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 > 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<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<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<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.

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.

Consolidation with Alemtuzumab in First Remission Induces Pronounced MRD Reduction and Clinical Remissions - Update on a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2506-2506 ◽  
Author(s):  
Matthias Ritgen ◽  
C. Schweighofer ◽  
Günther Fingerle-Rowson ◽  
Barbara Eichhorst ◽  
Raimunde Busch ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Late Stage ◽  
Clinical Remission ◽  
Lymphocytic Leukaemia ◽  
Phase Iii ◽  
Remission Induction ◽  
Control Group ◽  
Consolidation Therapy ◽  
Phase Iii Trial

Abstract The monoclonal antibody alemtuzumab is known to be effective in combination or alone in patients with late stage chronic lymphocytic leukaemia. Flow cytometric studies on minimal residual disease (MRD) showed the high potency beyond clinical response criteria even in late stage chronic lymphocytic leukaemia (CLL). The aim of the phase III trial of the GCLLSG was to investigate the role of alemtuzumab as consolidation therapy in CLL patients in first clinical remission after fludarabin (F) or F plus cyclophosphamide (FC). Patients in partial or complete clinical remission were randomized to either arm A (alemtuzumab 3 x 30 mg i.v. for up to 12 wks) or no further treatment (arm B). From 21 eligible patients 11 (1CR, 1 nPR, 9PR) were randomized to arm A. All patients received standard infection prophylaxis with famciclovir and trimethoprim/sulfamethoxazole. Before, at 6 and 12 weeks after start of consolidation therapy and regulary during follow up blood and bone marrow samples were send for molecular MRD assessment by allele specific real time PCR. The PCR allowed MRD assessment with a sensitivity of at least 10E-4 in 11 eligible cases. Results: MRD analysis showed clear reduction of CLL content by first line treatment to a median MRD level of 2.2E-3. Short after alemtuzumab treatment all treated patients showed pronounced MRD reduction to a median MRD level of 5.0E-5. During molecular follow-up median MRD level remained below 1E-4 for one year with a tendency to increase afterwards. After a median follow-up of 31.3 months from start of initial treatment occurred one relapse in the treatment arm compared to 7 of 10 in arm B. The median progression free survival (PFS) calculated from start of consolidation therapy was significantly shorter in the control group versus the treatment group (pfs 25.2; p= 0.04). Nevertheless due to severe acute infections (CTC III and IV) this study had to be stopped prematurely. Conlusion: The addition of alemtuzumab as a consolidation regimen after remission induction by F or FC is highly effective and leads to sustained MRD reduction below 10E-4. This translates into significant improved clinical outcome even in this small patient cohort compared to the control group. Encouraged by the molecular responses the GCLLSG initiated a new phase I/II trial as a dose finding study in CLL patients after F based induction of clinical remission.

Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2570-2570
Author(s):  
Federica Giannotti ◽  
Annalisa Ruggeri ◽  
Gerard Michel ◽  
Jean-Hugues Dalle ◽  
Tracey O'Brien ◽  
...  
Keyword(s):  
Single Unit ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Median Number ◽  
Cell Dose ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

Post-Transplant Cyclophosphamide and Bortezomib Combination for Prevention of GvHD after Allogeneic Blood and Marrow Transplantation Is Feasible and Produces Favorable Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3920-3920
Author(s):  
A. Samer Al-Homsi ◽  
Tara S Roy ◽  
Kelli Cole ◽  
Marlee Bogema ◽  
Stephanie F Williams ◽  
...  
Keyword(s):  
T Cells ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Post Transplant ◽  
Blood And Marrow Transplantation ◽  
Gvhd Prophylaxis ◽  
Cmv Reactivation ◽  
Grade Iii

Abstract Graft versus host disease (GvHD) remains a major barrier to the progress of blood and marrow transplantation and limits its wide applicability. Standard prophylactic regimens essentially targeting T lymphocytes are partially effective and burdensome. Cyclophosphamide (Cy) administered post-transplant selectively deletes alloreactive proliferating T cells, promotes expansion of regulatory T cells, and induces long-lasting depletion of intrathymic host-reactive T cells. It is an attractive option for prevention of GvHD and has already been used alone in matched related and unrelated donor transplants. However, despite a low incidence of chronic GvHD, acute GvHD still occurs in 50% of cases and is grade III-IV in 15% of cases. Dendritic cells (DCs) play a pivotal role in the early phase of GvHD. Proteasome inhibitors such as bortezomib (Bor) have a number of immunomodulatory effects including inhibition of DCs maturation and function. We therefore initiated a phase I feasibility study combining post-transplant Cy & Bor. Twelve patients with hematological malignancies undergoing peripheral blood allogeneic transplantation from matched related (n=6) or unrelated (n=6) donors have so far been enrolled. Disease risk index (DRI) was low in 4, intermediate in 3 and high or very high in 5. The conditioning regimen combined fludarabine and busulfan (total 6.4 mg/kg). Patients receiving graft from unrelated donors also received rabbit anti-thymocyte globulin at 5-8 mg/kg. The dose of Bor was escalated in standard fashion. Three patients in each of cohorts 1 and 2 received 0.7 and 1 mg/m2 respectively. The subsequent 6 patients received 1.3 mg/m2. All patients received 2 IV doses, 6 hours after graft infusion and 72 hours thereafter. Cy was given at 50 mg/kg IV on days +3 and +4. Steroids were not allowed after day 0. Engraftment was prompt in all patients. Median time to neutrophil engraftment was 15.5 days (range 14-25). One patient failed to meet criteria for platelet engraftment. The patient had acyclovir-resistant herpes genitalis and CMV reactivation requiring protracted therapy with foscarnet. The remaining patients had a median time to platelet recovery of 28 days (range 15-109). All patients achieved full chimerism by day 20 except one who had residual CLL and did not reach full chimerism until day +119. No patient developed secondary graft failure. Two treatment-related deaths occurred on day +150 due to RSV pneumonitis and on day +200 due to acute sepsis. One patient with recurrent multiple myeloma after autologous transplantation died due to progressive disease. No other Common Toxicity Criteria grade 3 or 4 occurred in any patient. With a median follow-up of 21 months (range 1-27), the overall 2-year predicted disease free survival and overall survival were both 60%. Incidence of acute GvHD in 11 patients with follow-up > 100 days, was 64%: grade I 55%, grade II 9%, and grade III-IV 0%. GI and liver acute GvHD were not encountered. Only 4 patients received systemic steroids for acute GvHD; only one required > 20 mg/day of prednisone. One patient developed chronic GvHD of the liver (biopsy-proven). Another patient developed poor appetite and weight loss on day +138. Endoscopy showed gastric ulceration. No biopsy was obtained. Neither calcineurin nor m-TOR inhibitors were ever used. Two patients developed extensive HSV-genito-rectal ulcers; one had prior history of recurrent flares. When institutional guidelines were changed to start acyclovir at the beginning of conditioning as opposed to day +5, no other cases was noted. Seven patients developed CMV reactivation and required preemptive therapy only. One patient developed BK virus-induced hematuria and 1 patient developed CNS toxoplasmosis. In summary, the calcineurin and m-TOR inhibitor-free post-transplant Cy & Bor combination for GvHD prophylaxis is feasible and safe. Although the small number of patients prevents any definite conclusion, the absence of incidence of grade III-IV acute GvHD and the sparing of the GI tract and liver are promising. Furthermore, the completion of GvHD prophylaxis by day +4 without the need for close renal and drug level monitoring are both practical and appealing. Updated results with longer follow-up will be reported at the meeting. A confirmatory phase II study is underway. Disclosures Al-Homsi: Millennium Pharmaceuticals: Research Funding. Off Label Use: Bortezomib use for aGvHD prevention.

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.

Low Rates of Toxicity, GVHD, and Relapse Using Sirolimus (SRL)-Based GVHD Prophylaxis in Pediatric Related and Unrelated Transplant Recipients with High-Risk ALL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2876-2876
Author(s):  
Michael Pulsipher ◽  
Donna Wall ◽  
Stephan Grupp ◽  
Rakesh Goyal ◽  
Nancy Bunin
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
Phase Iii ◽  
Significant Activity ◽  
Target Level ◽  
Gvhd Prophylaxis ◽  
Cell Sources ◽  
Grade Iii

Relapse after allogeneic SCT remains a significant risk for children with ALL. In-Vitro and NOD-SCID xenogeneic models have shown significant activity of sirolimus (SRL) against human ALL blasts, resulting in apoptosis and cell death at serum levels commonly used for immune suppression. We hypothesized that SRL would decrease relapse after allogeneic transplantation for ALL, as well as contribute to prevention of GVHD. We conducted a pilot trial at four pediatric centers designed to assess the feasibility and toxicity of SRL-based GVHD prophylaxis using multiple stem cell sources. After a preparative regimen of TBI (1200cGy in 6 fractions over 3d), Thiotepa (5mg/kg/d x 2), and cyclophosphamide (60mg/kg/d x 2), recipients received continuous infusion tacrolimus starting on day -2 (target level 5–10ng/mL), PO sirolimus starting on day 0 (2.5mg/m2, max 4mg daily, target level 3–12ng/mL), and IV methotrexate (5mg/m2, d+1, +3, and +6 for all recipients, d+11 for recipients of UD BM/PBSC). Tacrolimus was given orally when tolerated, and tapered between d+42–96 for MSD and d+100–180 for mismatched related, UD or UCB. Sirolimus was tapered at 6 months after transplant over 1 month. Thirty patients were enrolled, with median age of 9 yrs (1–18). Immunophenotypes included pre-B 23, T-cell 6, and MLL 1. Five patients were in CR1 (Ph+ 2, failed remission 2, 2° ALL 1), 16 were in CR2 (9 CR1 <18 months), and 8 were in CR3. Stem cell sources included: UCB 15, MSD-BM 13, 5/6 mismatched RD-BM 1, 9/10 mismatched UD-PBSC 1. SRL was successfully administered to all pts and therapeutic drug levels achieved. PK studies were obtained and are being analyzed. Three patients had SRL held briefly for high levels or toxicity and three patients stopped the medication due to toxicity (VOD/TAM). Engraftment occurred in 28 pts at median of 20d (13–62); one CB recipient engrafted successfully after a second infusion and a second patient relapsed prior to engraftment. Overall grade II–III aGVHD occurred in 11/30 pts (37%) including 3/14 MRD (21%) and 8/16 CB/UD (50%, 38% grade III). No grade IV aGVHD occurred and the grade III aGVHD (all diarrhea) was rapidly controlled with prednisilone in all patients. 3/18 (17%) of evaluable patients developed chronic GVHD. Relapses occurred in 5 pts at a median of 94 days (34–362); 3 were T cell, 1 was CR3. TRM occurred in 3 patients (10%: MSOF/sepsis/VOD in 2 pts d+34 and d+39, cGVHD/infection in 1pt d+789). Other significant toxicities included one case of IPS with engraftment requiring intubation (resolved), 1 case of nonfatal VOD, and two cases of reversible TAM. With a median f/u of 7m (1–36m) the 1 year EFS and OS are 68.5% (SE 11.5) and 77.1% (SE 8.6), respectively. In this very high risk cohort of children with ALL, we have demonstrated that GVHD prophylaxis with SRL, tacrolimus, and methotrexate is feasible using multiple stem cell sources, resulting in low rates of TRM, acute and chronic GVHD, and relapse. A randomized phase III trial comparing this approach to tacrolimus/methotrexate in children with CR2 ALL is currently being planned through the Children’s Oncology Group.

HLA-DP Mismatches Increase the Risk of Acute GVHD after Unrelated Donor Hematopoietic Transplantation (UDT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3125-3125 ◽  
Author(s):  
Marcos de Lima ◽  
Simrit Parmar ◽  
Ping Liu ◽  
Poliana A. Patah ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract The HLA class II DP locus encode for both subunits of DPB1 heterodimers, which have low levels of expression on the cell surface of antigen presenting cells. We hypothesized that donor-recipient HLA-DP mismatch would lead to an increased incidence of acute (a) graft-versus-host disease (GVHD), and that 2 mismatches would likely be even more significant. Methods: We studied 84 consecutive patients (pts) with myeloid leukemias in complete remission (CR) transplanted from 01/02 to 02/06. Preparative regimens were ablative IV Busulfan-based (n=58) or Cy/TBI (n=2), and reduced intensity (Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=8), and Flu/Melphalan 140 mg/m2 (n=16). Stem cell (SC) source was bone marrow (n=70) or peripheral blood (n=14). ATG was given in 78 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 31 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, and SBT/SSOP for HLA-C. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free (RFS) survival. Variables with a p-value <0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. AGVHD-free survival was calculated from transplant date to date of development of grade II–IV GVHD or completion of 100 days of follow-up. Results: Median age was 48 yrs (range, 14–72). Diagnoses were MDS (n=5), AML (n=58), and CML (n=21). 54 pts (64%) were beyond 1st CR; all CML pts were in >1st chronic phase (CP). Sixty-one pts were 10/10 HLA match (A, B, C, DRB1, DQB1), and 23 had one or more mismatches. All but one pt engrafted neutrophils at a median of 13 days. 33 pts (39%) and 13 pts (15%) developed grade II–IV and III–IV aGVHD, respectively. Chronic GVHD incidence was 51%. With a median follow-up of 18 mo. (range,1.3–52) 60 pts are alive; 40 pts have relapsed or died. Median survival has not been reached. Number of DP mismatches and incidence of aGVHD is shown in the table. The following covariates influenced aGVHD-free survival by MV analysis: Flu-based regimen (P=0.005; HR 0.25 (95%CI 0.1–0.66), reduced intensity regimens (p=0.02; HR 0.35 (95%CI 0.15–0.83) and presence of 2 DPB1 mismatches (p=0.02; HR 3.07 (95%CI 1.19–7.95). Presence of 1 DPB1 mismatch was not significantly associated with aGVHD. There was no statistically significant correlation between presence of 2 DP mismatches and RFS (P=0.17;HR 0.3 (95%CI 0.06–1.65);HR 0.75 for 1 mismatch) or with cGVHD. Actuarial 2-yr survival for 10/10 matched pts without DP mismatches (12/12) versus those with DP mismatches is 82% versus 71%(P=0.6). In the 10/10 matched group, GVHD was the cause of death only among recipients of 2 DP mismatches transplants (n=4). Conclusion: Mismatching at HLA-DPB1 may increase the risk of aGVHD following UDT. The role of DP in the development of GVHD and GVL effects merits future study. Incidence of acute GVHD 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 8% 0% 1 23% 8% 2 45% 18% < 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 45% 15% 1 82% 36% 2 80% 40%

A Matched Controlled Analysis of Post-Transplant Cyclophosphamide (CY) Versus Tacrolimus and Mini-Dose Methotrexate in Matched Sibling and Unrelated Donor Transplant Recipients Receiving Reduced-Intensity Conditioning: Post-Transplant CY Is Associated with Higher Rates of Acute Gvhd

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4200-4200 ◽  
Author(s):  
Amin M. Alousi ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Borje S Andersson ◽  
Issa Khouri ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Control Group ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Matched Sibling ◽  
And Control

Abstract Abstract 4200 Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period. Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results: The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, >CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion: Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

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.

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