC on DFS. Disclosures:No relevant conflicts of interest to declare.

Comparison of Outcomes Between Transplantation From Unrelated Donor Umbilical Cord Blood and From Unrelated Donor Bone Marrow or Peripheral Blood in Children with Acute Leukemia.

Abstract 4340 IntroductionAlthough umbilical cord blood (UCB) is an accepted alternative to bone marrow or peripheral blood (BM/PB) for transplantation, allele-matched marrow or peripheral blood is generally regarded as the preferred graft source. Our aim is to compare leukemia-free survival after transplantation of unrelated donor UCB and allele-matched BM/PB, and to provide guidelines for selection of an appropriate donor and graft source in children with acute leukemia. Patients and MethodsOutcomes of 22 children with acute leukemia and transplanted with single unit UCB were compared with outcomes of 34 BM/PB recipients. All transplantations were performed in Samsung Medical Center between May 2003 and June 2009. Recipients of UCB were transplanted with grafts that were HLA-matched (n = 3) or HLA-mismatched for one (n = 15) or two antigens (n = 4). BM/PB recipients were transplanted with grafts that were HLA-matched (n = 20) or mismatched (n = 14). While allele-level typing for HLA-A, HLA-B, HLA-DRB1 and antigen-level typing for HLA-C was used for BM/PB transplantation, antigen level typing for HLA-A, HLA-B and HLA-DRB1 was used for UCB transplantation. Myeloablative conditioning regimens were used for both BM/PB and UCB transplantation. ResultsThe median times to neutrophil and platelet recovery were 15 (range 10–21) and 22 (12–29) days after BM/PB transplantation, and 17 (13–44) and 34 (24–148) days after UCB transplantation, respectively. The 4-year probabilities of leukemia-free survival were 58.0% after HLA-matched BM/PB transplants, 65.9% after HLA-mismatched BM/PB transplants, 66.7% after HLA-matched UCB transplants, 67.5% after one-mismatched UCB transplants with high cell dose (NC > 3.0 × 107/kg), 40.0% after one-mismatched UCB transplants with low cell dose (NC < 3.0 × 107/kg), and 33.3% after two-mismatched UCB transplants. The incidence of grade 3-4 acute graft-versus-host disease (GVHD) were 12.1% after BM/PB transplantation and 5.3% after UCB transplantation, respectively (P = 0.64). Rates of extensive chronic GVHD were 53.8% after BM/PB transplantation and 23.1% after UCB transplantation, respectively (P = 0.09). Transplant-related mortality rates were higher after UCB transplantation (21.7%) than BM/PB transplantation (2.9%) (P = 0.03). Relapse rates were similar after BM/PB transplantation (29.4%) and UCB transplantation (21.7%) (P = 0.56). ConclusionThese results support the use of HLA-matched or one-antigen HLA mismatched UCB in children with acute leukemia who need transplantation. Faster identification of a suitable cord blood unit may result in a timely transplantation avoiding delay that could expose the patient to the risk of losing the eligibility for transplant due to relapse or other complications. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

“Human Development Index” Correlates with Rates and Influences Outcome of Hematopoietic Stem Cell Transplantation for Patients with Acute Leukemia.

Abstract 1193Poster Board I-215Human Development Index (HDI) is used by the United Nations to evaluate socio-economic status (SES) of countries all over the world. It is calculated based on 3 sub-indices: 1) Life Expectancy Index (LEI), reflecting general health status of a population; 2) Eduction Index (EI), assessing literacy and school enrollment, and 3) Gross Domestic Product Index (GDPI). Although most of the European countries are classified as well-developed with HDI >0.85, the differences between countries exist. The goal of this study was to evaluate whether HDI influences the rates of hematopoietic stem cell transplantation (HSCT) as well as transplantation outcome for adult patients with acute leukemia.For the analysis of HSCT rates, all adult patients with acute leukemia (n=16403) treated with HSCT in 30 European countries, and registered in the EBMT database between 2001 - 2005 were included. Highly significant correlations were found for HDI and the number of HSCT per population for all types of transplants (R=0.78; p<0.0001), as well as separately for sibling-HSCT (R=0.84; p<0.0001), URD-HSCT (R=0.66; p<0.0001) and autoHSCT (R=0.43; p=0.02). When sub-indices were analyzed separately, the strongest correlations were found between the total HSCT rates and LEI (R=0.84; p<0.0001) as well as GDPI (0.77, p<0.0001), while correlation with EI was less pronounced (R=0.39; p=0.03).Association of HDI and the outcome of HSCT was evaluated only for adults with acute myeloid leukemia treated with myeloablative, T-cell replete, allotransplantation (either sibling- or URD-HSCT), excluding cord blood transplants. Overall 2015 patients, aged 18-70 years (median 40) were included. Countries were classified according to HDI percentiles into 5 categories and the classes were tested for differences with regard to leukemia-free survival (LFS), relapse, and non-relapse mortality (NRM). The probabilities of LFS for the 5 consecutive classes with increasing HDI were as follows: 56%, 59%, 63%, 58%, and 68% (p=0.01). In a multivariate analysis transplants performed in countries belonging to the upper HDI category were associated with significantly higher LFS compared to the remaining ones (HR=1.36, p=0.008), which resulted mainly from reduced risk of relapse (HR=1.38, p=0.04) and to a lesser extent, reduced NRM (HR=1.32, p=0.1). In a univariate analysis, among HDI sub-indices, only the GDPI but not LEI and EI influenced outcome (p=0.01). CONCLUSIONS:Results of our study indicate that the HDI, being a surrogate of the SES influences the rates of all types of HSCT in Europe. In case of patients with AML treated with allo-HSCT, the HDI influences outcome, however, the positive effect is seen only with regard to few countries with particularly high HDI, while the outcome in the remaining ones is comparable. As the effect on LFS depends mainly on differences in relapse incidence, it may result from either more intense induction-consolidation therapy, more intense conditioning regimen or better immunomodulation after alloHSCT in countries with the highest HDI. Further studies should focus on detailed aspects of the SES to clarify the background of our results. Disclosures:Blaise:Gemzyme: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pierre-Fabre: Consultancy, Research Funding.

Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL

The role of autologous hematopoietic SCT (autoHSCT) in the treatment of high-risk (HR) adult ALL is controversial. In this study, we retrospectively analyzed the results of autoHSCT according to the status of minimal residual disease (MRD) at transplantation, as a joint analysis of the European Study Group for Adult ALL (EWALL). Data on 123 recipients of autoHSCT, aged 31 (16-59) years, with B-lineage (n=77) or T-lineage (n=46) ALL were included. In a cohort of Ph-negative ALL, the probability of leukemia-free survival at 5 years was higher for patients with MRD <0.1% compared with those with MRD > or = 0.1% (57 vs 17%, P=0.0002). The difference was significant for T-lineage ALL (62 vs 8%, P=0.001), and a tendency was observed for B-lineage ALL (54 vs 26%, P=0.17). In a multivariate analysis, adjusted for other potential prognostic factors, high MRD level remained the only independent factor associated with increased risk of failure (risk ratio, 2.8; P=0.0005). We conclude that MRD determines the outcome of autoHSCT in HR adult ALL. Our results suggest the need to reevaluate the role of this treatment option in prospective trials.

A comparative study of outcomes of idarubicin- and etoposide-intensified conditioning regimens for allogeneic peripheral blood stem cell transplantation in patients with high-risk acute leukemia

Aim:To analyze the results of idarubicin (IDA)- versus etoposide (VP16)-intensified myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-SCT) for high-risk acute leukemia.Methods:From January 2005 to June 2008, 48 consecutive patients (male: n=29; median age: 30 years, range 14–51 years) with high-risk acute leukemia underwent allo-SCT following an IDA- or VP16-intensified conditioning regimen. The conditioning regimens were modified BUCY2 (busulfan+cyclophosphamide) consisting of IDA (15 mg/m2 per day, days -12 to -10) or VP16 (25 mg/kg per day, days -3 to -2) and CY/TBI (cyclophosphamide/total body irradiation) intensified with IDA (15 mg/m2 per day, days -6 to -5) or VP16 (25 mg/kg per day, days -3 to -2) for acute myeloid leukemia and acute lymphoblastic leukemia, respectively.Results:Between the two groups, no significant differences in terms of baseline characteristics, incidence of acute or chronic graft-versus-host disease (GVHD) or transplant-related mortality (TRM) (P=0.50) were observed. However, the IDA group demonstrated higher incidences of mucositis and Aspergillus pneumonia (P<0.01 and P=0.03, respectively). For the IDA and VP16 groups, relapse rates were 28% and 50%, respectively (P=0.13). For the same groups, the 2-year probabilities of leukemia-free survival (LFS) and overall survival (OS) were 72% versus 51% (P=0.04) and 74% versus 53% (P=0.04), respectively.Conclusion:This retrospective analysis suggests that conditioning regimens intensified with IDA can achieve better outcomes than conditioning regimens with VP16 in patients preparing to undergo allo-SCT for high-risk acute leukemia.

Hematopoietic Cell Transplantation for Children with Acute Lymphoblastic Leukemia in Second Complete Remission: Similar Outcomes in Recipients of Unrelated Marrow and Umbilical Cord Blood versus Marrow from HLA Matched Sibling Donors

Transplant decisions for children with acute lymphoblastic leukemia (ALL) in second complete remission (CR2) are often based on the type of available donor. In many cases, allogeneic hematopoietic cell transplantation (HCT) is considered only if a human leukocyte antigen (HLA) matched sibling donor (MSD) is available. The role of unrelated donor (URD) HCT in this patient population is not well established. As advances in supportive care and donor selection have improved, the use of URD HCT in such patients should be reevaluated. We analyzed the outcomes of 87 consecutive children with ALL in CR2 who underwent allogeneic HCT at the University of Minnesota between 1990 and 2007. Donor sources included MSD bone marrow (n = 32), well and partially matched (M, n = 18) and mismatched (MM, n = 16) URD bone marrow and URD umbilical cord blood (UCB, n = 21). Although the incidence of neutrophil recovery was similar in all groups, the overall incidence of grades II-IV acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 37% and 9%, respectively, with a higher incidence of aGVHD in recipients of URD grafts. Leukemia-free survival (LFS) at 5 years was lower in recipients of MM-URD grafts, but was comparable in all other groups. Although relapse at 5 years was highest in recipients of MSD (50%), results were not significantly different compared to recipients of M-URD (17%), MM-URD (6%), and UCB (33%) (P = .17). The development of grades II-IV aGVHD and a first remission >3 years were associated with a lower risk of relapse (relative risk [RR] 0.2, P = .03; RR 0.2. P = .01 respectively). Together, these results support the continued investigation of URD HCT for ALL in CR2, and suggest the timing of HCT in these children should be based primarily on the risk of relapse with conventional chemotherapy and not on the type of donor available.

Late Mortality and Relapse following BuCy2 and HLA-Identical Sibling Marrow Transplantation for Chronic Myelogenous Leukemia

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for chronic myelogenous leukemia (CML). Failure, because of relapse or nonrelapse mortality (NRM), generally occurs within 3 years of transplantation, but large studies with long-term follow-up are limited. We present mature results in 335 patients with CML who underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings following busulfan and cyclophosphamide (BU/Cy2). Two hundred twenty-nine were in chronic phase (CP) and 106 in accelerated or blastic phase at transplantation. Median follow-up exceeded 14 years. The estimated probability of 18-year leukemia-free survival (LFS) for CP patients was 55.6% and for those beyond CP, 10.5%. Of 182 patients who survived leukemia-free at 3 years, the estimated probability of LFS at 18 years was 61.9%. Late relapse (P = .039) and late NRM (P = .008) occurred at higher rates in patients beyond CP at transplantation. There was no plateau in LFS.

Role of Antithymocyte Globulin and Granulocyte-Colony Stimulating Factor-Mobilized Bone Marrow in Allogeneic Transplantation for Patients with Hematologic Malignancies

The main obstacle for allogeneic transplantation is delayed hematologic reconstitution and serious graft-versus-host disease (GVHD). The results of 128 patients with hematologic malignancies undergoing HLA -identical (n = 52) or HLA-haploidentical/mismatched (n = 76) hematopoietic stem cell transplantation (HSCT) performed during the same time period were compared. Patients with HLA-identical HSCT received unmanipulated granulocyte-colony stimulating factor -mobilized peripheral blood stem cells (G-PBSCs). Forty-six patients with HLA-haploidentical related HSCT received antithymocyte globulin (ATG) in conditioning regimens followed by the transplantation of the combination of unmanipulated G-PBSCs and granulocyte-colony stimulating factor -mobilized bone marrow (G-BM) and 30 patients with HLA-mismatched unrelated HSCT received ATG in conditioning regimens followed by the transplantation of unmanipulated G-PBSCs. All patients got successful hematopoietic engraftment. The cumulative incidences of grades I to II acute GVHD (aGVHD) on day 100 in the identical, haploidentical related and mismatched unrelated cohorts were 21.2%, 43.5%, and 53.3%, respectively. The cumulative incidences of chronic GVHD (cGVHD) in the identical, mismatched unrelated, and haploidentical related cohorts were 34.6%, 33.3%, and 10.9%, respectively. The 2-year relapse and treatment-related mortality (TRM) rates were 19.2%, 23.9%, 23.3%, and 9.6%, 8.7%, 10% for patients who underwent identical, HLA-haploidentical related, and mismatched unrelated transplantation, respectively. The 2-year probabilities of leukemia-free survival and overall survival were 72.2%, 70.6%, 68.1%, and 76.5%, 77.8%, 70.0% after identical, haploidentical related and mismatched unrelated transplantations, respectively. Multivariate analyses showed that only advanced disease stage and a diagnosis of disease had increased risk of relapse, treatment failure, and overall mortality. In conclusion, it is a feasible approach with acceptable outcomes for patients undergoing HLA-haploidentical related HSCT by the combination of G-PBSCs and G-BM with conditioning regimens including ATG.

Treatment of Acute Leukemia with Unmanipulated HLA-Mismatched/Haploidentical Blood and Bone Marrow Transplantation

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 granulotyce-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.

Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematologic Malignancies in Children

To evaluate the efficacy and safety of haploidentical (from family member donors) hematopoietic stem cell transplantation (HSCT) for children. Fifty-eight children under fourteen years old with hematological malignancies underwent haploidentical HSCT. Outcomes were analyzed. Of Fifty-eight patient/donor pairs, seven (12.1%) were mismatched in two HLA loci, twenty (34.5%) in three loci, and thirty-one (53.4%) in four loci. Follow-ups were performed for a median of 915 (227-1898) days after transplantation. All patients achieved stable engraftments. The cumulative incidence of acute graft-versus-host disease (GVHD) of grade 2-4 was 54.8%7.6%, and that of grade 3-4 was 11.4%4.8%. The cumulative incidence of chronic GVHD was 45.6%7.8% for total and 19.6%6.5% for extensive. Fourty patients survived with a 3-year probability of leukemia-free survival (LFS) 44.7%13.9%. Eighteen patients died, five from infection, eight from relapse of leukemia, two from heart failure, two from GVHD, and one from lymphoproliferative disorders. The results encourage extending haploidentical HSCT without T-cell depletion treatments to children with an indication for transplantation.

A High Long-Term Survival Were Produced by Early Sequential Intensive Consolidation Chemotherapy Followed by Autologous Stem Cell Transplantation in First Complete Remission in Patients with Adult Acute Lymphoblastic Leukemia.

Objective: To investigate the efficiency of our designed protocol with early sequential intensive consolidation chemotherapy followed by autologous stem cell transplantation (ASCT) in first complete remission (CR1)on adult acute lymphoblastic leukemia (ALL) patients who lack of matched sibling donors.Methods: The ALL patients were given a median 4 intensive/ consolidation therapy courses including high-dose of methotrexate, cytarabine and/or cyclophosphamide in CR1, followed by ASCT with total body irradiation (TBI)-based conditioning regimen. A 1 to 1.5 year maintenance chemotherapy with 6-mercaptopurine, methotrexate and vincristine-prednisone in combination with interleukin-2/IFN-α immunotherapy were administered after adequate hematological recovery.Results: A total of 83 patients were enrolled in this study. 78 patients reconstituted hematopoiesis except 5 patients died of early toxicity. By a median 47(3– 218) months follow-up after ASCT, the 5-year probabilities of leukemia free survival (LFS) and overall survival (OS) were 53.2%±5.9% and 54.4%±5.8%, respectively. The 5-year cumulative relapse rate (RR) was 35.7%±6.1%, and no patients relapsed more than 3 years after transplantation. According to the adverse features, age ≥35 years, WBC >30×109/L for B-cell ALL or >100×109/L for T-ALL, Pro-B and early T immunotyping, more than 4 weeks to attain remission, and high-risk karyotypes including t(9;22)/BCRABL, t(4;11)/ALL1-AF4 or t(1;19)/E2A-PBX1, the patients were identified in 3 prognostic risk groups of standard (24, 29.0%), intermediate(32, 38.5%), and high(27, 32.5%) with 0, 1, 2 or high-risk karyotypes adverse features, respectively. The 5-year probabilities of DFS were 80.36%±9.0%, 59.39%±9.2% and 24.78%±8.9% in these 3 group s, respectively. While, the 5-year cumulative incidences of relapse was 16.7%,37.5% and 70.4%, respectively.. The standard and intermediate -risk groups had significantly better OS and LFS than the high-risk group.Conclusion: Theses results indicated our designed protocol with early sequential intensive consolidation chemotherapy followed by autologous stem cell transplantation (ASCT) in first complete remission (CR1) could produced a relatively high log-term survival in standard and intermediate-risk group of adult ALL patients.

Unrelated Bone Marrow Transplantation for Children with Chronic Myeloid Leukemia (CML): A Report from the Japan Marrow Donor Program (JMDP).

Background: Chronic myeloid leukemia (CML) is a rare disease in children and accounts for approximately 2% to 3% of all childhood leukemia. Despite of introduction of tyrosine kinase inhibitors, allogeneic hematopoietic stem cell transplantation is still the only proven curative treatment for patients with CML. Few studies have specifically addressed transplantation outcomes in childhood CML.Patients and Methods: We analyzed the clinical data of 125 children (81 boys and 44 girls) with CML undergoing unrelated bone marrow transplantation (UBMT) through the Japan Marrow Donor Program (JMDP) between 1993 and 2006 (median observation period, 95 months). The recipients' median age at transplantation was 14 years (range, 1 – 19 years). The disease phases at conditioning were chronic phase (CP) 1 (n=88), CP2 (n=12), CP3 (n=1), accelerated phase (n=11) and blastic crisis (n=13). The median interval from diagnosis to BMT was 14 months (range, 2 – 111 months). 95 (76%) patients received interferon-alpha (IFN-alpha), and 17 (14%) received imatinib mesylate (IM) before BMT. 96 (77%) patients received total body irradiation (TBI) containing a conditioning regimen, and 29 (23%) received a non-TBI regimen. Cyclosporine A (CSA)-based graft-versushost disease (GVHD) prophylaxis was used for 81 (65%) patients, and tacrolimus based prophylaxis was used for 43 (34%) patients. One patient received methotrexate only for GVHD prophylaxis. HLA matching data based on high-resolution DNA typing for HLA-A, -B, -Cw, -DRB1 and -DQB1 alleles were available in 99 (79%) patients; 41 of 99 (41%) patients were “fully matched (10/10)”. The median infused cell number was 314×106/kg (range, 27 – 880×106/kg).Results: Five-year overall survival (OS) and leukemia-free survival probabilities were 59.3% ± 4.5% and 55.5% ± 4.5%, respectively. Grade II to IV acute GVHD occurred in 50 (40%) patients, and chronic GVHD occurred in 51 (41%) patients. Six (5%) patients did not achieve engraftment. In multivariate models for OS, disease phase (advanced phase/CP1) (p=0.008, RR 2.431 (1.261–4.689)), infused cell number (<314×106/kg/ ≥314×106/kg) (p=0.004, RR 2.917 (1.404–6.060)), HLA-A allele mismatch (p=0.001, RR 4.076 (1.798–9.236)), and age at transplantation (≥15/ <15 years) (p=0.031, RR 2.236 (1.076–4.651)) were independent risk factors. For transplant-related mortality (TRM), disease phase (advanced phase/CP1) (p=0.021, RR 2.341 (1.137–4.820)) and infused cell number (<314×106/kg/ ≥314×106/kg) (p=0.001, RR 3.792 (1.686–8.529)) were significant risk factors. HLA-B, -Cw, -DRB1, and -DQB1 allele mismatch were not significant risk factors for OS and TRM on univariate and multivariate analyses. Subgroup analyses of CP1 patients (n=88) showed that cytogenetic response (with or without major cytogenetic response) at BMT was a strong risk factor for OS (5-year OS: 91.4% ± 6.0% vs 53.4% ± 8.1%, p=0.001). For the 29 patients who achieved major cytogenetic response at BMT, the probability of OS was not statistically different between patients treated with IM (n=15) and those treated with IFN-alpha (n=14) before BMT (p=0.722).Conclusions: Disease phase, infused cell number, HLA-A allele mismatch, patient age and cytogenetic response at transplantation were important risk factors for transplant outcomes. This is one of the largest cohorts studied to date, and the results provide important information to assess the indications and to improve the outcomes of children with CML undergoing UBMT.

Unrelated Donor Bone Marrow Transplantation for Children With Acute Myeloid Leukemia Beyond First Remission or Refractory to Chemotherapy

Identify prognostic factors that influence outcome after unrelated donor bone marrow transplantation in children with acute myeloid leukemia (AML). Included are 268 patients (age <or= 18 years) with AML in second complete remission (n = 142), relapse (n = 90), or primary induction failure (n = 36) at transplantation. All patients received bone marrow grafts from an unrelated donor and a myeloablative conditioning regimen. Cox regression models were constructed to identify risk factors that influence outcome after transplantation. In this analysis, the only risk factor that predicted leukemia recurrence and overall and leukemia-free survival was disease status at transplantation. The 5-year probabilities of leukemia-free survival were 45%, 20%, and 12% for patients who underwent transplantation at second complete remission, relapse, and primary induction failure, respectively. As expected, risk of acute but not chronic graft-versus-host disease (GVHD) was lower with T-cell-depleted bone marrow grafts; T-cell-depleted grafts were not associated with higher risks of leukemia recurrence. We observed similar risks of leukemia relapse in patients with and without acute and chronic GVHD. Children who underwent transplantation in remission had a superior outcome compared with children who underwent transplantation during relapse or persistent disease. Nevertheless, 20% of children who underwent transplantation in relapse are long-term survivors, suggesting that unrelated donor bone marrow transplantation is an effective therapy in a significant proportion of children with recurrent or primary refractory AML.

Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematological malignancies in children

To investigate the efficacy and safety of haploidentical (from family member donors) hematopoietic stem cell transplantation (HSCT) for children. 42 children under 14 yrs old with hematological malignancies underwent haploidentical HSCT. Outcomes were analyzed. Thirty-three children were classified as high-risk candidates. Of 42 patient/donor pairs, 4 (9.5%) were mismatched in 2 HLA loci, 15 (35.7%) in 3 loci, and 23 (54.8%) in 4 loci. Follow-ups were performed for a median of 1110 (449-1959) days after transplantation. All patients achieved stable engraftments. The cumulative incidence of acute graft-versus-host disease (aGVHD) of grade 2-4 was 57.2%, and that of grade 3-4 was 13.8%. The cumulative incidence of chronic graft-versus-host disease (cGVHD) was 56.7% for total and 29.5% for extensive. Twenty-seven patients survived with a 3-yr probability of leukemia-free survival (LFS), 57.3±8%, 18 of them were in the high-risk group. Fifteen patients died, 4 from infection, 7 from relapse of leukemia, 2 from heart failure, one from severe aGVHD, and one from lymphoproliferative disorders. The results encourage extending haploidentical HSCT without T cell depletion treatments to children with an indication for transplantation.