scholarly journals Unrelated Cord Blood Versus Non-T Cell Depleted Haploidentical Stem Cell Transplantation: Comparable Results in Adults with Acute Leukemia, a Eurocord and ALWP-EBMT Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1227-1227
Author(s):  
Annalisa Ruggeri ◽  
Myriam Labopin ◽  
Guillermo F. Sanz ◽  
Simona Piemontese ◽  
William Arcese ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Unrelated Cord Blood

Abstract Unrelated cord blood transplantation (UCBT) and related Haploidentical non T-cell depleted stem cell transplantation (Haplo) are alternative options to treat patients with high risk acute leukemia. Both techniques have shown encouraging results. The current retrospective analysis aimed to compare the outcomes of both approaches in adults with ALL and AML receiving either UCBT (n=928) or Haplo (n=518) reported to EBMT centres between 2007 and 2011. Diagnosis was ALL for 716 patients (Haplo=158 and UCBT=558) and AML for 730 (Haplo=360, UCBT=370). Haplo grafts were not T-cell depleted, with 236 patients receiving unmanipulated bone marrow (BM), 253 receiving peripheral blood stem cells (PBSC) and 29 receiving BM+PBSC. For UCBT, 431 patients were treated with a single unit, while 497 received double unit UCBT. Compared with recipients of UCBT, Haplo recipients were more likely to have AML (69% versus 40%, p=<0.001), and were transplanted more recently (2011 versus 2009, p=0.001), had a longer median interval from CR1 to transplant (139 versus 126 days, p=0.07), and had more frequently advanced phase of disease at time of transplant (35% versus 17%, p=0.001). Median follow-up was 19 months and 25 months, (p=0.007) for Haplo and UCBT, respectively. The type of conditioning regimen (MAC or RIC) was similar between both groups, with MAC representing 60% and 56% for Haplo and UCBT, respectively. For Haplo, the most frequently used regimens were Thiotepa-Busulfan-Fludarabine (TBF) for MAC and Treosulfan-based regimens for RIC. Graft versus host disease (GVHD) prophylaxis included CsA+MMF (41%), Sirolimus (15%), while 163 patients received post-transplant Cyclophosphamide (Cy). For UCBT cases, the most common MAC regimens were TBF for 33% of cases, CyFluTBI-12Gy for 27% and CyTBI12Gy for 17%. The most frequently used RIC was CyFluTBI-2Gy in 72% of the cases. GVHD prophylaxis was CsA+MMF in 70% of cases. In univariate analysis, cumulative incidence (CI) of neutrophil engraftment was 92% vs 84% (p=<0.001) for Haplo and UCBT; CI of acute GVHD was 27% vs 32% (p=0.11) and for chronic GVHD it was 30% vs 25% (p=0.06) for Haplo and UCBT. For non-relapse mortality (NRM), relapse incidence (RI) and leukemia-free survival (LFS) outcomes were analyzed separately according to disease status, and no statistically significant differences were observed between Haplo and UCBT. According to disease status, for patients in CR1 (n=610), 2 years RI was 27% versus 28%, p=0.67; NRM 26% versus 29%, p=0.30; and 2 years LFS 48% versus 43%, p=0.16; for Haplo and UCBT, respectively. For patients in CR2 (n=502), 2 years RI was 33% versus 28%, p=0.51; NRM 33% versus 33%, p=0.93; and 2 years LFS 34% versus 39%, p=0.61, for Haplo and UCBT, respectively. For patients in advanced disease status (n=334), 2 years LFS was 11% versus 14%, p=0.92 for Haplo and UCBT, respectively. Infections and GVHD were the most common causes of transplant-related deaths in both groups, (infection 30% in both groups, GVHD 15% and 9%, after Haplo and UCBT, respectively), and 40% of deaths were due to disease recurrence in both Haplo and UCB recipients. In multivariate analysis, UCBT was associated with lower incidence of chronic GVHD (HR= 0.62; p<0.001) and higher NRM (HR= 1.28; p=0.04) when compared to Haplo. No statistically significant differences were observed between Haplo and UCBT for RI (HR= 0.87; p=0.24) and LFS (HR= 1.06; p=0.47). Factors independently associated with lower LFS were disease status at transplant (HR 2.69, p=<0.001), and use of ATG (HR 1.28, p=0.001). In conclusion, in this retrospective analysis, non TCD Haplo and UCBT showed similar RI, NRM, and LFS, highlighting that both approaches are valid for this population of patients. Longer follow-up, more homogeneous transplant strategies (stem cell source, type of conditioning regimen and GVHD prophylaxis) are needed for further evaluation. While waiting for the results of the BMT CTN trial on non TCD Haplo using post-transplant Cy and double UCBT both in the RIC setting, the choice of the specific approach for Haplo or UCBT should be likely based on transplant centre expertise and policy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Novel Improvement of Haploidentical Hematopoietic Stem Cell Transplantation for Advanced Refractory/Relapsed Acute Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4593-4593
Author(s):  
Fei Pan ◽  
Peihua Lu ◽  
Zhijie Wei ◽  
Rong Yang ◽  
Shuquan Ji
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Median Time ◽  
Mononuclear Cells ◽  
Chronic Gvhd ◽  
Hematopoietic Stem

Introduction The advanced refractory/relapsed acute leukemia has a very dismal prognosis even with the salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT). To develop a novel transplant protocol to achieve a rapid engraftment and quick graft-versus leukemia (GVL) effect is crucial. Based on previous observation, the G-CSF primed bone marrow (BM) plus peripheral blood mononuclear cells (PBMNCs) could not only increase mononuclear cells and CD34 cells, but also change T-cell biology by down-regulating the expression of adhesion and CD28/B7 molecules and increase the absolute number of D2APCS, which promotes a T-cell shift from T1 to T2 subset to secrete a higher anti-inflammatory cytokines of IL-4 and IL-10. After going through a rigorous conditioning, the recipients' T-cells are incapable to attack host. We propose that reinfusion of G-CSF primed donor PBMNCs to recipient on transplant day + 6 may cross mismatched MHC barrier thus accelerating engraftment. Patients and Methods From April 2018 to June 2019, 30 advanced-stage patients with refractory/relapsed acute leukemia were enrolled and underwent a salvage haploidentical (haplo)-HSCT. The median age was 12 (2-63) years with M/F ratio of 17/13. There were 21 patients with acute myelocytic leukemia (AML, 70%), 4 -cell acute lymphoblastic leukemia (B-ALL, 13%), 2 biphenotypic acute leukemia (BAL, 7%), 1 juvenile myelomonocytic leukemia (JMML, 3%), and 2 T-lymphoblast leukemia (T-LBL, 7%). The median BM blasts were 40% (5%-90%). Twenty-eight patients received a conditioning regimen including fludarabine 30mg/m2/d×4 day, cytarabine 2.0g/m2/d×4 days, busulfan 3.2mg/kg/d Q6h×4days, cyclophosphamide 1.5g/m2/d×2 days and melphalan 110mg/m2/d×1 day. Two patients with T-LBL received BCNU+Etoposide+Cytarabine+Melphalan (BEAM) regimen. Graft-versus-host disease (GVHD) prophylaxis contained methotrexate (MTX), cyclosporine A (CsA) and mycophenolate mofetil (MMF), plus ATG (Rabbit anti-human thymocyte immunoglobulin, Sangstat) 1.5mg/kg/d iv daily from day -4 to -1 and additional 1.5mg/kg on day +7 (total dose of 7.5 mg/kg). In addition, anti-CD25 monoclonal antibody (basiliximab) 20 mg on day+1 and +4 was given iv. Donors were primed with G-CSF at 3-4 ug/kg/d sq d1-5. On day 4 of G-CSF, donor BM cells were harvested and were infused unmanipulated on the same day to patient on transplant day 01. On day 5 of G-CSF injection, donor primed PBMNCs were harvested, part of which were immediately infused unmanipulated to recipient on transplant day 02. Part of the cells were cryopreserved and stored in the liquid nitrogen, which were then thawed and reinfused unmanipulated to recipient on day +6 (Table 1). Results All patients achieved a trilineage engraftment with a median time of 13.5 (5-16) days. The median neutrophil and platelet engraftment were 13 (11-19) days and 10 (5-22) days respectively (Fig.1). Among 29 evaluable patients, acute GVHD occurred in 10 (34.5%, Fig. 2) with a median time of 32 (14-60) days, including 5 cases (17%) of grade Ⅱ, 3 (10%) of grade Ⅲ and 2 (7%) of grade Ⅳ. Among the 28 evaluable patients for chronic GVHD, only 6 (21.4%, Fig.3) developed limited chronic GVHD with a median time of 103 (90-180) days. Twenty seven out of thirty (90%) patients achieved disease-free survival (DFS) with a median follow-up time of 6 (5-14) months. Three patients died from transplant related complication, including infection for 2 and GVHD for 1 respectively. Conclusion In this study, with an intensive myeloablative condition and salvage haplo-HSCT, by reinfusing additional unmanipulated donor PBMNCs to recipients on day +6 during their transplantation, a short engraftment time without engraftment failure, low lethal GVHD incidence, and a lower infection rate were able to be achieved. More importantly, most patients remain DFS at a median follow-up time of 6 months. Despite short-term follow-up. the outcomes are particularly encouraging. Disclosures No relevant conflicts of interest to declare.

Comparison Between Related T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (TCD-Haplo) and Umbilical Cord Blood Transplantation (UCBT) in Pediatric Patients with Acute Leukemia, a Eurocord, PDWP-EBMT Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1215-1215
Author(s):  
Franco Locatelli ◽  
Myriam Labopin ◽  
Gerard Michel ◽  
Rupert Handgretinger ◽  
Cristina Diaz de Heredia ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Leukemia ◽  
Advanced Disease ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Risk Of Relapse

Abstract Both TCD-Haplo and UCBT are used for treating children with either acute lymphoblastic (ALL) or myeloid (AML) leukemia in need of an allograft and lacking a suitable donor. Although both these types of HSCT have been shown to be effective in curing children with acute leukemia, to date, no study has compared the outcomes of these two types of transplant. We performed a retrospective registry-based study on children (less than 18 years) with either ALL or AML, receiving, after a myeloablative conditioning regimen, a TCD-Haplo (CD34+ cell positive selection, CD3+ negative or TCR alpha/beta+ cell depletion) or single unit UCBT. Patients given pharmacological graft-versus-host disease (GVHD) prophylaxis after graft infusion in haplo HSCT were excluded. Transplants were performed from 2001 to 2012 in EBMT centers; 1067 patients received single UCBT and 266 TCD-Haplo for AML (n=478) or ALL (n=855). Median follow up was 28 (range 1-150) and 20 (range 1-152) months for UCBT and TCD-Haplo, respectively. Compared to TCD-Haplo, UCBT recipients were younger (median age 5.96 years vs 9.6 years, p=<0.0001), were transplanted more frequently in CR1 (42% vs 24%, p=<0.001), less frequently in advanced disease (10% vs 21%, p=<0.001) and had more often negative cytomegalovirus (CMV) serology (45% vs 31%, p=<0.001). Conditioning regimen was mainly total body irradiation (TBI)-based, 56% versus 50% for TCD-Haplo and UCBT, respectively. For UCBT, patients CSA+steroids was the most commonly used (72%) GVHD prophylaxis. A higher proportion of patients transplanted with TCD-Haplo received ATG in the conditioning regimen (90% vs 74%, p=<0.001). Acute GVHD (grade II-IV) incidence was 16% and 28% (p<0.001) while that of chronic GVHD was 14% and 16%, (p=0.40) for TCD-Haplo and UCBT respectively. Since diagnosis was the most important factor influencing outcome, the analysis was performed separately for patients with ALL and AML. For ALL (n=855) in univariate analysis, the 2-year probability of leukemia-free survival (LFS) was 35% and 43% (p=0.08), for TCD-Haplo and UCBT, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) was 28% and 29% (p=0.57), and relapse incidence (RI) was 36% and 28% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=300), 2-year RI was 21% versus 20%, p=0.75; NRM 30% versus 24%, p=0.59; and 2- year LFS 49% versus 56%, p=0.87; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=478), 2-year RI was 34% versus 29%, p=0.75; NRM 28% versus 32%, p=0.29; and 2- year LFS 38% versus 39%, p=0.63, for TCD-Haplo and UCBT, respectively. For patients in advanced disease (n=77), 2-year LFS was 5% versus 8%, p=0.08 for TCD-Haplo and UCBT, respectively. For patients with AML (n=478), 2-year probability of LFS was 21% and 58% (p=<0.0001), for TCD-Haplo and UCBT, respectively. CI of NRM was 43% and 19% (p=<0.001), and RI was 36% and 23% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=207), 2-year RI was 31% versus 14%, p=0.06; NRM 45% versus 16%, p=0.002; and 2-year LFS 24% versus 69%, p=<0.001; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=180), 2-year RI was 28% versus 24%, p=0.49; NRM 44% versus 21%, p=0.004; and 2- year LFS 28% versus 55%, p=0.0005, for TCD-Haplo and UCBT, respectively. For patients in advanced disease status (n=91), 2-year LFS was 10% versus 22%, p=0.44 for TCD-Haplo and UCBT, respectively. In multivariate analysis adjusted for differences between the 2 groups, for patients with ALL, no statistically significant differences were observed according to the graft source. Disease status was the only factor associated with better LFS (HR 4.84, p<0.0001). TCD-Haplo was associated with greater risk of RI (HR 1.58, p=0.01). For AML, in multivariate analysis, TCD-Haplo was associated with greater risk of relapse (HR 1.67, p=0.05) and of NRM (HR= 1.94; p=<0.001), and worse LFS (HR 1.94, p=<0.001) when compared to UCBT. Advanced disease at transplantation (HR 2.89, p=<0.001) was the other factor associated with LFS and RI. This retrospective analysis demonstrates that children with ALL have comparable probability of LFS after either UCBT or TCD-Haplo. By contrast, in children with AML, UCBT is associated with lower risk of relapse and NRM than TCD-Haplo, this translating into better LFS. These results may help guide physician choices for transplanting children with acute leukemia. Disclosures No relevant conflicts of interest to declare.

Risk Factors for Mortality In Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4539-4539
Author(s):  
Fátima de la Cruz Vicente ◽  
Omar BenMarzouk-Hidalgo ◽  
Irene Gracia-Ahufinger ◽  
Raul García-Lozano ◽  
Manuela Aguilar-Guisado ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Viral Replication ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cmv Infection ◽  
Gvhd Prophylaxis

Abstract Abstract 4539 BACKGROUND: Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). Described risk factors for CMV infection are pretransplant CMV seropositive status of the recipient, non related donor or umbilical cord transplant, depleted lymphocyte graft, high intensity conditioning regimen, severe graft versus host disease (GVHD), CD34+ selection of the graft and delayed CMV specific immune reconstitution. OBJETIVES: To identify different profiles of allogeneic stem cell recipients based on their previously described risk factors for CMV infection and its association with their clinical outcomes. PATIENTS AND METHODS: A prospective study of consecutive recipients of Allo-SCT was performed from June 2008 through December 2009 at a single institution. Patients were sequentially monitored both clinically and analytically. CMV viral load was determined by real time PCR and CMV-specific T cell response was determined by flow cytometry. Non-normal distribution data were expressed as median values (range). Chi-square test or Fisher exact test were used to compare differences between groups of categorical data. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). RESULTS: Twenty-six patients were included with a median age of 33 years (range:15-61). The donor was an identical sibling in 42.3%, unrelated donor in 53.8% and a mismatched family member in 3.8%. The source was peripheral blood 76.9%, cord blood 15.4% and bone marrow in 7.7%. Previous positive serostatus for CMV was 76.9% in recipients, and 53.8% in donors. The conditioning regimen was myeloablative in 57.7% and reduced-intensity in 42.3%. Graf versus host disease (GvHD) prophylaxis was cyclosporine (CsA) plus methotrexate (MTX) in 57.7% and CsA plus mycophenolate mofetil (MMF) in 42.3%. The incidence of acute GvHD was 76.9% and chronic GvHD was 53.8%. Treatment of GVHD was steroids plus CsA or tacrolimus and/or MMF in 76.9% of acute and 46.2% of chronic GvHD. Previously described risk factors for developing CMV infection were compared between patients developing (n=18) and non-developing (n=8) CMV infection. A higher risk for developing CMV infection was associated with previous CMV positive serostatus of the recipient (84% in viremic patients vs. 16% in non-viremic patients; p=0.01) and CsA plus MMF as GvHD prophylaxis (90.9% vs. 9.1%; p=0.04). We analyzed whether having several risk factors for developing CMV infection has an effect on the risk for developing CMV replication after the transplant. Patients that presented four or more risk factors, developed viral replication more frequently than patients having less than four risk factors (91.6% vs. 8.3%; p=0.02). Patients who acquired an earlier specific CMV immune reconstitution did not developed CMV replication, opposite to those with later immune reconstitution (week 2 vs. week 8, p= 0.01). Overall survival at one year was of 44.4% in the group with viral replication, and 100% in the group with no viral replication, p=0.014 (Figure 1). CONCLUSIONS: Patients that did not developed episodes of CMV replication after the transplant presented less than four risk factors for developing CMV infection, developed an early T-cell mediated CMV immune response and had better overall survival. The development of CMV specific immunity able to control CMV replication may be considered as a paradigm of post-transplant immune reconstitution with potential influence on overall survival. Disclosures: No relevant conflicts of interest to declare.

The Addition of ONE-Day Rest Between LAST ATG Infusion and STEM CELL Infusion DID NOT Affect Gvhd Occurrence After Allogeneic TRANSPLANTATION with Fludarabine-Busulfan-ATG Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3029-3029
Author(s):  
Roberto Crocchiolo ◽  
Sabine Fuerst ◽  
Jean El-Cheikh ◽  
Angela Granata ◽  
Claire Oudin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Progression Rate ◽  
Gvhd Prophylaxis

Abstract Abstract 3029 Introduction: Antithymocyte globulin (ATG) is part of many conditioning regimens for allogeneic stem cell transplantation (AlloSCT) with the aim of reducing graft-versus-host disease (GvHD), due to in vivo T-cell depletion. ATG administration may be accompanied by fever, chills, headache or other side effects that affect patient's management and can cause a delay in stem cell infusion. In order to improve ATG tolerance, since November 2010 we modified our fludarabine-busulfan-ATG (FBA) conditioning for RIC transplants with the addition of 1-day rest between the last ATG administration and stem cell infusion. No modification of drugs or GvHD prophylaxis occurred: five days of fludarabine, two days of i.v. busulfan and two days of ATG Thymoglobuline (10 mg/kg total dose) were administered during conditioning, and ciclosporine for GvHD prophylaxis together with MMF only in the presence of a mismatched unrelated donor (MMUD). Aim: To analyse whether the addition of 1-day rest between ATG administration and stem cell infusion impacted on outcome of adult patients receiving AlloSCT after FBA conditioning with respect to previous no-rest modality, in particular acute grade 2–4 or grade 3–4 GvHD. Methods: The 1-day rest cohort (ATG-rest) was compared with a previous consecutive cohort of patients (no rest) transplanted at our center. Analysis of acute GvHD among the two groups was performed as well as of chronic GvHD, OS, PFS, NRM, relapse/progression. Results: A total of 64 and 63 patients were included in ATG-rest and no-rest cohorts respectively. First patient in the no-rest cohort received AlloSCT on November 2008. Follow-up was thus longer in this cohort: median 27 months (21–37) vs. 15 (11–20), p<0.0001. No significant differences of patients' age, diagnosis and disease status at AlloSCT between the two groups were observed; matched unrelated donors (MUDs) were higher in the ATG-rest group whereas the number of MMUDs was similar in both groups (see Table 1). Rate of acute and chronic GvHD and NRM, probabilities of OS and PFS did not differ between the two groups (Table 1). Unexpectedly, relapse/progression rate was lower in the ATG-rest groups (p=0.002), although disease status at AlloSCT was not significantly different between the two cohorts. Median day of relapse or progression from AlloSCT in the no-rest group was +165 (35–476) vs. +57 (8–215) in ATG-rest one, p=0.004. No difference in relapse/progression was observed according to donor (HLA-identical sibling vs. MUD vs. MMUD) and a lower relapse risk in 1-day rest group is confirmed after adjustment for type of donor: HR = 0.29 (0.12–0.72), p=0.01. Conclusion: The addition of 1-day rest between last ATG administration and stem cell infusion did not impacted on GvHD occurrence after AlloSCT after FBA conditioning. The finding of a reduced rate of relapse/progression in the ATG-rest group deserves to be investigated and requires longer follow-up. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Modifying Conditioning and Immunosuppressive Strategies in Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5714-5714
Author(s):  
Nawar Dakhallah ◽  
Mylène Beauchemin ◽  
Johanne Richer ◽  
Sonia Cellot ◽  
Pierre Teira ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Current Approach ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Background:Hematopoietic stem cell transplants (HSCT) is indicated for some very high-risk childhood acute lymphoblastic leukemia (ALL) patients in complete remission 1 (CR1) and for patients in >CR2. Relapse remains the most frequent complication after transplant. In 2012, in order to decrease the relapse rate, we modified our conditioning and GVHD prophylaxis regimen. Total body irradiation doses were increased, etoposide removed and fludarabine introduced. Anti-thymocyte globulin (ATG) was removed of GVHD prophylaxis regimen and mycophenolate mofetil was added for unrelated marrow grafts. The aim of this study was to compare outcome between previous (PS) and new strategies (NS) prior and after 2012. Methods: This retrospective study included all 47 patients aged 0 to 18 years old who underwent a first HSCT for ALL at Sainte-Justine University Health Center from 2007 to 2017. Our primary endpoint was 2-year event-free survival (EFS) between PS (n=22) and NS (n=25) groups. Secondary endpoints included overall survival (OS), relapse, GVHD, immunological recovery and infection rates. Results: Demographic parameters and leukemia characteristics were not significantly different between groups. In the PS group, median age was 6.1 years [2.7;13.5] and 41% of patients were female. In the NS group, median age was 7.1 years [2.4;11.4] and 44% of patients were female. B-cell and T-cell lineage leukemias were present in respectively 82% and 18% of PS and 76% and 24% in NS. Fourteen percent of patients were transplanted in CR1 in the PS versus 40 % in the NS group. EFS at 2 and 5 years were respectively 46% and 36% with the PS compared to 60% and 53% with the NS (p=0.170). OS at 5 years was significantly higher with the NS (46% vs 75%, p=0.05). Morphologic relapse rates at 5 years of PS and NS were 55% and 30% (p=0.14). Acute GVHD rate at 6 months was superior with the NS (41% vs 80%, p=0.002). Chronic GVHD rate at 5 years was similar between groups. At least one proven infection at 100 days was documented in 96% compared to 88% of patients with the PS and NS respectively (p=0.08). Neutrophil recovery at 60 days and platelets recovery at 180 days were not significantly different. T-cell Immune recovery at 6 months was superior in the NS. Median (min;max) CD3 counts in PS and NS were respectively 339 (132;1152) versus 946 (284;1944) (p=0.009), CD4 counts were 221 (65;612) versus 594 (238;920) (p=0.046) and CD8 counts were 55 (34;414) versus 320 (210;1104) (p<0.001). Conclusion: Compared to the PS, the NS of conditioning regimen and GVHD prophylaxis shows a significant improvement in OS and a tendency towards decreased relapse and increased EFS. However, we found a significant increase in acute GVHD with this regimen, which is explained by the removal of ATG from the regimen. These results highlight the necessity to adjust our strategy with HSCT ALL with the aim of maintaining graft versus leukemia effect without increasing GVHD. Emerging immunotherapy (such as antibody-based and chimeric antigen receptor T cell therapies) might shift the management of refractory and relapsed ALL and our current approach to HSCT. Disclosures Bittencourt: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Travel, accommodations expenses.

Prediction of Relapse Risk by Day 100 BCR-ABL Quantification after Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukaemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2020-2020
Author(s):  
Marie T. Rubio ◽  
Vahid Asnafi ◽  
Eric Delabesse ◽  
Gandhi Damaj ◽  
Nathalie Dhedin ◽  
...  
Keyword(s):  
T Cell ◽  
Residual Disease ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Objective Evaluation ◽  
Early Evaluation ◽  
Post Transplant ◽  
Negative Results

Abstract CML relapse after allogeneic SCT is a relatively frequent situation and is clearly correlated to disease status, time from diagnosis to transplant and T cell depletion. Defining other risk factors could help modulate post transplant immunosuppression. We evaluated the value of early minimal residual disease (MRD) quantification to predict relapse of CML patients receiving standard allogeneic SCT. MRD was analysed by RQ-PCR at Day 100 in 38 patients with a follow up after transplant > 1 year and was expressed as BCR-ABL/ABL, qualified by objective evaluation of RNA amplifiability relative to local normal values for MRD samples (the Quality Index or QI). This QI allows objective evaluation of the degree of correction for positive results and modification of the limits of detection for negative results. Thirty six of 38 patients received conventional conditioning regimen with either BU/CY or TBI/CY and classical prevention of GVHD based on cyclosporin and methotrexate. The median time from diagnosis to transplant was 21 months and median follow up of the cohort was 76.8 months. Patients were allocated to two groups according to their Day 100 RQ PCR level. We compared the characteristics and evolution of the 14 patients with a high MRD level (Day 100 RQ PCR >10−4) to that of the 24 patients with a low MRD level (Day 100 RQ PCR <10−4). There were no significant differences in terms of disease status at transplant, median age at transplant, time from diagnosis to transplant, type of conditioning regimen, source of stem cells, sex mismatch, grade of acute GVHD or incidence of chronic GVHD between the two groups. We show that Day 100 BCR-ABL transcript levels >10−4 by RQ-PCR represents an independent risk factor of relapse after conventional non T cell depleted SCT. These data should favour risk-adapted post transplant immunosuppression based on a single time point early evaluation of MRD.

Stem Cell Transplantation (SCT) for Acute Myeloid Leukemia (AML): A Single Center in over 25 Years Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5351-5351
Author(s):  
Stella Santarone ◽  
Erminia Di Bartolomeo ◽  
Paolo Di Bartolomeo
Keyword(s):  
Stem Cell ◽  
Multiorgan Failure ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Stem Cell Source ◽  
Short Course ◽  
Gvhd Prophylaxis

Abstract In this study we report the results of SCT in 116 patients (M51, F65) with AML transplanted from HLA identical (n=111) or 1 antigen mismatched (n=5) related donors between 1981 and 2006. The median age was 33 years (1–63). At time of SCT, 76 patients were in CR1, 23 in CR2 and 17 in CR>2 or in relapse. The stem cell source was bone marrow for 94 patients, PBSC for 21 and cord blood for 1. The conditioning regimen was myeloablative for 110 patients (BU CY for 87 and TBI CY for 23) and not-myeloablative for 6 (Thiotepa CY). For GvHD prophylaxis, 30 patients received cyclosporine (CSA) alone and 86 were given CSA and short course methotrexate. All patients engrafted with a median time to achieve 0.5 ×109/L neutrophils and 50×109/L platelets of 20 (10–37) and 22 (11–103) days respectively. One patients lost the graft six months after SCT and was successfully retransplanted. Acute GvHD grade II–IV occurred in 24%. Chronic GvHD occurred in 21% (9% limited, 12% extensive). The overall transplant related mortality (TRM) was 15.5% at 12 months (14,4% in CR1, 8,7% in CR2 and 29% in CR>2 or in relapse). Causes of death were: GvHD in 6 patients, infection in 6, multiorgan failure in 3, renal insufficiency in 1, encephalopathy in 1, pancreatitis in 1. The overall incidence of relapse was 29% (25% in CR1, 26% in CR2, 53% in CR>2). Twelve patients (1 in CR1, 5 in CR2 and 6 in >CR2 or relapse) underwent a second SCT from the same donor after a median interval from the first and second SCT of 456 (203–1946) days. The TRM post-second SCT was 16%. Nine of 12 patients are now living and cured after a median follow-up of 5,4 years (1–16,8). Overall, after a median follow-up of 8.08 (0.3–22) years, 71 out of 116 patients (61%) are living and cured. The 20 years probability of disease free survival is 68% for patients in CR1, 74% for patients in CR2 and 18% for patients in CR>2 or relapse (Fig. 1). In univariate analysis the patient age < 30 years, the BUCY regimen as compared to the TBI regimen and a dose of marrow cells > 3.0 × 108/Kg are associated with a better survival. We conclude that SCT is a curative treatment for patients with AML. In our experience second SCT gives results comparable to those of first transplant. Fig 1. Probability of DFS according to phase of disease at SCT Fig 1. Probability of DFS according to phase of disease at SCT

Intravenous Busulfan-Based Conditioning Prior to Allogeneic Stem Cell Transplantation in Adults Patients with AML - An ALWP-EBMT Survey.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1995-1995 ◽  
Author(s):  
Arnon Nagler ◽  
Myriam Labopin ◽  
Avichai Shimoni ◽  
Donald Bunjes ◽  
Pedro Pimentel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Advanced Disease ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
The Impact

Abstract Oral Busulfan (Bu) is the historical backbone of pre-allogeneic stem cell transplantation (alloSCT) conditioning regimen. However, oral Bu has an erratic and unpredictable absorption with wide inter and also intra-patient (pt) variability. In contrast, I.V. Busulfan (IV Bu) is with more predictable pharmacokinetics and favorable toxicity profile. In order to assess the impact of the use of IV Bu, the ALWP of the EBMT performed a survey in AML pts who received IV-Bu as part of their pre-alloSCT conditioning regimen. 36 EBMT centers participated in this study: 9 centers performed more than 10 transplants each. Overall, 271 alloSCT were analyzed. Age was 44 (range, 16–67) years. 146 were males (54%) and 125 (46%) were females. Disease status at alloSCT was CR1-53%, CR2-16%, primary refractory-13%, Rel1-12%, Rel2-5% and untreated-1%.77% of the pts were with intermediate, 15% with poor and 8% with good risk cytogenetics, respectively. Median WBC at diagnosis was 26×109/L. Conditioning consisted of IV Bu and cyclophosphamide (IV BuCy) in 52%, IV Bu and fludarabine (IV BuFlu) in 38% and various other IV Bu containing regimens in 10% of the pts, respectively. Overall, conditioning was myeloablative in 80% and reduced-intensity (RIC) in 20% of the alloSCT, respectively. Donors were: identical siblings-59%, matched unrelated-28%, mismatched unrelated-10%, mismatched family donors-2%, syngeneic 1%. 83% of the pts were transplanted with mobilized PBSC grafts while 17% received BM grafts. GVHD prophylaxis consisted of CSA and MTX in 85% of the transplants. With median follow up of 24 (range, 1–66) months, 53% of the pts are alive while 47% have died. Day 100 mortality was 7%. The incidence of veno-occlusive disease of the liver (VOD) was 10.4%. VOD was more frequent in pts that were transplanted from unrelated donors in comparison to those who were transplanted from sibling donors (18% vs. 5%, respectively). It was also more common after myeloablative conditioning than RIC (11.5% vs. 5.5%, respectively). Median age of pts with VOD was 42(17–65) years, not different than the age of the whole group, but they had more advanced disease (primary refrectory-35%, Rel2-30%). Day of onset of VOD was +10(range, 1–162). VOD was severe in only 15% of the pts and only 6 pts died of VOD. All together 30% of the pts with VOD are alive. Overall, alloSCT transplant related mortality (TRM) was 22±4% for pts transplanted at CR1 vs 33±8% for pts transplanted at advanced disease. Similarly, leukemia free survival (LFS) for pts transplanted at CR1 was 55±4% vs. 21+5% for pts transplanted in advanced disease. In summary, IV Bu based conditioning reduced the incidence and severity of VOD post alloSCT for AML as compared to published figures for historical controls. A randomized trial assessing VOD incidence and TRM using IV BuCy vs. IV BuFlu with 2 vs. 4 days of IV Bu, respectively may be indicated.

Donor Lymphocyte Infusions and Second Transplantation as Salvage Treatment for Relapsed Myelofibrosis After Reduced-Intensity allografting.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1300-1300
Author(s):  
Nicolaus Kröger ◽  
Evgeny Klyuchnikov ◽  
Daniel Wolff ◽  
Martin Bornhäuser ◽  
Guido Kobbe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Complete Loss ◽  
Donor Lymphocyte Infusions

Abstract Abstract 1300 Introduction: Around 20–30% patients (pts) with primary myelofibrosis (PMF) experience relapses within 3 years after dose-reduced conditioning followed by allogeneic stem cell transplantation (HSCT). The prognosis for those pts is unclear, and standard treatment recommendations have not yet been proposed. Early withdrawal of post-transplant immunosuppression, use of dose escalating donor lymphocyte infusions (DLIs), and/or 2nd HSCT have been suggested as therapeutic options for pts relapsing after HSCT. Although DLIs were found to be effective in certain disease as salvage approach, the role of 2nd HSCT for non-responding patients remains controversial. Here we report on our multicenter experience on the use of a two-stage salvage strategy including DLIs and a 2nd RIC-HSCT in pts with post-transplant relapse of PMF. It was planned to start salvage therapy with DLI and only non-responding patients as well as patients with transformation to blast crisis and complete loss of donor chimerisms were assigned to receive a second allogeneic stem cell transplantation. Responses were evaluated using the International Working Group consensus criteria for treatment response in myelofibrosis. Additionally, the JAK2V617F mutation level (in 1 case, the MPLW515mut level) and donor chimerism were used to assess the molecular remission status. Patients/Methods: Thirty pts with morphologic (n=24) or molecular (n=6) relapse of PMF after 1st HSCT were proceeded to a salvage strategy, including DLIs and/or 2nd RIC-HSCT. Median time from transplantation to relapse was 9 months (range, 2–62). 26 pts received a median of 3 (range, 1–5) DLIs. The initial median dose was 1.2×106 (range, 0.3×104 – 8×107) consequently being increased up to 4×107 CD3+ cells/kg (range, 1×107 – 1.3×108). As a second stage, 13 non-responding pts as well as those who received no DLIs (transformation to blast phase, n=1; complete loss of donor chimerism, n=3) underwent a 2nd RIC-HSCT. The median interval between 1st and 2nd HSCTs was 17 months (range, 11–77). The majority of the patients received a reduced busulfan/fludarabine conditioning regimen for the 1st HSCT. Conditioning regimen at the 2nd RIC-HSCT for most pts (12/17, 71%) consisted of a combination of treosulfan (30-36 g/m2) with fludarabine (150-180 mg/m2), and anti-thymocyte globuline (Thymoglobulin®, 2.5–8 mg/kg). The majority of pts (15/17, 82%) received 2nd allografts from alternative unrelated (HLA-matched, n=8; mismatched, n=5), related (matched, n=1), and haploidentical donors (n=1). Results: After DLIs, responses were observed in 10/26 pts (39%; complete remission (CR): n=8; CRu (unconfirmed: no bone marrow histology: n=2). All pts maintain the response during a median follow-up of 31 months (range, 13–45). Acute (grade II-IV) and chronic GvHD occurred in 3/26 (12%) and 7/25 (28%) pts, respectively There were no cases of non-relapsed mortality (NRM), while 3/26 pts expired from progression. Seventeen pts received a 2nd RIC-HSCT and engraftment was documented in 16/17 pts (leukocytes: median, d +14; platelets: median, d +18). Responses were observed in 12/15 evaluable pts (80%; CR, n=8; CRu, n=1; partial remission (PR), n=3). Acute (II-IV) and chronic GvHD were observed in 8/17 (47%) and 6/14 pts (43%), respectively. The 1-year cumulative incidence of NRM was 6% (95% CI: 0%-18%). The cumulative incidence of relapse at 1 year was 24% (95% CI: 0%-50%). Overall for whole study population, after a median follow-up of 27 mo (range, 9 – 61), the 2-year probabilities of OS and PFS was 80% (95% CI: 62% - 98%) and 72% (95% CI: 52% - 92%), respectively. Conclusions: DLIs and/or 2nd HSCT are effective and well tolerated salvage approaches, which resulted in the majority of patients in long-term freedom from disease. Disclosures: No relevant conflicts of interest to declare.

Different Approaches Of Allogeneic Stem Cell Transplantation For Acute Leukemias In Suzhou (China) Lead To Similar Outcome Compared With European Group For Blood and Marrow Transplantation (EBMT) Results: A Pair-Matched Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2131-2131
Author(s):  
Jia Chen ◽  
Yin Lu ◽  
Myriam Labopin ◽  
Depei Wu ◽  
Mohamad Mohty ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Multivariate Analyses ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Acute Leukemias ◽  
Significant Difference

Abstract The first affiliated hospital of Soochow University initiated a program of stem cell transplantation for hematological malignancies in 2001 and has done until December 2011 a total of 460 transplants. The EBMT presently handles a registry with information on more than 450 000 transplants including over 100 000 transplants for Acute Leukemias. In order to evaluate the outcome of patients transplanted in Suzhou and to compare it with results from the EBMT, we collected the necessary information on all patients transplanted in Suzhou and we did a pair matched analysis. In Suzhou, the patient population studied consisted of 382 first allografts (322 adults and 60 children less than 18 years old). There were 223 Acute Myelocytic Leukemias (AML), 148 Acute Lymphoblastic Leukemias (ALL) and 11 biphenotypic leukemias. The median age of the patients was 32 years (4-63). By cytogenetics, 9% of the patients were good risk, 57% intermediate risk and 34% poor risk. Molecular biology was not available. 286 patients were transplanted in first remission (CR1), 63 in CR2 and 30 in more advanced disease. Donors were identical siblings in 57%, unrelated in 30%, mismatched relatives in 13%. The source of stem cells was bone marrow (BM) (harvested after stimulation of the donor by GCSF) in 40%, Peripheral Blood (PB) in 36%, BM + PB in 17% , Cord Blood in 4% and other in 3%. 97% of the patients received myeloablative conditioning (MAC) with no Total Body Irradiation (TBI) in 76%, and 3% reduced intensity conditioning (RIC). 98% of the patients engrafted. Acute Graft versus Host Disease (aGVH) grade >=2 occurred in 43%. The cumulative incidence of chronic GVHD at 2 years was 26±2%. With a median follow up of 21 months (1-143), 2 year overall survival (OS), Leukemia free survival (LFS), Relapse Incidence (RI) and non Relapse Mortality (NRM) in patients allografted in CR1 were 76± 3, 65± 3, 18± 2 and 17 ± 2% and in CR2 52± 7, 36± 7, 37± 7 and 28 ± 6%. TBI in MAC was associated with poorer results (p< 0.01 for OS,LFS,RI). By multivariate analyses, The NRM was lower with PB (p=0.04) and PB+BM (p= 0.01) compared to BM and the OS higher ( p=0.05 and 0.01 respectively). In a pair matched analysis 246 adult patients from Suzhou transplanted in CR with BM and/or PB were matched with 484 patients from the ALWP EBMT registry. Matching factors were age, diagnosis (AML and ALL), disease status (CR1 or CR2), Cytogenetics and donor origin (identical siblings, unrelated, mismatched relatives). Patients from Suzhou were transplanted more recently ; the interval from diagnosis to transplant was shorter (138 days vs 154 days, p<0.0001). TBI was less frequently used for MAC both for AML and ALL (p< 0.0001 for each) and PB + BM was used in 17% of the cases versus 0% for EBMT (p < 0.0001). By univariate analyses the results were: Suzhou versus EBMT: OS 72 ± 3 vs 61 ±2 % (p= 0.05), LFS 62 ± 3 vs 55 ± 2% (p= 0.17), RI 19 ± 3 vs 22 ± 2% (p= 0.25), NRM 20 ± 3 vs 22 ± 2% (p = 0.67), incidence of chronic GVH 30± 3 vs 48 ± 2% (p< 0.0001). By multivariate analyses, there was no significant difference for OS (HR: 0.9 range 0.59-1.39), LFS (HR: 0.93, range 0.63-1.38), RI ( HR: 0.72, range 0.41-1.28) and NRM (HR: 1.21, range 0.70-2.10). We conclude that the results from Suzhou are identical to those obtained using the EBMT database, even though some approaches (GCSF stimulated BM, BM+PB, conditioning regimen) were different. Disclosures: No relevant conflicts of interest to declare.

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