Chronic Graft-Versus-Host Disease: Lessons From a Randomized Trial on GvHD Prophylaxis with or without Anti-T-Cell Globulin ATG-Fresenius (ATG-F) In Allogeneic Hematopoietic Cell Transplantation (HSCT) From Matched Unrelated Donors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 212-212
Author(s):  
Gérard Socié ◽  
Claudia Schmoor ◽  
Wolfgang Andreas Bethge ◽  
Hellmut Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Chronic Gvhd ◽  
Late Complication ◽  
Group Versus ◽  
Control Group ◽  
Term Survival ◽  
Gvhd Prophylaxis

Abstract Abstract 212 Background: Chronic GvHD (cGvHD) is the leading late complication after allogeneic HSCT. Most previous randomized studies in GvHD prophylaxis failed to demonstrate reduced incidence and severity of cGvHD, and shorter time to discontinuation of immunosuppressive therapy (IST). Aims: We previously reported that addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control group) significantly reduced severe acute and chronic GvHD (Finke et al., Lancet Oncology, 2009). Here we present final data and unpublished results on cGvHD with extended follow-up [median of 3 (25%-quartile 2.5, 75%-quartile 3.9) years] on 201 patients with median age of 40 (range 18–60) years, transplanted between 2003 and 2007, with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94). Results: With extended follow-up the cumulative incidence (CI) of extensive cGvHD after three years was 12.2% in the ATG-F group versus 45.0% in the control group (p<0.0001) (Figure1) [CI of limited + extensive was 30.0% and 60.0% in the ATG-F versus control, respectively, p<0.0001]. CIs were reduced in all main cGvHD target organs: skin [3-year CI, 5.6% to 27.0%; (hazard ratio (HR) =0.18, p=0.0006)], eyes [3-year CI, 2.2% to 20.7%; HR =0.10, p=0.0025)], mouth [3-year CI, 4.4% to 18.8%; HR =0.24, p=0.013)], lung [3-year CI, 3.3% to 16.3%; HR =0.17 p=0.006)], and liver [3-year CI, 16.7% to 33.8%; HR =0.43, p=0.009]. Chronic GvHD decreased relapse rate resulting in HR of 0.49 (p=0.037), 3-year CI of relapse was 32.6% in the ATG-F and 28.2% in the control group (HR=1.21, p=0.47). Extensive cGvHD increased non-relapse mortality (NRM) rate resulting in a HR of 2.1 (p=0.075), 3-year CI of NRM was 19.4% in the ATG-F and 33.5% in the control group (HR=0.68, p=0.47). The 3-year CI of late bacterial infection (post Day+100) was 26.3% and 39.9% in the ATG-F versus control, respectively (HR=0.65, p=0.12). Cox regression analyses on risk factors for developing extensive cGvHD adjusted for treatment arm and acute GvHD (time dependent) found two factors associated with increased extensive cGvHD risk: donor age more than 40 years (HR= 2.02, p=0.025) and disease type [HRs=3.90, 1.56 and 2.62 for patients with MDS, ALL and CML/OMF as compared to AML, respectively; p=0.04]. Overall survival after three years was 55.2% in the ATG-F and 43.3% in the control group (HR=0.84, p=0.39). The HR for receiving IST was 0.58, p<0.00001, and the HR for stopping IST was 1.37, p=0.006 (ATG-F versus control, respectively). At 3 years, the probability of being alive without IST was 46.9% and 18.1% and that of being alive with IST was 8.4% and 26.1 % in the ATG-F versus control, respectively. Conclusion: The addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis significantly reduces the incidence and severity of cGvHD, and the risk of receiving IST without increasing relapse rate. Although the 3-year CI of NRM (19.4% in the ATG-F and 33.5% in the control group, p=0.18) are still non-significantly different, these data demonstrate that ATG-F prophylaxis decreases cGvHD morbidity and may thus provide a long-term survival advantage. Disclosures: Bethge: Fresenius Biothech GmbH: Lecture remuneration. Finke:Fresenius Biothech GmbH: Research Funding.

A Randomized Prospective Multicenter Phase III Trial Comparing Standard GvHD Prophylaxis with Cyclosporine and Methotrexate with Additional Pretransplant ATG Fresenius (ATG-F) in Allogeneic Stem Cell Transplantation from Matched Unrelated Donors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 57-57 ◽  
Author(s):  
Jürgen Finke ◽  
Wolfgang Andreas Bethge ◽  
Claudia Schmoor ◽  
Hellmut Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Group Versus ◽  
Phase Iii ◽  
Control Group ◽  
Phase Iii Trial ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Treatment Comparisons ◽  
Grade Iii

Abstract Graft versus host disease is a major cause of morbidity and mortality after allogeneic stem cell transplantation from unrelated donors. Strategies using intensified GvHD prophylaxis including T cell depletion did not result in better outcome due to increased risks of infection and relapse. The use of ATG in the conditioning regimen for in vivo-Tcell depletion for GVHD prophylaxis has been reported by several groups but not been tested in a large prospective randomized trial. Here we report on results from the first large prospective, randomized, multicenter, open-label, phase III trial comparing standard GvHD prophylaxis with cyclosporine A (CyA) and short course methotrexate (Mtx) days +1, +3, +6, +11 (15/10/10/10 mg/m2) with or without 3×20mg/kg ATG-Fresenius (ATG-F) after a median follow-up time of two years. Between 2003 and 2007, 201 patients, median age 40 (range 18–60) years with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94), were transplanted from HLA-A and -B (2 digit), DRB1, DQB1 (4 digit) identical unrelated donors after highdose myeloablative conditioning with marrow (n=37) or PBSC (n=164) grafts. Median follow up time was 732.5 (25%-quartile 604, 75%-quartile 1097) days. For treatment comparisons with regard to the occurrence of aGvHD grade III-IV or death within 100 days post Tx, logistic regression adjusted for status of disease, source of stem cells, and center was used. For treatment comparisons with regard to time-to-event variables, cumulative incidence rates considering relapse and death as competing events were estimated, and Cox regression modelling the event-specific hazard rates and adjusting for status of disease and source of stem cells was used. Engraftment with WBC &gt; 1000/μl was achieved in 97% in the ATG-F group after median 26 days, and in 95% in the control group after median 19 days (p&lt;0.0001). At day +100, the rate of patients experiencing the primary efficacy endpoint-severe aGvHD (grade III–IV) or death - was 21.4% in the CyA/Mtx/ATG-F arm versus 33.7% in the CyA/Mtx only arm (p=0.1286). Incidence of grade III–IV acute GvHD was 11.7% in the ATG-F arm and 24.5% in the control group (p=0.054), grade II–IV aGvHD was 33.0% vs. 51.0% (p=0.0108), and grade I–IV aGvHD was 56.3% vs. 74.5% (p=0.0073). Incidence of chronic GvHD (limited and extensive) after two years was 30.8% in the ATG-F group versus 58.8% in the control group (p&lt;0.0001). Incidence of extensive chronic GvHD after two years was 12.2% in the ATG-F group versus 42.6% in the control group (p&lt;0.0001). Disease-free survival (DFS) after two years was 51.6% in the ATG-F and 47.5% in the control group (p=0.65). Incidence of relapse/progression after two years was 28.9% in the ATG-F and 23.6% in the control group (p=0.55). Incidence of death without former relapse/progression (TRM) after two years was 19.6% in the ATG-F and 28.9% in the control group (p=0.198). Overall survival (OS) after two years was 59.2% in the ATG-F and 51.9% in the control group (p=0.47). Number of infections per follow up year was 4.54 in the ATG-F and 4.76 and in the control group. The addition of ATG-F to standard CyA/Mtx prophylaxis results in decreased incidence of acute and chronic GvHD without increase of relapse or TRM rates. This is the first randomized trial answering the long-standing question regarding the beneficial effect of additional ATG-F to a standard GvHD prophylaxis. A reduction of GvHD without compromising survival could be demonstrated.

Randomized Trial on GvHD Prophylaxis with or without Anti-T-Cell Globulin ATG-Fresenius (ATG-F) In Allogeneic Hematopoietic Cell Transplantation From Matched Unrelated Donors: Final Results and Analysis of Prognostic Factors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1249-1249 ◽  
Author(s):  
Jurgen Finke ◽  
Claudia Schmoor ◽  
Wolfgang Andreas Bethge ◽  
Hellmut Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Advanced Disease ◽  
Chronic Gvhd ◽  
Group Versus ◽  
Control Group ◽  
Donor Age ◽  
Patient Age ◽  
Gvhd Prophylaxis ◽  
Grade Iii

Abstract Abstract 1249 Previously, we could demonstrate that addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control group) significantly reduces severe acute and chronic GvHD, without negatively affecting non-relapse mortality (NRM), relapse rate (RR), disease-free survival (DFS) or overall survival (OS) (Finke et al., Lancet Oncol, 2009). Here we present final data of extended follow-up with a median of 3 (25%-quartile 2.5, 75%-quartile 3.9) years on 201 patients with median age of 40 (range 18–60) years, transplanted between 2003 and 2007, with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94). At Day +100, the primary efficacy endpoint - severe acute GvHD (aGvHD grade III-IV) or death was reached in 21.4% of patients in the ATG-F group versus 34.7% in the control group (p=0.098). Incidence of grade III-IV aGvHD was 11.7% in the ATG-F group and 25.5% in the control group (p=0.039). With extended follow-up the incidence of extensive chronic GvHD (cGvHD) after three years was 12.2% in the ATG-F group versus 45.0% in the control group (p<0.0001). DFS after three years was 48.0% in the ATG-F and 38.4% in the control group (p=0.71). Incidence of relapse after three years was 32.6% in the ATG-F and 28.2% in the control group (p=0.47). Incidence of NRM after three years was 19.4% in the ATG-F and 33.5% in the control group (p=0.18). OS after three years was 55.2% in the ATG-F and 43.3% in the control group (p=0.39). The effects of the prognostic factors patient age, donor age, patient/donor sex mismatch, patient/donor CMV status, HLA-C difference, type and status of disease, conditioning regimen, source of stem cells, cyclosporine trough levels during the first 30 days, on occurrence of aGvHD III-IV, extensive cGvHD, DFS, relapse, NRM, and OS were analyzed. Factors showing an effect with p<0.05 in univariate analyses were analyzed in multivariate analyses (both adjusted for treatment). Donor age above 40 years negatively affected the risk for aGvHD III-IV (hazard ratio (HR)=2.6, p=0.009), extensive cGvHD (HR=2.1, p=0.021) and OS (HR=1.7, p=0.016); patient age above 40 years negatively influenced NRM (HR=1.8. p=0.041), whereas advanced disease was a risk factor for aGvHD III-IV (HR=2.1, p=0.018), DFS (HR 1.7, p=0.004), relapse (HR=1.7, p=0.038), and OS (HR=1.9, p=0.002). Conclusion: ATG-F significantly reduces severe acute and chronic GvHD. Younger donors are to be preferred in unrelated donor transplantation. Older and advanced disease patients need special precautions to improve outcome. Disclosures: Finke: Fresenius Biothech GmbH: Research Funding. Bethge:Fresenius Biothech GmbH: Lecture remuneration.

Randomized Trial on GvHD Prophylaxis with or without Anti-Human T-Lymphocyte Immunoglobulin ATG-Fresenius (ATG-F) in Allogeneic Hematopoietic Cell Transplantation from Matched Unrelated Donors: Final Long-Term Results after 8.6 Years Median Follow-up

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 853-853
Author(s):  
Jürgen Finke ◽  
Claudia Schmoor ◽  
Wolfgang A Bethge ◽  
Hellmut Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Immunosuppressive Therapy ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Control Group ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Long Term Follow Up

Abstract Background: Previously, in 201 adult patients with allogeneic hematopoietic cell transplantation from matched unrelated donors, we demonstrated that the addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control) significantly reduces acute and chronic GvHD without negatively affecting relapse and survival [1,2,3]. Methods: Now, we present final results after an extended follow-up (median 8.6, Q1 8.0, Q3 9.3 years) with regard to chronic GvHD, non-relapse mortality (NRM), relapse, relapse mortality, disease-free survival (DFS) and overall survival (OS). Additionally, we analyse the effect of ATG-F vs control on the composite endpoint severe GvHD (acute GvHD III-IV, extensive chronic GvHD) and relapse-free survival, and on time under immunosuppressive therapy. Since mortality within the first year after transplantation is usually high, we also analyse conditional survival, i.e. the OS probability after having survived 1 and 2 years after transplantation. Results: The incidence of extensive chronic GvHD after 8 years was 13.5% in the ATG-F group vs 51.8% in the control group (p<0.0001). The 8-year rates with respect to outcome were: NRM 20.5% vs 34.0% (p=0.15), relapse 35.2% vs 29.9% (p=0.54), relapse mortality 30.8% vs 28.8% (p=0.90), DFS 44.3% vs 36.1% (p=0.60), and OS 48.7% vs 36.8% (p=0.31), ATG-F vs control, respectively. ATG-F substantially increased the combined severe GvHD/relapse-free survival rate. The rates were 48.5% vs 20.4% after 1 year and 33.6% vs 13.0% after 8 years (p=0.0003), ATG-F vs control, respectively (see figure). The probability of being alive and free of immunosuppressive therapy was 46.8% in the ATG-F group and 11.2% in the control group at 8 years (p=0.0002). The survival probabilities increased when patients had survived the first year. The conditional 8 years-survival probability increased in the ATG-F group from 48.7% (unconditional) to 70.6% and 80.9% (conditional on having survived 1 and 2 years after transplantation), and in the control group from 36.8% (unconditional) to 58.5% and 71.7% (conditional on having survived 1 and 2 years after transplantation). Conclusion: The long-term follow-up of 8.6 years shows that ATG-F GvHD prophylaxis provides a sustained protective effect without increasing relapse and compromising survival. ATG-F in addition to standard cyclosporine, methotrexate as GvHD prophylaxis results in significantly improved severe GvHD/relapse-free survival. Furthermore, the stable results from our prospective trial after an extended long-term follow-up demonstrate that the choice to use ATG-F in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression. References: [1] Finke et al. Lancet Oncol 2009;10:855 [2] Socie et al. Blood 2011;117:6375 [3] Finke et al. Biol Blood Marrow Transplant 2012;18:1716 Disclosures Bertz: GILEAD Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti–T-cell globulin ATG-Fresenius

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6375-6382 ◽  
Author(s):  
Gérard Socié ◽  
Claudia Schmoor ◽  
Wolfgang A. Bethge ◽  
Hellmut D. Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Group Versus ◽  
Long Term Results ◽  
Control Group ◽  
Host Disease ◽  
Graft Versus Host ◽  
Probability Of Survival ◽  
Gvhd Prophylaxis

Abstract Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

Immunotransplantation for multiple myeloma using allogeneic peripheral blood stem cell transplantation

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17516-17516
Author(s):  
E. S. Santos ◽  
S. Shah ◽  
J. Rink ◽  
R. S. Weiner ◽  
A. M. Miller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Post Transplantation ◽  
Gvhd Prophylaxis ◽  
Methylprednisolone Treatment

17516 Background: Despite the improvement seen in patients with multiple myeloma (MM) treated with autologous hematopoietic cell transplantation (auto-HCT), most of the patients relapse or die of their disease. The objective of the study was to decrease toxicity of allogeneic HCT for MM patients while allowing the benefit of graft-versus-myeloma effect by using a non-myeloablative HCT (NM- HCT) approach. Methods: Newly diagnosed or previously treated myeloma patients of any stage were enrolled. All patients but one received VAD regimen prior to conditioning regimen which consisted of Fludarabine at 30 mg/m2/day on days -5, -4, -3 and Melphalan at 80 mg/m2 x 2 on days -2 and -1. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine 3 mg/kg intravenously on day -2 and methotrexate at 10 mg/m2 intravenously on days 3, 6, and 11. Results: A total of 8 MM patients (4 IgG, 1 IgA, 1 light chain restriction, 2 non-secretory MM) with a median age of 46 years old (range, 35 to 57 years) have been enrolled. Only one patient received 3 regimens prior to NM-HCT. The initial responses to therapy prior to NM-HCT were: 2 CR, 1 nCR, and 5 PR. All patients received identical 6/6 HLA sibling donor stem cells. All patients but one attained CR (88%) after NM-HCT. The median time for ANC engraftment (≥ 500/mm3) was 12.5 days (range, 10–22 days). Four patients developed acute GVHD grade I-II (3 skin, 1 gastrointestinal); all of them responded well to methylprednisolone treatment. Four patients developed chronic GVHD (grade I-II). The 100-day mortality rate was 12% (1 patient died at day + 96 without evidence of MM). Post-transplant, all patients have reported a Karnofsky’s scale performance status between 80%-100%. Two patients relapsed after 31 months post-transplantation. After a median follow-up of 46 months, median survival has not been reached. Only 1 patient who relapsed has received treatment including auto-HCT. Conclusions: NM-HCT is a feasible treatment option in MM patients with a manageable toxicity profile and acceptable treatment-related mortality. Longer follow-up is needed to evaluate for graft-vs- myeloma effect using this approach. No significant financial relationships to disclose.

T-Cell Depletion in Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia: A Retrospective EBMT Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2307-2307
Author(s):  
Johannes Schetelig ◽  
Donald Milligan ◽  
Dietger Niederwieser ◽  
Liisa Volin ◽  
J. Maertens ◽  
...  
Keyword(s):  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Adjusted Hazard Ratio ◽  
Gvhd Prophylaxis ◽  
Matched Sibling

Abstract Abstract 2307 Poster Board II-284 Objectives: T-cell depletion (TCD) is controversial in patients with chronic lymphocytic leukemia (CLL). While TCD is a powerful tool to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) concern is raised about an increased incidence of relapse. The aim of this retrospective analysis was to study the impact of in vivo TCD in patients with CLL registered with the EBMT database. Patients and Methods: Patients with CLL who received allogeneic HCT from a matched sibling (SIB) or unrelated donor (UD) and cyclosporine-based GVHD prophylaxis between 2001 and 2008 were eligible. Patients who received ex vivo T-cell depleted grafts were excluded. The outcome of three major groups of patients was compared: Patients who were transplanted without TCD, those who received anti-thymocyte globulin (ATG) and patients who received alemtuzumab (CAM). Baseline and follow-up data were downloaded from the EBMT database. Results: 413 patients were eligible. 73% of patients had SIB donors and 27% matched UD. Reduced intensity conditioning regimens were applied for the majority of patients (82%). No TCD was used in 234 patients, while 100 patients received CAM and 79 patients ATG. The median follow-up after HCT was 22 months (1 to 92 months). Univariate comparisons of GVHD and the rates of DLI are reported for patients with matched sibling donors only. After SIB-HCT the cumulative incidence of acute GVHD II-IV was 7% with CAM, 22% with ATG and 34% without TCD (gray test, p=0.0001). Subsequently, 28% of patients with CAM received prophylactic donor lymphocyte infusions (DLI) compared to 5% of patients with ATG and 9% without TCD (p=0.03). DLI for any reason was given to 45% of patients with CAM, 24% with ATG and 15% without TCD (p=0.009). As a result of late-onset GVHD the incidence of chronic GVHD after TCD with CAM increased from 20% at 1 year to 60% at 4 years after SIB-HCT. At 4 years after HCT comparable cumulative incidences of chronic GVHD were observed (70% without TCD, 59% after ATG and 60% after CAM; p=0.1). For the whole cohort of patients 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% CI, 50% to 64%) and 44% (95% CI, 37% to 51%). At 4 years the cumulative incidence of relapse was 28% (95% CI, 17% to 39%) and the incidence of non-relapse mortality was 28% (95% CI 18% to 38%). In multivariate Cox regression analysis of PFS when GVHD prophylaxis without TCD was used as reference category the adjusted hazard ratio for TCD with CAM was 1.4 (95% CI, 0.9 to 2.2, p=0.2) and for TCD with ATG 1.4 (95% CI, 0.9 to 2.3, p=0.1). For relapse incidence the adjusted hazard ratio for TCD with CAM was 1.4 (95% CI, 0.7 to 2.6, p=0.3) and for TCD with ATG 1.0 (95% CI, 0.5 to 2.1, p=0.9) and for non-relapse mortality the adjusted hazard ratio for TCD with CAM was 1.4 (95% CI, 0.8 to 2.8, p=0.3) and for TCD with ATG 1.9 (95% CI, 1.0 to 3.5, p=0.06). Conclusion: In patients with CLL the combination of in vivo TCD and DLI appears to result in comparable rates of chronic GVHD and PFS compared to T-cell replete HCT. Disclosures: Schetelig: Bayer Schering: Research Funding.

Fludarabine-Based HLA-Identical Sibling HSCT for Patients with Severe Aplastic Anemia (SAA) Older Than 30 Years: A Study from the French (SFGM-TC) and Italian (GITMO) Registries.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2028-2028
Author(s):  
S. Maury ◽  
B. Bruno ◽  
Z. Chir ◽  
F. Garban ◽  
D. Blaise ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Prospective Trial ◽  
Conditioning Regimen ◽  
Term Survival ◽  
Blood And Marrow Transplantation ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Related Mortality

Abstract Survival after HSCT from HLA-identical siblings is inferior in SAA patients 30 years or older as compared with younger patients, with long-term overall survival of 58% and 80%, respectively (Bacigalupo et al, Semin in Hematol 2000). In order to improve survival in patients >30 years, the use of a less toxic regimen including low dose cyclophosphamide (<200 mg/kg) in combination with ATG, while adding fludarabine, might be an option to explore with the aim to reduce transplant-related mortality (Marsh et al, Br J Haematol, 2003). In order to evaluate the toxicity profile, engraftment potential, and efficacy of HLA-identical HSCT using such fludarabine-based conditioning regimen, we conducted this study from the SFGM-TC and GITMO databases, focussing on patients older than 30 years or those younger than 30 years but with co-morbidities at HSCT. From December 1998 to June 2004, 15 HSCT were performed in 14 patients (median age 39 years, range 16–60 years), for idiopathic SAA (n=13), or paroxysmal nocturnal hemoglobinuria (PNH) (n=1). HSCT was performed either as first-line treatment (n=8), or after failure of immune suppression with ATG/ciclosporine (CsA) (n=4), or failure of a first allogeneic HSCT (n=3). In addition to fludarabine (120 mg/m2) and ATG (3.75 mg/kg x 2 to 4 days), the patients received two different reduced doses of cyclophosphamide of 120 mg/kg (n=4) or 20 mg/kg (n=9). Two patients received only ATG and fludarabine (175 mg/m2) without cyclophosphamide. Marrow (n=12, median dose of nucleated cells 5.108/kg, range 2–15.108/kg) or PBSC (n=3) grafts were unmanipulated. GVHD prophylaxis consisted of CsA/methotrexate (n=11), CsA alone (n=1), methotrexate alone (n=1), or nothing (n=2 second grafts). Graft rejection occurred in one patient, who received a second graft from the same donor with the same conditioning regimen (fluda/ATG/cyclophosphamide 20 mg/kg) successfully. All other patients engrafted with a neutrophil (ANC >500 cells/μL) and platelet (PLT >50 000/μL) recovery occurring at a median of 18 days (range 12–28 days), and 26 days (range 11–272 days) after transplant, respectively. Acute GVHD occurred in 3 patients with a maximum grade II in 2 patients and grade III in one. Among 11 evaluable patients, six developed chronic GVHD (limited in 3 cases). Four patients died of infection (n=3) or multi-organ failure (n=1), within the 3 months post-HSCT for 3 of them. With a median follow-up of 28 months (range 11–48 months), 10/14 patients survived with long-term engraftment and full (n=8) or mixed (n=2) donor chimerism (KM probability of long-term survival 71%-see figure). In conclusion, reduced intensity fludarabine-based conditioning regimen is feasible in SAA patients over the age of 30 and produces encouraging survival: a prospective trial is being conducted within the European Group for Blood and Marrow Transplantation (EBMT). Figure Figure

HLA-Identical Sibling-Matched, CD34+ Selected, T Cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning for First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 655-655 ◽  
Author(s):  
Steven M. Devine ◽  
Robert J Soiffer ◽  
Marcelo C. Pasquini ◽  
Shelly Carter ◽  
Parameswaran N Hari ◽  
...  
Keyword(s):  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Abstract 655 Allogeneic hematopoietic cell transplantation (HCT) is the most effective means to prevent relapse in patients (pts) with AML in complete remission (CR). However, quality of life and overall survival (OS) are often affected by both acute and chronic graft versus host disease (GVHD). GVHD is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but has been limited in its use by logistical difficulties, lack of an FDA-approved method, and concerns regarding potential risk of graft rejection, post transplant infections, and leukemic relapse. Most reported TCD studies represent single centers, multiple disease types and processing methods with varying degrees of TCD, all of which affect outcome. Therefore we designed a trial using a single processing method providing extensive TCD that did not require post transplant GVHD prophylaxis involving adult pts with AML in first or second CR. We hypothesized that the undesired side effects of TCD HCT would be reduced if combined with a conditioning regimen that was highly immunosuppressive and anti-leukemic. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months (mos) post transplant that exceeded 75%. Secondary objectives included assessments of engraftment, transplant related mortality (TRM), GVHD, relapse, and performance of a single TCD method (CD34+ cell selection using the Miltenyi CliniMACS device) at participating centers. From 10/2005 to 12/2008, 47 pts were enrolled and 44 transplanted at 8 different centers. Median age was 48.5 years (range 21-59) with 28 female and 16 male pts. Of 37 AML CR1 pts, 49% had an unfavorable cytogenetic or molecular risk profile. The conditioning regimen consisted of hyperfractionated total body irradiation (1375cGy in 11 fractions) with partial lung shielding, thiotepa (10mg/kg), cyclophosphamide (120mg/kg), and rabbit antithymocyte globulin (2.5mg/kg). The donors, all HLA-identical siblings, were given G-CSF for mobilization and scheduled to undergo at least 2 leukapheresis procedures to ensure a graft with a high CD34+ cell content. All allografts were CD34-enriched and were targeted to contain ≥ 5×10e6 CD34+ cells/kg and < 1.0×10e5 CD3+ cells/kg. The median CD34+ and CD3+ doses achieved were 8.1 × 10e6/kg (range 2.4-46.2) and 0.07 × 10e5/kg (range 0.01-0.85), respectively. The majority (81%) of pts received the targeted CD34+ cell dose and no pt received > 1.0×10e5 CD3+ cells/kg. No pharmacological GVHD prophylaxis was given post transplant. There were no significant toxicities related to infusion of the CD34 enriched allografts. The most common grade 3-5 regimen-related toxicities included grades 3 or 4 mucositis (39%) and grades 3-5 pulmonary abnormalities (11%). Only 1 pt experienced hepatic veno-occlusive disease. All pts engrafted rapidly with a median time to neutrophil recovery (ANC > 500/ul) of 11 days (range 9-19). There was 1 secondary graft failure. The assessed outcomes are shown below.Estimate (95% Confidence Interval)Outcome100 Days6 Months12 MonthsAcute GVHD II-IV20.5% (8.7 – 23.3%)Acute GVHD III-IV4.5% (0 – 10.6%)Chronic GVHD17.7% (5.8-29.6%)Extensive Chronic GVHD7.6% (0-15.7%)TRM17.8% (5.8-29.8%)Overall Relapse18.2% (5.9-30.5%)Relapse 1st CR9.6% (0- 19.8%%)Relapse 2nd CR64.3% (27.5-100%)DFS81.3% (66.1-90.2%)64.0% (46.5-77.1%)DFS 1st CR89.2% (73.7-95.8%)72.1% (53.0-84.6%)OS74.3% (57.3-85.4%) The absolute peripheral CD4+ cell count remained on average below 200/ul until day +365. Donor cell chimerism increased in the CD3+ cell compartment through day +365. There were 14 deaths. The most common causes of death were relapse (N=5) and pulmonary toxicity (N=4). The median follow-up of survivors is 489 days (range 96-776). There was no difference in OS or DFS for pts above or below the median age of 48.5 years. We conclude that TCD HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a single TCD method without additional post transplant prophylaxis with excellent DFS and OS, consistent engraftment, low TRM, and low incidence of relapse even in pts with unfavorable risk AML in CR1. The low incidences of acute and chronic GVHD in the absence of post transplant prophylaxis were particularly encouraging. A follow-up study of TCD HCT in AML recipients of unrelated donor allografts is being planned by the BMT CTN Disclosures: No relevant conflicts of interest to declare.

RELATED FACTORS TO RELAPSE IN DEPRESSED PATIENTS AFTER COGNITIVE BEHAVIOURAL THERAPY DURING ONE YEAR PROSPECTIVE FOLLOW-UP

2011 ◽  
pp. 13-19
Author(s):  
Nhu Minh Hang Tran ◽  
Huu Cat Nguyen ◽  
Dang Doanh Nguyen ◽  
Van Luong Ngo ◽  
Vu Hoang Nguyen ◽  
...  
Keyword(s):  
Cognitive Behavioral Therapy ◽  
Relapse Rate ◽  
Behavioral Therapy ◽  
Cognitive Behavioral ◽  
Control Group ◽  
Controlled Clinical Trial ◽  
Related Factors ◽  
Depressed Patients ◽  
One Year

Objectives: To determine factors impact on the relapse in depressed patients treated with Cognitive Behavioral Therapy (CBT) during one year follow-up. Materials and Methods: 80 depressed patients divided into two groups, group 1: included 40 patients treated with CBT; group 2: 40 patients on amitriptyline. Non-randomized controlled clinical trial, opened, longiditual and prospective research. Results and Conclusions: relapse rate after CBT during 1 year follow-up is 10% (compared to 25% in control group), related factors to relapse rate in depression after CBT are age and education. Shared predictors between 2 groups are severity and recurrence of depression. Key words: Depression, relapse, Cognitive Behavioral Therapy (CBT)

Regression of cardiac amyloid deposits with novel therapeutics: reaching new frontiers in cardiac ATTR amyloidosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Chacko ◽  
A Martinez-Naharro ◽  
T Kotecha ◽  
R Martone ◽  
D Hutt ◽  
...  
Keyword(s):  
Treatment Group ◽  
Cardiac Amyloidosis ◽  
T1 Mapping ◽  
Group Versus ◽  
Control Group ◽  
Cardiac Amyloid ◽  
Attr Amyloidosis ◽  
Amyloid Load ◽  
The Impact

Abstract Background Cardiac involvement is the main driver of outcome in ATTR amyloidosis. Advances in therapeutics hold potential in transforming the course of the disease but the impact on cardiac amyloid load is unknown. The aim of this study was to evaluate the impact of patisiran, a new double stranded RNA based gene silencing therapy and a stabilizer, diflunisal, on cardiac amyloid load as measured by CMR and T1 mapping, in patients with ATTR amyloidosis. Methods and results Thirty-two patients with hereditary cardiac amyloidosis were studied. Sixteen patients received treatment with patisiran, and sixteen control subjects did not receive any disease modifying treatment. Patients were assessed with echocardiogram, CMR, NT-proBNP and six-minute walk time measurements at baseline and at 1 year (Mean interval 11.45±3.08 months in treatment group, mean interval 12.82±5.06 months in the control group). CMR analysis comprised LV volumes, T1 mapping to measure the extracellular volume (ECV) occupied by amyloid, T2 mapping and late gadolinium enhancement imaging. At 1-year follow-up, there was a substantial reduction in cardiac amyloid burden, in keeping with cardiac amyloid regression in 45% of patients on treatment. Overall the treatment group showed a reduction in ECV at 1 year follow up compared to an increase in ECV at 1 year in the control group (−1.37%, 95% CI: −3.43 to 0.68% versus 5.02%, 95% CI: 2.86% to 7.18% respectively, p&lt;0.001). The treatment group also showed an improvement in change in 6MWT at 1 year follow up compared to 6MWT at 1 year in the control group (−8.12 meters, 95% CI: −50.8 to 34.6 meters in the treatment group versus −132.27 meters, 95% CI: −216 to −48.6 meters in the control group, p=0.002). The treatment group showed a reduction in BNP at 1 year follow up compared to an increase in the control group (−567.87, 95% CI: −1288.90 to 153.15 in the treatment group versus 2004, 95% CI: 12.82 to 3995.45 in the control group, p&lt;0.001). There was no significant difference from baseline and 1-year data between the control and treatment groups for the difference in echocardiographic parameters, native T1, T2. There was a significant reduction in the percentage of injected dose by 99Tc-DPD scintigraphy in treated patients at 1 year compared to baseline. Conclusions These findings provide the first compelling evidence of substantial cardiac amyloid regression in ATTR amyloidosis, as well as the potential for CMR to be used to track response in treated patients with ATTR cardiac amyloidosis. Combination therapy with transthyretin knock down and stabilizing agents may well be synergistic given enhanced stoichiometry of stabilizers in the face of much reduced plasma transthyretin concentration. Funding Acknowledgement Type of funding source: None

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