Potential Increase in Graft Failure Risk after Reduced Intensity Conditioning Stem Cell Transplant (RIT) Using Umbilical Cord Blood for Children with Primary Immunodeficiency.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2006-2006
Author(s):  
Jessica Guarino ◽  
Morris Kletzel ◽  
Reggie Duerst ◽  
David Jacobsohn ◽  
Jennifer Schneiderman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Median Time ◽  
Primary Immunodeficiency ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Cd34 Cells ◽  
Unrelated Donors ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation is curative for patients with primary immunodeficiency. A unique reduced intensity conditioning regimen has been developed to maximize cure rate and minimize transplant-related toxicity. Between 2000 and 2007, we performed 16 RIT in patients with hyper-IgM syndrome (n=2), severe combined immune deficiency (SCID) (n=10), immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) (n=2), Wiskott-Aldrich syndrome (n=1), and X-linked lymphoproliferative disease (n=1). There were 12 males and 4 females, with a median age at the time of RIT of 8.0 months (range 1.1 months to 8.9 years). Donor sources included peripheral blood stem cells (PBSCs) from matched related donors (n=7) or unrelated donors (n=2), and cord blood units (CBUs) (n=7). The median cell dose was 8.55 × 108 total nucleated cells (TNC)/kg and 6.7 × 106 CD34+cells/kg for the PBSC group, and 1.99 × 108 TNC/kg and 0.71 × 106 CD34+cells/kg for the CBU group. The conditioning regimen consisted of Fludarabine (Flu), days -10 through -5, intravenous Busulfan (Bu), days -5 and -4, and Anti-thymocyte globulin (ATG), days -4 through -1. GVHD prophylaxis included tacrolimus/prednisone (n=1), cyclosporine A (CSA) alone (n=2), and CSA/mycophenolate mofetil (n=13). All patients who received PBSCs from related and unrelated donors engrafted (9/9), whereas only 4/7 (57%) patients who received CBUs engrafted. The 3 patients who experienced primary graft failure had the following diagnoses; IPEX, T−B−NK+ SCID and T−B+NK+ SCID. Their cord blood doses were 0.78, 1.19 and 1.99 × 108 TNC/kg, and 0.11, 0.69, and 0.55 × 106 CD34+cells/kg, respectively. For the 13 patients who engrafted, median time to absolute neutrophil count (ANC) >1000 was 19 days (range 4 to 53) and median time to platelets >50K was 23 days (range 14 to 90). The ANC never dropped <500 for 8/13 (62%) patients, and platelets never dropped <20K for 9/13 (69%) patients who engrafted. VNTR analysis of donor cell contribution showed that full donor chimerism was achieved in 8/16 patients (50%; 6 received PBSCs and 2 received CBUs), and, partial donor chimerism was achieved in 5/16 patients (31%; 3 received PBSCs and 2 received CBUs). Toxicities within 100 days post-RIT included bacteremia (n=8), candidemia (n=1), and viral infection (n=6). All infections were effectively treated and patients fully recovered. No episodes of seizure or veno-occlusive disease were experienced. No mucositis or severe nausea/vomiting was reported. No grade III/IV acute graft-versus-host disease (GVHD) or chronic GVHD was seen. Three patients died within 100 days post-RIT from causes related to primary or secondary graft failure. The overall survival was 81.0% at 2 year post-RIT (95% CI 89.5–71.5). All deceased patients received CBUs as the donor source. One of these patients were considered high-risk with pre-RIT Lansky score =30%. If this patient was excluded from analysis, the 100 day RIT related mortality was 13.3%. This retrospective analysis revealed that RIT with Flu/Bu/ATG conditioning is well tolerated in children with primary immunodeficiency. The use of CBUs, however, appeared to increase the risk of graft failure. A larger study of the use of RIT in primary immunodeficiency could further examine this hypothesis.

Phase II Prospective Multicenter Study of Treosulfan Based Reduced Intensity Conditioning In Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2353-2353 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Nathalie Tedone ◽  
Jacques-Olivier Bay ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Abstract 2353 Background: The key point in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to find the optimal balance between the graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect particularly in the unrelated HSCT settings, without forgetting the important role of conditioning. Objective: To evaluate the toxicity and efficacy of a new reduced intensity conditioning regimen including Treosulfan, followed by allo-HSCT from a 10/10 HLA identical unrelated donor. Materials and Methods: This prospective study included adult patients presenting a hematological malignancy in need of allo-HSCT using a 10/10 HLA identical unrelated donor. Accepted diagnoses were: CML in 1st chronic phase (CP) resistant to imatinib, in 2nd CP or in complete remission (CR) after blast crisis. Multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) in stage B or C in response after relapse post-auto-HSCT. Acute lymphocytic or myeloid leukemia (ALL, AML) patients in CR1 at high risk or <CR1. Myelodysplasic syndrome (MDS) with poor prognostic factors. The conditioning included: Treosulfan 12g/m2/day intra-venous (day-6 to day-4), fludarabine 30mg/m2/day intra-venous (day-6 to day -2) and ATG 2.5 mg/kg/day (day-2 to day-1). GVHD prophylaxis used cyclosporine A oral (5mg/kg/day) or iv. (3mg/kg/day) from day-1. Peripheral stem cells after mobilization by G-CSF were used as HSC source. Results: Between February 2005 and July 2009, 56 patients were included in 5 different French centers, 30 (54%) males and 26 females with a median age of 57 years (18-65.5). There were 38 (68%) myeloproliferative disorders [29 AML (14 in CR1, 14 CR2 & 1<CR), 8 MDS (1CR1 and 7<CR) and 1 CML in CR1] and 18 (32%) lymphoprolifative disorders [9 MM in PR, 6 CLL (2CR1 & 4PR) and 3 ALL(1CR1 & 2CR2)]. Among 45 explored for cytogenetics, 23 (51%) were normal and 22 with poor prognostic. Before transplantation, two patients did not receive any previous treatment, 21 received 1 line, 22 two lines and 11 > 2 lines. For sex-matching, 49% of patients were sex-mismatched (half of them were F>M). For CMV, 43% were -/-, 25% +/+, 28% +/&minus; and 1% -/+. For ABO matching, 52% were compatible, 24% major incomp. & 24% minor incopm. The median time between diagnosis and allograft was 15 months (4-168). The median number of infused CD34+ cells was 6.5 × 106/Kg(1-17.2) Fifty-four (96%) patients engrafted with a median time to neutrophils (>0.5G/l), and platelets (>50G/l) recovery of 16 days (4-86), 11 (4-82) respectively. Seventeen patients developed aGVHD grade ≥II (8 grade II, 2 grade III & 7 grade IV) with a cumulative incidence at 3 months of 31% (25-38). The cumulative incidence of cGVHD was, at 12 months: 32% (25-39) limited and 6% (2-10) extensive; at 18 months: 34% (27-47) limited and 8% (5-12) extensive. After a median follow-up of 13 months (1-57), the median overall survival (OS) was not reached with a 3 years probability of 52% (38-71). The median time of event free survival (EFS) was 15 months (8 - 57) with a 3-years probability of 47% (35-64). The cumulative incidence of relapse at 3 years was 25% (19-31) and the cumulative incidence of transplant-related mortality (TRM) at 12, 18 and 36 months was 20% (16-27), 23% (16-29) (same at 18 & 36 months) respectively. At the last follow-up, 22 patients died, 7 due to relapse and 15 due to TRM (5 pneumonia, 4 GVHD, 1 secondary malignancy and 6 other causes). We showed in a univariate analysis a higher 3-years OS of patients in CR1 (65%) compared to those <CR1 (44%) at transplantation with a significant better benefit for AML patients (76%). Patients with active cGVHD seem to benefit for the GVL effect on OS with a high significant difference (HR=0.2 (0.1-0.6) p=0.002). The multivariate analysis studying age, sex matching, ABO compatibility, CMV matching, type of disease, CD34+ cells number, cytogenetics, number of previous treatments, disease status and interval diagnosis-allo-HSCT showed: a negative significant impact of both minor ABO incompatibility (p<0.001) and CMV+/&minus; (p=0.01) on OS, a negative significant impact of patients <CR (p=0.03) on relapse. There was no impact of studied factors on TRM. Conclusion: We showed very promising results in terms of OS, relapse and TRM with an impressive GVL effect, in heavily pre-treated patients and transplanted using unrelated donors. Treosulfan appears to be a good choice for conditioning especially with a better outcome in AML patients in CR1. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ex Vivo Mesenchymal Precursor Cell-Expanded Cord Blood Transplantation Following Reduced Intensity Conditioning Regimens

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1190-1190 ◽  
Author(s):  
Rohtesh S. Mehta ◽  
Rima M Saliba ◽  
Kai Cao ◽  
Indreshpal Kaur ◽  
Katayoun Rezvani ◽  
...  
Keyword(s):  
Cord Blood ◽  
Median Time ◽  
Cumulative Incidence ◽  
Ex Vivo ◽  
Patient Characteristics ◽  
Reduced Intensity Conditioning ◽  
Cd34 Cells ◽  
Mesenchymal Precursor ◽  
Reduced Intensity ◽  
Neutrophil Engraftment

Abstract Introduction: Double-unit cord blood (CB) transplantation (DCBT) after myeloablative conditioning, where one CB unit is expanded ex-vivo with mesenchymal precursor cells (MPC)-co-culture led to significantly improved neutrophil and platelet engraftment compared to historical controls.1 Our aim was to determine the efficacy of this technique after reduced-intensity conditioning (RIC) regimens. Methods: We evaluated consecutive adult patients with hematological malignancies who received RIC regimens followed by DCBT where one unit was infused unmanipulated and second unit was expanded ex-vivo with MPC prior to infusion ("MPC group" n=27), as described previously,1 andcompared themwith historical cohort who received two unmanipulated CB units ("controls" n= 51) from 2003-2015. Two RIC regimens were used - Flu/Cy/TBI (flu 40 mg/m2, cy 50 mg/kg and TBI 200cGy) (n=40) and Flu/Mel (flu 40 mg/m2 and mel 140 mg/m2) (n=38) with rabbit ATG 3mg/kg. Tacrolimus and MMF were used for GVHD prophylaxis. Primary endpoint was median time to engraftment of neutrophils (≥ 0.5 X 109/L X 3 consecutive days) and platelets (≥ 20 X 109/L X 7 consecutive days without transfusion). Results: Diagnoses were AML/MDS (N=38; 49%), ALL (N=13; 17%),NHL (N=18; 23%), HD (N=3; 4%), CML (N=1; 1%), and CLL (N=4; 5%). Baseline patient characteristics were similar among the groups [Table 1]. Majority of CB units (66%) were 5-6/8 matched at HLA-A, B, C and DRB1 by high resolution testing. Infused median total nucleatedcells (TNC) (x107/Kg) were 4 and 8, and median CD34 cells (x105/Kg)were 4.3 and 19.7, respectively for control and MPC groups. Co-culture with MPCs led to expansion of TNC by a median of 11.1 and of CD34+ cells by a median of 49.3. Among engrafted patients, median time to neutrophil engraftment was 12 (range 1-28) days in MPC group as compared with 16 (range 5-48) days in controls (p=0.02); the median time to platelet engraftment was 31 days and 37 days, respectively (P=0.3). On day 26, the cumulative incidence of neutrophil engraftment was 78% in MPC group versus 67% in controls (P=0.1). On day 60, the cumulative incidence of platelet engraftment was 74% and 74%, respectively (P=0.7). [Figure 1] Conditioning regimen also affected the time to neutrophil recovery. Among patients with Flu/Mel, the median time to neutrophil engraftment was 14 days in MPC-group (n=13) compared with 22 days in controls (n=19) (p=0.001). Patients with Flu/Cy/TBI regimen had faster time to engraftment; median time to neutrophil engraftment was 6 days in MPC group (n=10) and 11 days in controls (n=27) (p=0.04). However, the median time to platelet engraftment was similar in MPC- and control groups in patients who received either Flu/Mel (37 vs 44 days, p=0.1) or Flu/Cy/TBI regimen (29 vs 31 days, p=0.5). There was no difference in the cumulative incidence of day 100 non-relapse mortality (4% vs. 11%, p=0.6), 6th month mortality (25% vs 24%, p=0.6), grade II-IV acute GVHD (28% vs 27%, p=0.9), 2-year chronic GVHD (29% vs 20%; p=0.9) and estimates of 2-year OS (32% vs. 34%) between patients with ex-vivo expanded and unmanipulated CB units. Conclusions: Transplantation of CB units expanded with MPC appeared to be safe and effective. Using MPC-expanded CB units significantly improved time to engraftment following Flu/Mel or Flu/Cy/TBI RIC regimens as compared with unmanipulated units. Table 1. Patient characteristics Control(N=51) MSC group(N=27) P value Age, years (median, interquartile range) 57 (48, 63) 59 (49, 67) 0.3 Disease Status CR1/CR2 20 (40%) 12 (45%) Advanced 31 (61%) 15 (56%) 0.7 Disease Risk Index, n (%) V. High/High 8 (16%) 9 (33%) Intermediate 38 (75%) 16 (59%) Comorbidity index 0-1 24 (47%) 13 (48%) 2-4 22 (43%) 11 (41%) >4 5 (10%) 3 (11%) 0.97 Flu/Mel regimen 22 (43%) 16 (59%) 0.2 References 1. de Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. NEJM. 2012;367(24):2305-2315 Disclosures Kaur: UT MD Anderson Cancer Center: Employment. Alousi:Therakos, Inc: Research Funding. Skerrett:Mesoblast: Employment. Burke:Mesoblast: Employment.

The Influence of Human Plateley Antigen Match on the Success of Stem Cell Transplantation after Myeloablative or Reduced-Intensity Conditioning Regimen.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5127-5127
Author(s):  
Gerda C. Leitner ◽  
Hildegard T. Greinix ◽  
Peter Kalhs ◽  
Hoecker Paul ◽  
Panzer Simon
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Platelet Antibodies ◽  
Reduced Intensity Conditioning Regimen ◽  
Unrelated Donors ◽  
Reduced Intensity ◽  
Platelet Transfusions

Abstract Background: Mismatches between donor and recipient for human platelet antigens (HPA) may affect the success of transplantation due to: a) serving as minor histocompatibility antigens and therefore render recipients at risk for GvHD, b) inhibition of thrombopoiesis due to platelet antibodies. Patients and Methods: We evaluated in 54 patients receiving hematopoietic stem cell transplantation (HSC T) from HLA matched siblings after a myeloablative conditioning regimen the occurrence of GvHD, transplant related mortality (TRM), and the need of platelet support by prospective analyzes of donor-recipient pairs for HPA -1, -2, -3, and -5 allotypes. Patients were screened for platelet antibodies prior to transplantation and in weekly intervals until day 100 after transplantation. Forty five patients receiving HSCT from related or unrelated donors after a reduced-intensity conditioning regimen (RIC) were enrolled retrospectively after a median observation time of 372 days. Results: Neither the incidence of GvHD and TRM, nor the onset of thrombopoiesis, nor the CCI after platelet transfusions, nor the frequency of platelet transfusions were affected by HPA mismatches. TRM among patients receiving a RIC was higher when grafts were from unrelated donors with 2 or more mismatches. Six of 7 patients who died due to TRM had 2 mismatches in the HPA system, although TRM was not significantly associated with mismatched HPA (p = 0.06). However, within donor-recipient pairs with more than one HPA mismatch TRM occurred when grafts were from unrelated donors (p = 0.03). Conclusion: Thus, the HPA match does not affect the success of transplantation.

Reduced Intensity Umbilical Cord Blood Transplantation(RI-UCBT) in Adult Patients with Graft Failure or Relapse after First Allogeneic Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5121-5121
Author(s):  
Kazuhiro Masuoka ◽  
Koichiro Yuji ◽  
Yuji Miura ◽  
Tomohiro Myojo ◽  
Daisuke Kato ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Blood Transplantation ◽  
Reduced Intensity ◽  
Neutrophil Engraftment

Abstract Background: Graft failure, graft rejection, or disease relapse post allogeneic hematopoietic stem cell transplantation(HSCT) is life-threatening and serious complication that necessitate consideration for a second transplantation. Graft failure has been more frequently reported in patients with aplastic anemia with T-cell depletion of the graft, in cord blood transplants, or when unrelated or HLA-mismatched related donors were used. In second allogeneic stem cell transplant setting, current questions include suitable stem cell source, additional conditioning, immunosuppression, and the use of a different donor, still remain unknown. We performed a feasibility study of reduced intensity umbilical cord blood transplantation (RI-UCBT) in adult patients with graft failure or disease relapse after first allogeneic transplantation. Patients and Methods: Nine patients (median age, 53 years; range 17–68) with advanced hematological diseases [AML (n=4), ALL (n=2), MDS (n=2), ATL (n=1)] who showed relapse or graft failure after first allogeneic transplantation underwent RI-UCBT with single cord blood unit at Toranomon Hospital between May 2003 and February 2004. Eight cases were in non-CR at transplant. A median time from first to second transplant was 226 days (range 31–475). The median number of mononuclear cells transfused was 2.3 x 107 /kg (range 1.8–3.5). HLA disparities were as follows; 5/6 in two cases, 4/6 in seven cases. Conditioning regimen mainly consisted of fludarabine 25 mg/m2 on days -7 to −3, melphalan 40mg/m2 (n=8) or busulfan 4mg/kg(n=1) day −3 to −2, and 4 Gy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis was composed of ciclosporin alone (n=6) and tacrolimus alone (n=3). Results: All of them achieved primary neutrophil engraftment (&gt;500/μL) after a median of 22 days (range, 15–32) and achievement of donor T-cell chimerism was confirmed. Four cases developed grade II-IV GVHD, and one case developed limited chronic GVHD. Of all the nine cases received RI-UCBT, seven died from relapse (n=4), sepsis (n=2), and TMA (n=1). Two survived without relapse for +232 and +81 days, respectively. Discussion: Although the number of patients is small and the follow-up period is short, our results corroborate that RI-UCBT for graft failure or relapse post first transplant is tolerated and may be worth considering for further evaluation. Neutrophil engraftment was achieved, however, disease relapse rate and treatment-related mortality is high. The management of disease status and development of ideal conditioning regimen will be the focus of future investigation.

Grafts From HLA-Identical Siblings Versus HLA-Allelic-Matched Unrelated Donors (10/10) In Patients Undergoing Allogeneic Stem Cell Transplantation Following Reduced-Intensity Conditioning Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2380-2380
Author(s):  
Eva De Berranger ◽  
Mathieu Wemeau ◽  
Charles Herbaux ◽  
Cracco Pascale ◽  
Jean-Pierre Jouet ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Conditioning Regimen ◽  
Hla Class I ◽  
Hla Typing ◽  
Class I ◽  
Reduced Intensity Conditioning ◽  
Conditioning Treatment ◽  
Unrelated Donors ◽  
Reduced Intensity

Abstract Abstract 2380 Nonmyeloablative, or reduced-intensity conditioning (RIC), regimens before allo-SCT have emerged as an attractive modality to decrease transplant-related toxicity while preserving the graft-versus-tumor effect. However, as for standard myeloablative allo-CST, only one third of patients have an HLA-identical sibling donor. Indeed, with the increase in the number of single-child families, stem cell grafts from unrelated donors are being increasingly used. We have previously reported, that in patients with standard-risk malignancy undergoing allo-SCT with CPM and TBI as conditioning treatment, unmodified marrow as a source of graft, and Cs-A plus short-course MTX as GVHD prophylaxis, there were no significant differences between the outcomes of patients receiving graft from siblings and those from unrelated fully HLA-matched donors (Yakoub-Agha et al, JCO 2006). However, no conclusions can be drawn with certainty concerning patients with more advanced disease, those who received a peripheral blood graft or especially those with a non-myeloablative conditioning regimen. Here we report a retrospective study of 58 consecutive patients who received RIC allo-CST. Donors were HLA-identical sibling (n=35) and unrelated molecularly HLA-identical donor. All donor/recipient pairs were typed at the allelic level. They were first typed at 2-digit level for HLA class I (HLA-A, B and Cw) and class II (HLA-DRB1 and DQB1) using published HLA class I PCR-SSO and/or SSP typing protocols. For unrelated donors, HLA-A, B, Cw, DRB1, B3, B4, B5 and DQB1 subtyping was performed using different PCR-SSP kits. HLA typing was performed according to the current use of the EFI Histocompatibility Laboratory standards. Only donor/recipient unrelated pairs matched for both alleles were included in this study. Diagnosis were AML (n=27), ALL (n=3), myelodysplastic syndrome (n=13), and myeloproliferative syndrome (n=15). Of the 32 (55%) males patients, 14 (43%) received graft from female donor (classical sex-mismatch). Medians age of recipients and donors at transplantation were 58 years (41.3-65.5) and 47.1 years (22.2-67.5), respectively. Patients received either low-dose TBI (2Gy) (n=46) or Busulfan-based (n=12) conditioning regimen. Antithymoglobulin was given to 12 patients. As usual in RIC setting, Peripheral Blood Stem Cells was the main source of graft (n=38; 65%), otherwise marrow graft (n=20). Results: with the median of follow-up of 27.2 months (range, 8.1–79.4), 24 patients died including 9 from TRM. Relapse was recorded in 21 patients. Eighteen patients experienced acute GVHD (aGVHD) including 12 with II-IV grades and 7 with III-IV grades. Contrary to what we have previously reported in myeloablative allo-CST sittings, patients who underwent RIC and received graft from unrelated HLA-matched (10/10) donor, experienced worse outcomes compared to those transplanted with an HLA-identical sibling. Indeed, in multivariate analyses, donor type (unrelated HLA-matched 10/10 vs HLA-identical sibling) was the most important risk factors negatively influenced the overall survival and EFS [p=.01; HR=3.068; [95%CI: 1.312–7.174]) and (p=.050; HR=2.081; [95%CI: 1.001–4.347]), respectively. To our knowledge, this is the first study which compares results of sibling transplantation to HLA-allellically-matched (10/10) unrelated transplantation. Even though, results of the latter did not compare favorably to those obtained with an HLA-identical sibling donors, grafts from HLA-matched unrelated donors, are still an attractive option especially for patients with high-risk malignancy. Our data emphasis the need of prospective studies evaluating factors influencing outcomes of HLA-allellically-matched (10/10) unrelated transplantations. Disclosures: No relevant conflicts of interest to declare.

Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Multicenter Open French Study In High-Risk pediatrics

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 534-534
Author(s):  
Catherine Paillard ◽  
Patrick Lutz ◽  
Guy Leverger ◽  
Gerard Michel ◽  
Pierre Bordigoni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Solid Tumors ◽  
Median Time ◽  
Graft Failure ◽  
Hematological Malignancies ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Abstract 534 Introduction: There is increasing information about reduced intensity conditioning regimen AlloHSCT (Allogeneic Hematopoietic Stem Cell Transplantation) in children. The safety of this approach is now well established but data regarding efficacy are limited and the role in pediatric cancer has yet to be defined. Materiels and methods: We report results of a French pediatric AlloHSCT protocol with ATG-fludarabine (180 mg/m2) - Busilvex (3.2 at 4.8 mg/kg/d for 2 days) conditioning regimen. Related, unrelated bone marrow (BM) and Peripheral blood stem cell (PBSC) donors and Cord blood units (CB) were allowed. In case of CB a TBI 2 grays, Cyclophosphamide 50 mg/kg, Fludarabine 100 mg/m2 conditioning regimen was recommended. GVH prophylaxis consists in cyclosporine alone. A rapid discontinuation of systemic immunosuppression and re-injecting donor lymphocytes to initiate graft-versus-tumor effect are based on tumor assessment and blood chimerism. Inclusion criteria are children with malignancies that can be potentially cure by allograft but a conventional conditioning regimen being impossible due to toxicity and children with solid tumor or hematological malignancy remaining unresponsive to the reference strategies according to French best practices in pediatrics. Results: From April 2007 to April 2010, 40 RIC AlloHSCT were performed in 10 different French pediatric graft centers: 13 Hodgkin Lymphoma, 7 acute myeloblastic leukaemia, 2 acute lymphoblastic leukaemia, 6 neuroblastoma, 8 rhabdomyosarcoma, 3 desmoplastic tumor and 1 Ewing sarcoma. Median age at transplantation was 15 years and median time from diagnosis to transplant was 18 months. Before transplant, 15 patients are in complete response and 25 patients (14/18 solid tumors) have active disease (11 progressive, 14 partial response). 21 had already received a myeloablative therapy (18 autograft and 3 allograft). Graft source was PBSC in 17 cases (7 related and 10 unrelated), BM in 18 (10 related and 8 unrelated), and 5 CB. The RIC Bu-flu conditioning regimen permits rapid engraftment without major toxicity contrary to the Cy-TBI in CB. 1 patient had primary graft failure: 1 CB and 5 patients experienced secondary graft failure: 3 CB, 1 PBSC and 1 BM. Median time to reach an ANC of 0.5 109/l was 16 days. Median time to reach a platelet count of 20 × 109/l was 2 days. Platelet count did not decrease below 20 109/l in 10 allografts. At day 30 post-transplant, chimerism is mainly donor for 30 and partial for 6 children. At day 100 post transplant, 4 out of 6 with initial mixed chimerism were converted into full donor chimerism. 8 patients received DLI and 17 patients experienced acute graft versus host disease (GvH) (2 grade IV and 15 grade ≤ II). A low day 365 TRM of 5% is reported in these heavily pre-treated patients. With a median follow-up of 15 months, the estimated 2 yr overall survival (OS) was respectively 57 % (71% for hematological malignancies and 42% solid tumors) (fig 1) and event free survival (EFS) 36% (50% for hematological malignancies and 19% solid tumors). Univariate analysis of EFS and OS showed no effect of related versus unrelated stem cell sources and BM versus PBSC. Our analysis identified a group of patients, who had no measurable disease at transplant, with a 2 yr OS and EFS of 86%. In term of efficacy, we observe a graft versus lymphoma effect in patients with advanced active Hodgkin lymphoma. Concerning solid tumors, all children included had a very bad prognosis and detectable disease before transplant. Our results may suggest that an immune-mediated effect cannot be excluded in some refractory solid pediatric tumors particularly in neuroblastoma. The main cause of failure of this approach is disease progression. Immunologic approaches after transplantation may help cure more of these very-high-risk patients. Conclusion: Even if further follow up is needed, this prospective study suggest that RIC regimen provides promising outcome in children previously not eligible for myeloablative AlloHSCT. This study “RICE” was registered at www.clinicaltrials.gov as NCT 007 50 126 Disclosures: No relevant conflicts of interest to declare.

Graft Failure In Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4559-4559
Author(s):  
Richard Olsson ◽  
Daniel Moreno Berggren ◽  
Olle Ringden ◽  
Jonas Mattsson ◽  
Mats Remberger
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Solid Tumors ◽  
Graft Failure ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Increased Risk ◽  
Unrelated Donors ◽  
Reduced Intensity

A decade ago reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was successfully introduced to facilitate transplantation in patients with co-morbidities. In contrast to myeloablative conditioning regimens RIC transplants are associated with less toxicity and thus preferred in the elderly population. However, there are also disadvantages with RIC such as the increased risk of graft failure caused by rejection by remnant recipient T-cells at transplant, which often results in mixed chimerism during the first months post-transplant. Here, we present risk factors for graft failure in all first RIC allo-HSCTs performed at our center from 1995 to mid-2010 (n=357). Graft failure was defined as >95% recipient T-cells any time after engraftment or reinfusion of donor cells due to >50% recipient cells with no clinical or laboratory signs of relapse. Thirty-six patients (10%) experienced graft failure. The median age of the patients was 51 and 57% were males. In univariate analysis, graft failure was 3-fold increased in male compared to female patients (15% versus 4%; P<0.01). Furthermore, patients with non-malignant disorders (26% versus 2%; P<0.01) and solid tumors (20% vs. 2%; P<0.01) had an increased risk of graft failure when compared to acute leukemia. Graft versus host disease (GVHD) prophylaxis using cyclosporine A (CSA) in combination with mycophenolate mofetil (MMF) resulted in increased numbers of graft failure when compared to our standard regimen with CSA and methotrexate (18% vs. 5%; P<0.01). The graft failure rate was the lowest among HLA-identical sibling donors (6%), slightly higher in 8/8 matched unrelated donors (10%), and the highest in 6/6 matched unrelated donors (18%; P<0.01). Total nucleated cell (TNC) dose was also important with less graft failures when the TNC dose was >10 x 108/kg, whereas CD34+ cell dose had no impact on graft failure (P=0.15). Moreover, in univariate analyses year of transplant, donor sex, cell source, CMV mismatch, ABO mismatch, or pre-planned G-CSF did not influence graft failure rates (P>0.05). In multivariate analysis (Table 1), solid tumors were associated with markedly increased risk of graft failure (RR=10.95; P=0.03), whereas there was a tendency towards increased graft failure risk in non-malignant disorders (RR=8.01; P=0.05). Graft failures were also increased in male recipients (RR=3.27; P<0.01), in grafts with a TNC dose less than 10 x 108/kg (RR=2.17; P=0.03), when using MMF containing GVHD prophylaxis (RR=3.61; P<0.01), and in transplants with HLA match less than 8/8 (RR=4.94; P<0.01). In conclusion, graft failure is augmented in male recipients, and associated with diseases which usually do not receive high-dose chemotherapy pre-transplant such as solid tumors. HLA mismatch as well as TNC dose and GVHD prophylaxis were also important risk factors for graft failure in the present study.Table 1Multivariate analysis of risk factors for graft failure in reduced intensity conditioning allo-HSCT.CharacteristicsNRR95% CIP-valueNo of patients357Recipient sexFemale1531Male2043.271.35-7.93<0.01DiseaseAcute leukemiaa661CML276.810.70-66.310.10CLL225.380.55-52.630.15Lymphoma361.540.10-24.830.76MDS324.260.38-47.190.24MPD187.400.67-82.360.10Multiple myeloma2300-82.361Aplastic anemia382.540.25-26.210.43Non-malignant disorders348.010.96-66.800.05Solid tumors6110.951.34-89.170.03HLA matchHLA-identical sibling1561Unrelated donor 6/6454.941.84-13.24<0.01Unrelated donor 8/81232.160.90-5.180.09Other matched300-13.241Other mismatched303.301.18-9.240.02Total nucleated cell dose (x108/kg)0-58615-10920.540.24-1.220.1410-14870.370.15-0.940.04>14870.240.08-0.750.01GVHD profylaxisCSA+MTX2401CSA+Pred142.160.63-7.400.22CSA+MMF403.611.38-9.44<0.01Fk 506 +Rapamune451.320.43-4.080.63Other176.242.27-17.16<0.01aAML (n=60) and ALL (n=6). Disclosures: No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for MDS Patients More Than 70 Years of Age: a Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party (CMWP) of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4390-4390
Author(s):  
Silke Heidenreich ◽  
Dimitris Ziagkos ◽  
Anja van Biezen ◽  
Jürgen Finke ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Remission Status ◽  
Unrelated Donors ◽  
Karnofsky Index ◽  
Reduced Intensity

Abstract Introduction Myelodysplastic syndromes (MDS) are diagnosed at median age of 70 years. Allogeneic stem cell transplantation (HSCT) is the only curative treatment option, but with an increasing age, morbidity escalates. Treatment guidelines suggest HSCT for intermediate-II and high risk constellations up to the age of 65, and reduced intensity conditioning (RIC) regimens are commonly used up to 70 years of age. However, increasing life expectancy, availability of RIC regimens and good Karnofsky performance status (KPS) of MDS patients more than 70 years of age, has led to an increased use of HSCT. We performed a retrospective analysis to investigate results after HSCT for those patients and influence of KPS on outcome. Patients and methods We analyzed data of 345 patients in the EMBT database older than 70 years with MDS/sAML. The disease status at transplantation was available in 233 patients and most of the them were in more advanced stage of the disease: RA/RARS,RCMD (n=25) , RAEB (n=68) and RAEB-T/secondary acute leukemia (sAL, n=140). Donor were: related (n=88) and unrelated (n=257). Cytogenetic data were available only in 73 patients and classified as good (58), intermediate (6), poor (5) and very poor (4). Median follow up was 29.7 months. Median age at transplantation was 72 years (70-79 years) with 249 male and 96 female patients. KPS was defined in 300 cases, being 90-100% in 61% and 80% or less in 39%. Stem cell source was peripheral blood (94%) or bone marrow (6%). The intensity of the conditioning regimen was mainly reduced intensity (78%) rather than myeloablative (22%). Negative or positive CMV sero-status of the patient were seen in 35% and 65%, respectively. Results The number of HSCT for MDS patients of 70 years or more has increased over time. While 2000-2004 only 19 patients received transplantation, the following 3-year periods included 28 (2005-2007), 97 (2008-2010) and 200 (2011-2013) patients, respectively. The estimated 3-year OS was 33% (27-39%). A significant better 3 year OS in the univariate analysis was seen for Karnofsky (90-100%) vs 80% or less (41 vs 23%, p=0.008) and for CMV negative sero-status (46% vs 27%, p> <0.001) while disease status, remission status, intensity of the conditioning regimen, and donor source did not influence OS significantly. The cumulative incidence of relapse at 3 years was 40% (95% CI: 32-48) and significantly lower with unrelated than related donors (24% vs 43%, p =0.004). There was only a trend for a lower incidence of relapse after myeloablative conditioning in comparison to RIC (22% vs 31%, p=0.09), while remission status, T-cell depletion or disease stage did not influence the risk of relapse. The cumulative incidence of non-relapse mortality at 1 year was 36% (95% CI: 30-42) and significantly influenced by CMV sero-negativity of the recipient (22% vs 38%, p=0.02) and by Karnofsky index 90-100% (29% vs 34% and at 2 years: 32% vs 46%, p=0.01). A trend for lower NRM was seen for related donors (24% vs 35%, p=0.07) and after reduced intensity conditioning (29% vs 41%, p=0.09). No impact on NRM was seen for disease and remission status. In a multivariate analysis (MVA) significant factor for improved OS was Karnofsky index of 90-100% (HR 0.65: 95% CI: 0.48-0.88, p=0.001) and for worse survival CMV sero-positivity (HR 1.61; 95% CI: 1.15-2.21, p<0.001). For relapse the only significant factor was the use of unrelated donors (HR 0.50; 95% CI: 0.32-0.80, p=0.004). Significant factors for NRM in the MVA were Karnofsky index 90-100% (HR 0.63; 95% CI: 0.42-0.96, p=0.03), CMV sero-positivity of the recipient (HR 1.76; 95% CI: 1.12-2.76, p=0.001) and unrelated donors (HR 1.67; 95% CI: 0.16-2.76, p=0.04). Conclusion HSCT from related or unrelated donor after myeloablative or dose reduced intensity conditioning for advanced MDS patients 70-years and more is a curative treatment option with a 3-year OS of 33%. Good performance, determined by KPS, and sero-negativity for CMV in the patient increase the 3 year estimated overall survival to 41 and 46%, respectively. Disclosures Platzbecker: Boehringer: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tischer:Sanofi-Aventis: Other: advisory board. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. de Witte:Novartis: Research Funding.

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