GM-CSF Secreting Leukemia Cell Vaccinations after Allogeneic Reduced-Intensity Peripheral Blood Stem Cell Transplantation (SCT) for Advanced Myelodysplastic Syndrome (MDS) or Refractory Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3680-3680 ◽  
Author(s):  
Vincent Ho ◽  
Glenn Dranoff ◽  
Haesook Kim ◽  
Mildred Pasek ◽  
Corey Cutler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Anticancer Activity ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Leukemia Cell ◽  
Neutrophil Recovery ◽  
Gm Csf ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Disease relapse is a frequent cause of treatment failure in patients undergoing reduced intensity allogeneic stem cell transplantation for advanced MDS and AML. Prior studies with GVAX, a cancer vaccine composed of irradiated autologous myeloblasts modified to secrete GM-CSF, suggested anticancer activity in MDS and AML after autologous SCT or in primary therapy. We investigated the feasibility and safety of administering GVAX after allogeneic SCT. Patients with MDS-RAEB or AML with >5% marrow blasts and with a donor matched at HLA-A,B, DRB1 were eligible. Prior to transplant, autologous myeloblasts were collected from the marrow or blood and transfected with an adenovirus vector bearing the GM-CSF gene to generate the GVAX vaccine. Patients were conditioned with fludarabine 30mg/m2/d IV days -6 to -3, and busulfan 0.8mg/kg IV q12H days -6 to -3 prior to allogeneic PBSC infusion. GVHD prophylaxis included tacrolimus and mini-methotrexate. GM-CSF (Leukine) 250 mg/m2 SC QD was administered from day +1 until neutrophil engraftment. GVAX was administered SC/ID weekly for the first three doses, then q2 weeks for the last three doses starting between day +30 to +45 if there was neutrophil recovery and no grade II-IV acute GVHD. Taper of tacrolimus began after vaccine completion. Eighteen patients (10 URD, 8 MRD) have been transplanted to date: 12 AML, 4 MDS/RAEB, 2 CML myeloid blast crisis. Median age was 63 (range, 41–71 years). Median marrow blast content at transplant was 31% (range, 6–91%). GVAX was successfully generated for all 18 patients. Median vaccine cell dose was 1.0 × 107 cells (range, 0.1–1.0 ×107), and median 24-hour GM-CSF secretion by the vaccine was 8.2 ng/ml/106 cells (range 0.4 – 195). Seven patients did not initiate vaccination due to: inadequate neutrophil recovery/leukemia progression (4); acute GVHD (2); sepsis/death (1). Two patients were recently transplanted and have not reached day 30 to start vaccination. Among 9 patients who received GVAX, vaccination was well tolerated. Mild injection site reaction with induration, erythema, or pruritus was the only common side effect. After vaccination, 1 patient developed grade II skin acute GVHD and 3 had cGVHD that resolved with steroids. Donor chimerism was not adversely affected by vaccination. Six of 9 patients who started GVAX are alive at a median follow up of 7.5 months post transplant (range 1–16 mos). These include 4 patients in complete remission (3 AML, 1 MDS-RAEB) between 5 and 16 months after transplant, and 2 patients with minimal persistent AML early after SCT. Four of 5 patients who completed 6 vaccines remain progression free. Histologic examination of vaccination and leukemia cell DTH sites revealed significant infiltration with inflammatory cells and eosinophils. These preliminary results suggest GVAX vaccination is safe and may have anticancer activity in patients with MDS/AML after reduced intensity allogeneic SCT.

Impact of HLA Allele Mismatch on the Outcome of Patients with Reduced-Intensity Allogeneic Haematopoietic Stem Cell Transplantation from Unrelated Donors: Analysis of 103 Patients of the French Registry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3149-3149 ◽  
Author(s):  
Andrea Toma ◽  
Marie-Lorraine Balere-Appert ◽  
Zina Chir ◽  
Jean-Michel Boiron ◽  
Pierre Bordigoni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donors ◽  
Grade Ii ◽  
The Impact ◽  
Hla Mismatches ◽  
Reduced Intensity

Abstract Reduced-intensity conditioning regimens (RIC) had become a classical strategy of allogeneic hematopoietic stem cell transplantation (HSCT) and many patients are now transplanted with unrelated donor. The aim of this restrospective study was to evaluate the impact of HLA mismatches between donor (D) and recipient (R) at the allelic level on survival after RIC. We analyzed 103 patients registered in France from Jan 1999 to Dec 2003 with a median age of 46 years (18–67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. Anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The main source of stem cells was PBSC (n=65). Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The results showed that 96% of patients engrafted. Acute GVHD grade II to IV and grade III/IV occurred in 46% and 19% of patients, respectively. The risk of developing cGvHD was 45% at 2 years. Overall survival (OS) was 42% at five years. Among the 47 patients alive, the median disease free survival (DFS) was 28 months. Among non-HLA parameters studied, the only factor associated with a good OS was the diagnosis of lymphoid disease (HD or NHL or CLL) (p=0.003). Recipient age <46y was only associated with less acute GvHD grade II to IV (p=0.008). Among HLA mismatches, we found that HLA-A and/or -B allelic mismatches had a negative impact on OS (p=0.006), DFS (p=0.006), acute GvHD grade II to IV (p=0.05). On the other hand, HLA-C or -DQB1 mismatches did not impact on OS, DFS, acute or chronic GvHD. We could not analyze DRB1 mismatch since there was only 2 patients reported. In conclusion, HSCT following RIC, with match or mismatch unrelated donors, is a feasible approach with best results observed for patients with lymphoid malignancies (NHL, CLL or HD). Among allelic HLA mismatches, HLA-A and/or -B seemed to be deleterious as compared to HLA-C or DQB1. These results help to identify most suitable donors and patients who are likely to benefit from RIC with unrelated donors when there is not a fully HLA match donor available.

Improved Immune Reconstitution Following Pre-Emptive CD8-Depleted Donor Lymphocyte Infusions (DLIs) after Haploidentical Stem Cell Transplantation (SCT) Using a Reduced-Intensity Conditioning (RIC) Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2908-2908
Author(s):  
Paolo Corradini ◽  
Anna Raganato ◽  
Matteo Carrabba ◽  
Lorenza Gandola ◽  
Claudia Lombardo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Total Dose ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Immune Recovery ◽  
Grade Ii ◽  
The Impact

Abstract Allogeneic stem cell transplantation (SCT) from an haploidentical family donor has been reported as a viable option in acute leukemias when matched donors are unavailable. However, the extensive T-cell depletion (TCD), required to prevent graft-versus-host disease (GVHD), is associated to delayed immune recovery and high transplant-related mortality. In an ongoing phase I–II trial for patients (pts) with advanced hematological malignancies, we combined a RIC regimen, including thiotepa (10 mg/kg), fludarabine (120 mg/ms), cyclophosphamide (60 mg/kg) and TBI (2 Gy), with pre-emptive administration of CD8-depleted DLIs (starting from 1x104 up to 1x105 cells/kg). Ex-vivo and in-vivo TCD were carried out by CD34+ cell selection using the CliniMACS device and alemtuzumab (30 mg day −2), respectively. The aim of the study was to investigate in a dose finding study the safety and the impact on immune-reconstitution of CD8-depleted DLIs. Six-teen pts with hematological malignancies (n=14 NHL/HD, n=1 ALL, n=1 AML) were included, median age was 35 years (range, 15–65), 10 (63%) were chemorefractory, and 68% and 75% had failed a previous auto or at least 3 CT lines, respectively. Pts received a median of 10.6 x106/Kg CD34+ and 1x104/kg CD3+. All pts engrafted with full donor chimerism from day +30. At a median follow-up of 9 months, 12 pts were alive and 4 died (n=1 infection, n=3 disease). The estimated OS at 2 years was 58%; 7 of 16 (44%) relapsed at median time of 100 days after SCT. CD8-depletion of 14 donor lymphocyte aphereses was performed with a new depletion protocol (Clinimacs CD8-Microbeads) that reduces the content of CD8+ cells by at least 3 logs. The median CD3+, CD4+, CD56+/CD3+, CD20+ cell recovery were 62% (range, 35–91%), 88% (63–128%), 51% (8–78%), 76% (33–128%), respectively. Before DLIs, only 1 of 16 pts (6%) developed de novo acute GVHD (grade II). A total of 22 CD8-depleted DLIs were administered to 9 of 16 pts without any engraftment problem. The first cohort of pts (n=5) received a total dose of 3–6x104/kg CD8depleted DLIs starting at day +45 divided in 3 monthly infusions: none of them developed aGVHD. Given no toxicity, we escalated doses and the second cohort (n=4) received a total dose of 10–25x104/kg CD8-depleted DLIs divided in 3 monthly infusions: 3 pts had acute GVHD (grade II). Overall, the incidence of acute GVHD was higher (75% vs 0%, P&lt;0.04) in pts receving larger numbers of donor cells. Interestingly, the median values of CD4+/ul and CD8+/ul were 98 (range, 8–612) and 150 (range, 15–988) at 4 months; 247 (range, 55–333) and 235 (range, 3–1000) at 5 months after SCT. The median value of CD19+/ul cells were 134 (range, 0–292) and 160 (range, 0–256) at 4 and 5 months, respectively. NK cells remained between the value of 394/ul and 569/ul in the first 6 months after SCT. Our results suggest that: (1) haploidentical SCT with RIC regimen is feasible with a high rate of engraftment and a low acute GVHD incidence; (2) pre-emptive CD8-depleted DLIs are feasible without GVHD until the total dose of 6 x104/kg; 3) higher doses can induce acute GVHD, but no grade III–IV was observed; 4) despite the limited number of pts, we observed a faster immune recovery and a relatively low mortality rate for infections.

Comparison between Anti-Thymocyte Globulin and Alemtuzumab and the Possible Impact of KIR-Ligand Mismatch in Melphalan/Fludarabine Dose-Reduced Conditioning Followed by HLA-Matched and Mismatched Unrelated Stem Cell Transplantation in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 980-980
Author(s):  
Nicolaus Kroeger ◽  
Brownen Shaw ◽  
Simona Iacobelli ◽  
Tatjana Zabelina ◽  
Karl Peggs ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Statistical Significance ◽  
High Dose ◽  
Grade Ii

Abstract We compared anti-thymocyte globulin (ATG-Fresenius median dose 60 mg/kg: n= 48) with alemtuzumab (Campath-1H 100mg: n=25) in 73 patients with multiple myeloma, who underwent dose-reduced conditioning with melphalan and fludarabine, followed by allogeneic stem cell transplantation from matched (n=63) or mismatched (n=10) unrelated donors. Patients of the ATG group had higher age (median 50 vs 47 years, p=0.05), more prior high-dose chemotherapies (p<0.001), while in the Campath group more bone marrow as stem cell source was used (p<0.001). No primary graft failure occurred in both groups. Patients receiving alemtuzumab had a significant faster engraftment of leukocyte (p=0.03) and of platelets (p=0.02) and a lower incidence of acute GvHD grade II-IV (24 vs 47%, p=0.05). However, after treatment with donor lymphocyte infusion due to persistent disease or mixed hematopoietic chimerism the difference of acute GvHD grade II-IV between alemtuzumab and ATG treated patients did not reach statistical significance (32 vs 47%, p=0.2). No difference in incidence of chronic GvHD was observed (25 vs 33%, p=0.6) More CMV seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs 47%, p=0.001). The cumulative incidence of treatment related mortality at 2 years for ATG and Campath was 29.3% (CI=17–50%) vs 28.5% (CI=15–54%), p=0.7. No significant difference could be observed in the estimated 2 years OS and PFS between ATG and Campath: 53% (CI:38–75) vs 45% (CI:28–73) and 29% (CI:16–54) and 36% (CI: 20–62), respectively. For PFS, in a multivariate analysis relapse to prior high-dose chemotherapy was the strongest negative factor: HR 2.9, p= 0.001. Including only those patients who did not experienced any relapse at time of allogeneic stem cell transplantation the Campath-group had a 2.5 fold higher risk of progression in comparison to the ATG group, but without reaching statistical significance (HR: 2.5, p=0.15). Ten out of 73 patients had KIR-ligand mismatch in GvH direction. While in patients without KIR-ligand mismatch the cumulative incidence of relapse at two years was 50%, none of the KIR-ligand mismatched patients relapsed so far (p=0.02). The immunosuppressive effect from Campath is stronger than ATG resulting in less acute GvHD, but requires more DLI procedures to control diseases and resulted in a trend to a lower PFS in chemosensitive patients. This preliminary data further implicated a major role of KIR-ligand mismatch transplantation in multiple myeloma

GM-CSF Secreting Leukemia Cell Vaccination after Allogeneic Reduced Intensity Hematopoietic Stem Cell Transplantation for Advanced Myeloid Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 825-825 ◽  
Author(s):  
Vincent Ho ◽  
Glenn Dranoff ◽  
Haesook Kim ◽  
Matthew Vanneman ◽  
Mildred Pasek ◽  
...  
Keyword(s):  
Immune Suppression ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Leukemia Cell ◽  
Sustained Remission ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Studies have shown that leukemia specific donor immune responses can be elicited by cancer vaccination after allogeneic SCT. Given the likelihood of disease progression in patients with active leukemia at the time of transplant, potential anti-tumor vaccines must be administered early post-transplant if they are to exert a meaningful effect. Early vaccination after SCT could capitalize upon the rapid homeostatic lymphoid expansion associated with post conditioning lymphopenia. However, there is concern about the efficacy of vaccinations early after allogeneic transplant when patients remain on immune suppression to prevent GVHD. GVAX, a cancer vaccine composed of leukemia cells genetically modified to secrete GM-CSF, has demonstrated activity in MDS and AML. We completed a trial investigating the feasibility and safety of administering GVAX early after allogeneic HLA matched reduced intensity conditioning (RIC) SCT for patients with MDS-RAEB or active AML. Prior to SCT, autologous myeloblasts were harvested and transfected with an adenovirus vector bearing the GM-CSF gene to generate the GVAX vaccine. Conditioning consisted of fludarabine 30mg/m2/d IV × 4, and busulfan 0.8mg/kg IV q12H × 8 doses prior to allogeneic PBSC infusion. GVHD prophylaxis included tacrolimus and mini-methotrexate. Vaccination started between day +30 to +45 post SCT if there was adequate count recovery and no grade II–IV acute GVHD. GVAX was administered SC/ID weekly × 3 doses, then q2 wks × 3 doses. Taper of tacrolimus began after vaccine completion (» d+120). Twenty four patients (13 URD, 11 MRD) were transplanted: 16 AML, 6 MDS/RAEB, 2 CML myeloid blast crisis. Median age was 62 (range, 41–71 years). Median marrow blast content at transplant was 22% (range, 6–91%). GVAX was successfully generated for all patients. Of the 24 patients transplanted, 9 could not start vaccine due to rapid leukemia progression (4); acute GVHD requiring systemic steroids (3); sepsis (1) and IPS (1); Among the 15 patients who started vaccination per protocol, 10 completed all 6 vaccines. Mild injection site reaction with induration, erythema, and pruritus was the only common side effect. After vaccination, 3/15 patients developed grade II acute GVHD and 7/15 had cGVHD. Relapse free (RFS) and overall survival (OS) at 2 years for patients who started GVAX were 46% and 56%, respectively. This is superior to the 2-yr DFS and OS of 12% and 16% (p=0.02), respectively, in a matched cohort of 34 patients with the same disease receiving RIC SCT during the same time period. Among the patients who completed all 6 vaccines, 9/10 remain in complete remission (6 AML, 3 MDS-RAEB) with median follow-up of 22.5 months post SCT (range, 7–38 mos). Three patients with disease relapse/progression early post SCT entered CR after vaccination and taper of tacrolimus. Pathologic examination of vaccination and leukemia cell DTH sites revealed significant infiltration with inflammatory cells and eosinophils in all patients who responded. Concordant with prior studies showing that anti-cancer activity after GM-CSF secreting tumor cell vaccines is associated with NKG2D-target-cell interactions mediated by NK and NK-T cells, our immunologic studies revealed progressively decreasing levels of soluble NKG2D ligands in patients with sustained remission after GVAX. Our results demonstrate that GVAX vaccination early after RIC SCT elicits important biologic activity despite administration during full immune suppression with tacrolimus. Given that all of the patients had active disease at transplant and received a reduced intensity conditioning regimen, we would have expected few to enter complete and sustained remission. Our encouraging results suggest GVAX vaccination is safe and may have anticancer activity in patients with MDS/AML after allogeneic SCT.

Risk Factors for Predicting CMV Infection in Allogeneic-PBSCT Setting: MNC Dose, Campath Use, and Acute GVHD Grade ≥II.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5298-5298
Author(s):  
Byung Min Ahn ◽  
Joon Ho Moon ◽  
Yoon Young Cho ◽  
Yee Soo Chae ◽  
Jong Gwang Kim ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Cmv Infection ◽  
Allogeneic Pbsct ◽  
Grade Ii ◽  
Conditioning Therapy

Abstract Risk factors for predicting CMV infection in allogeneic-PBSCT setting: MNC dose, Campath use, and acute GVHD grade ≥II Background: CMV infection remains an important complication of allogeneic stem cell transplantation (SCT). Campath-1H (anti-CD52) antibodies have been widely used in vivo for T-cell depletion following conventional and reduced intensity conditioning regimens and associated with a significant reduction in GVHD but at the cost of impaired immune reconstitution. We studied the risk factors, for the development of CMV infection after allogeneic SCT, including the use of Campath-1H. Methods: From Sep. 1998 to May 2006, 122 patients who received allogeneic peripheral blood stem cell transplantation were enrolled. CMV infection was routinely sought by at least weekly screening for CMV related matrix protein pp65 antigenemia after engraftment (WBC>1,500/uL) was achieved. CMV antigenemia was treated with ganciclovir 5mg/kg twice daily i.v. as preemptive therapy for at least 10 days. Results: The overall incidence of CMV infection was 56/122 (45.9%) cases with a median onset of 44 days post transplants. Risk factors for CMV infection in the multivariate analysis were acute graft-versus-host disease (GVHD) grade II-IV (p=0.015), use of Campath-1H in conditioning therapy (p=0.012), and mononuclear cell (MNC) doses in the transplants (p=0.010). Among conditioning therapies, the use of Campath-1H was associated with increased incidence of CMV infection (75.0%) compared with conventional conditioning therapy (40.9%)(p<0.01) and relatively early occurrence of CMV infection, median 22 days post transplant (p=0.016). Conclusion:The incidence of CMV infection was strongly associated with acute GVHD, MNC doses, and especially Campath-1H use in an allogeneic PBSCT setting. Multivariate Analysis for the Incidence of CMV infection RR 95% CI P-value Conditioning: use of Campath-1H 5.112 1.429–18.285 0.012 Acute GVHD, grade II-IV 2.696 1.209–6.010 0.015 Stem cell dose: MNC(×10^8/kg) 1.149 1.034–1.276 0.010 Stem cell dose: MNC ≥10 vs. MNC<10 2.613 1.165–5.859 0.020

Unmanipulated HLA-Haploidentical (2-3 antigen-mismatched) Stem Cell Transplantation Using Myeloablative or Reduced-Intensity Preconditioning Regimen,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4117-4117 ◽  
Author(s):  
Katsuji Kaida ◽  
Kazuhiro Ikegame ◽  
Satoshi Yoshihara ◽  
Kyoko Taniguchi ◽  
Shinichi Ishii ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Acute Gvhd ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Refractory Diseases ◽  
Reduced Intensity

Abstract Abstract 4117 Related haploidentical donors, as cord blood, can be alternative donor sources in stem cell transplantation (SCT). Severe GVHD, however, has interfered the progress of haploidentical SCT (haploSCT). To deal with this strong GVHD, T cell depletion has usually been used in US and European countries. In order to pursue the controllable GVL effect by T cells, we have performed unmanipulated haploSCT using myeloablative or reduced intensity preconditioning regimen accompanied with intensified GVHD prophylaxis, including steroids. In this meeting, we will summarize our experience of haploSCT for more than ten years. From August 1998 to September 2010, we have performed 351 cases of haploSCT (all cases were HLA 2–3 antigen mismatched in GVH direction). Patients' characteristics are sex: male 186, female 168, age: 16–65 years old (median 39), disease: AML/MDS 149, ALL 81, ML 67, others 54. Eighty-three percent of cases underwent SCT in non-complete remission (non-CR) status. Patients under 45 years old underwent myeloablative preconditioning regimen consisting of FLU/CA/CY/TBI 8Gy (haplo-full, n=100), and patients over 45 years old or with comorbidities or repetitive SCT (including second to fifth SCT) underwent reduced intensity preconditioning regimen consisting of FLU/(CA)/BU/ATG or FLU/(CA)/MEL/ATG (haplo-mini, n=251). High dose Ara-C (CA) was optional to reduce tumor burden. As ATG, ATG (Fresenius) 8mg/kg, or thymoglubulin (genzyme) 2–4mg/kg were integrated into conditioning treatments mainly for reduced-intensity transplantation. GVHD prophylaxis consisted of taclolimus (TAC), methylprednisolone (mPSL) 2mg/kg/day, short term MTX, and mycophenolate mofetil (MMF) 15mg/kg/day in haplo-full, and TAC, and mPSL 1mg/kg/day in haplo-mini, respectively. For elderly patients over 50 years old in haplo-mini, MMF was added. Hematopoietic engraftment in haploSCT was as rapid as that in HLA-identical SCT, except 10 cases of graft rejection. The median time to reach a neutrophil account of >0.5 × 109/l was 10 days for haplo-mini and 13 days for haplo-full. Platelet recovery was achieved in 66 % and 60% of patients undergoing haplo-mini and haplo-full, respectively. The median time to reach a nontransfused platelet count of 3 20 × 109/l was 22 days for haplo-mini and 33 days for haplo-full. Sixty percent of haplo-mini patients and 54 % of haplo-full patients did not develop acute GVHD. Acute GVHD (grade II-IV) was observed in 20% for haplo-mini and 36 % for haplo-full. Overall survival at five years was 30% for haplo-full and 40% for haplo-mini, respectively. If limited to CR cases, overall survival reached over 60% in haplo-mini. There is no difference in survival rate among patients' diseases. In multivariate analysis on survival using variables, including disease status before transplantation, haplo-full vs haplo-mini, mismatches in GVH direction, mismatches in HVG direction, patients' age, and the number of transplantation times, the disease status (CR) was found to be only a significantly favorable factor (P= 0.0026). Unmanipulated haploSCT is feasible and effective for refractory diseases. ATG dose used in haplo-mini is critical, and rather low compared with that of European cases reported so far. Although it should be too early to refer long term outcome, unmanipulated haploSCT could be considered as an option to control refractory diseases. Disclosures: No relevant conflicts of interest to declare.

CD8-Depleted Donor Lymphocyte Infusions Can Boost Immune Reconstitution after Haploidentical Stem Cell Transplantation Following Reduced-Intensity Conditioning Regimen.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3138-3138 ◽  
Author(s):  
Paolo Corradini ◽  
Anna Raganato ◽  
Cristiana Carniti ◽  
Matteo Carrabba ◽  
Farina Lucia ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Mean Value ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Abstract Haploidentical stem cell transplantation (SCT) can be used in relapsed haematological malignancies for patients lacking a matched sibling or unrelated donor. Major barriers of this strategy are the poor immune reconstitution and the high risk of relapse. Here, we report results of a phase I–II trial evaluating early add-backs of CD8-depleted donor lymphocytes (DLIs) (from 1x10^4 up to 1x10^5 cells/kg starting at day+45 up to day +105 at monthly intervals) after a reduced intensity conditioning (RIC) regimen [thiotepa (10 mg/kg), fludarabine (120 mg/sqm), cyclophosphamide (60 mg/kg) and TBI (2 Gy)]. Ex-vivo and in-vivo TCD were carried out by CD34+ cell selection using the CliniMACS device and alemtuzumab (15mg/m2, day-2), respectively. Twenty-one patients [n= 10 NHL (n=5 CLL, n=5 high-grade NHL), n=7 HL, n=1 MM, n=1 ALL, n=2 AML] were transplanted with advanced disease: 16 (76%) failed a previous autograft and 13 (62%) had refractory disease. A median of 10.4x10^6/Kg CD34+, 1x10^4/kg CD3+, 10x10^4/kg CD19+, 0.9 x10^4/kg NK+ were infused. All patients engrafted with full donor chimerism from day +90. At a median follow-up of 12 months (range, 4–41 months), 12 of 21 pts are alive (7 CR, 2 PR and 3 PD) and 9 died [n=3 infection with GVHD (+610, +187, +253), n=6 disease]. The estimated 2-year overall survival was 49%: pts transplanted in remission had better outcome (83% versus 31%, p=0.13). The estimated 2-year cumulative incidence of TRM and relapse were 27% and 58%, respectively. CMV reactivation and hospital readmissions for opportunistic infections occurred in 76% and 57% of patients, respectively. For CD8 depletion of donor leukaphereses, a new depletion protocol using clinical grade CD8 microbeads (Miltenyi) was applied. This procedure is efficient to reduce the content of CD8 T cells by 3 logs while the median cell recovery of CD3+, CD4+, CD56+/CD3+, CD 20+ was 60%, 86%, 54%, 72%, respectively. Before DLIs, only 2 of 21 patients (10%) developed acute GVHD (no grade III–IV). A total of 36 CD8-depleted DLIs were administered to 17 pts without any acute toxicity. Following DLIs, 6 pts (35%) developed acute GVHD (grade II) and 5 (30%) chronic GVHD (n=2 limited, n=3 extensive). Overall, the incidence of acute GVHD is higher (50% vs 22%, p=0.33) in pts receving larger numbers of donor cells (10–15x10^4/kg versus 3–5x10^4/kg CD8-depleted DLIs). The median values of CD4+/uL, CD8+/uL and NK+ were 100, 280 and 680 at 4 months and 220, 200, 500 at 6 months after SCT in patients receiving CD8-depleted DLIs. Measurable TREC/ucg DNA (mean value 316; mean value donors 3740) and polyclonal T cell repertoire, evaluated by spectratyping, were observed at 9 months in patients younger than 40 years and/or without GVHD. Our results suggest that: haploidentical SCT with RIC regimen provides high engraftment rate T-cell addback allows the achievement of more than 100/uL CD4+ at 4 months after SCT in the majority of patients Survival rate is promising in patients who had transplantation in remission suggesting that this strategy should be evaluated earlier in high risk haematological diseases.

Oligoclonal T Cells Associated with Gvhd Following Allogeneic Stem Cell Transplantation Conditioned with Thymoglobulin and Reduced Intensity Total Body Irradiation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4662-4662
Author(s):  
Masoud Manjili ◽  
Catherine H Roberts ◽  
Maciej Kmieciak ◽  
Madhu S Gowda ◽  
Andrea Ferreira-Gonzalez ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Count ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Recovery ◽  
Reduced Intensity

Abstract Abstract 4662 Patients undergoing unrelated donor stem cell transplantation following reduced intensity regimens are prone to acute graft vs host disease (GVHD). In vivo T cell depletion with rabbit anti-thymocyte globulin (r-ATG, Thymoglobulin, Genzyme inc. Cambridge MA) is consistently associated with reduced risk of acute GVHD however poor T cell reconstitution seen with current schedules results in a high incidence of opportunistic infections and relapse. We report data on immune reconstitution in patients participating in an ongoing clinical trial testing a novel conditioning regimen for allogeneic GCSF-mobilized blood stem cell transplantation. Patients were randomized to receive conditioning with either 7.5 or 5.1 mg/kg of r-ATG in divided doses between days -9 and -7, followed by 450 cGy total body irrradiation (TBI) in 3 fractions on day -1 and 0. GVHD prophylaxis was with tacrolimus (day -3 to 120) and mycophenolate mofetil (day 0-30). So far 10 heavily pre-treated (median number of prior therapies 4, prior autologous SCT n=5) patients have been transplanted; 6 from unrelated donors (1 bone marrow), 3 from matched related donors and 1 from an HLA-A mismatched sibling. Diagnosis includes MM (4), NHL (3), and CLL/PLL (3). Median patient age is 57 years. No patients have developed acute GVHD in the first 90 days. All patients achieved prompt engraftment of neutrophils and have demonstrated sustained complete myeloid donor chimerism (median <1% recipient DNA) at 3-6 months post transplant. NK cell recovery is prompt (mean±SD absolute CD56+ cell count 177±85/μL at day 30) and sustained (184±116 at day 90). T cell subset recovery is modest (absolute CD3+ cell count 861±934/μL at day 90) with predominantly cytotoxic T cells (CD3+/4+ cell count 143±116 and CD3+/8+ cell count 708±837). T cell chimerism at day 90 is mixed with either donor ('10% recipient DNA, n=5) or recipient dominance (>10% recipient DNA, n=3). Patients demonstrating dominant donor T cell chimerism at day 90 went on to develop either delayed onset acute GVHD (n=2/8 evaluable) or chronic GVHD (n=2/8) after withdrawal of immunosuppression. Patients demonstrating mixed T cell chimerism with recipient dominance did not develop chronic GVHD; one of these patients has relapsed, following an HLA-A mismatched SCT from his brother, and though he had predominantly recipient derived T cells, his granulocytes were completely donor derived indicating graft tolerance. T cell receptor beta locus was examined by RT-PCR for oligoclonality in all the donor-recipient pairs at baseline, day 90 and at onset of GVHD. Patients with GVHD demonstrated high level of expression of TCR V beta 23 and 24 (n=1/4), 11 (n= 1/4), 18 (n= 1/4), or 11 and 18 (n= 1/4) exclusively, in addition to TCR V beta 14, 16, 17, 22. The latter loci were also expressed in patients who had no GVHD with mixed T cell chimerism; this group of patients also expressed TCR V beta 4 (n=2/2), 13 and 19 (n=1/2) exclusively. All but one of the patients expressed the majority of TCR V beta loci at day 90 (with the exceptions noted above) indicating early polyclonal T cell recovery following transplantation. Asymptomatic CMV and EBV reactivation requiring therapy developed in one patient each. No patients have developed invasive fungal infections. In conclusion conditioning with Thymoglobulin and reduced intensity TBI results in stable myeloid engraftment in patients receiving unrelated and alternative donor transplants. In this small group of patients, GVHD appears to be associated with emergence of oligoclonal T cell populations which in the future may be selectively depleted ex vivo to allow engraftment without risk of chronic GVHD. Disclosures: McCarty: Celgene: Honoraria; Genzyme: Honoraria. Toor:Genzyme: Research Funding.

Donor Lymphocyte Infusions (DLI) After Peripheral Blood Stem Cell Transplantation. A Retrospective Analysis of 357 Patients by the Chronic Leukemias Working Party EBMT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3309-3309
Author(s):  
Grzegorz Wladyslaw Basak ◽  
Anja van Biezen ◽  
Ronald Brand ◽  
Christoph Schmid ◽  
Cesare Guglielmi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Molecular Cytogenetic ◽  
Stem Cell Source ◽  
Cell Source ◽  
Grade Ii

Abstract Abstract 3309 Poster Board III-197 Donor Lymphocyte Infusions (DLI) constitute a potent therapeutic option for treating relapse of chronic myelogenous leukemia (CML) after hematopoietic stem cell transplantation (SCT) inducing durable remissions in the majority of patients. A number of factors is known to influence the efficiency of DLI. A preliminary analysis of EBMT data had suggested that DLI efficiency might be inferior after peripheral blood stem cell transplantation (PBSCT) as compared to DLI following bone marrow transplantation (BMT) (Schmid et al. ASH, 2005). To control for a number of other factors that were not known at the time of the previous analysis, we repeated this analysis based on the results of 357 patients treated with DLI following PBSCT (N=108) and BMT (N=249). We limited the analysis to patients who relapsed after standard intensity conditioning SCT from HLA-identical family donors in first chronic phase of disease. The median age of patients was 39 years (range 18-60) with predominance of males (59%). 53% of patients with known data were CMV positive and in 44% of the patients there was a sex-mismatch with the stem cell donor. SCTs have been performed between 1994 and 2007 (median year: 1998) and the conditioning treatment included total body irradiation (TBI) in 68% and T cell depletion in 44% of patients. 92% of patients with known data achieved complete remission after SCT while grade II-IV acute GvHD occurred in 18% of patients and extensive chronic GvHD in 17% of patients. Median time to relapse was 17 months (range 0.6-129) and median time from SCT to first DLI infusion was 23 months (range 0.6-142). Looking at the patients with known data at the time of first DLI infusion, the relapse could be classified as molecular/cytogenetic in 63%, hematologic in 27% and transformed in 10% of patients. The median year of first DLI was 2000 ranging from 1995 to 2007. As the initial DLI infusion, 9% of patients received <1×10e6, 62% 1.1-10×10e6 and 29% received >10×10e6 CD3+ cells/kg. However, the comparative analysis of groups based on the stem cell source revealed that the group of patients transplanted with PBSCs included significantly more males (68 vs. 56%), were older (median age 42 vs. 39) and underwent more frequently T cell depletion at SCT (72 vs. 34%,). PBSCTs have been performed more recently (median year 1999 vs. 1997) and both duration of remission and time from SCT to first DLI were shorter after PBSCT (median duration: 12 vs. 21 months and 14 vs. 26 months respectively). The initial cell dose in patients from PBSCT arm was significantly lower than in BMT group (≤10×10e6 CD3+/kg in 89% vs. 65% of patients). Similarly to the previous study, we also observed a trend towards superior overall survival after DLI in BMT group compared to PBSCT group, especially in the early post-transplant period. The actuarial probability of survival at five years from DLI was 77% in PBSCT group and 79% in BMT group. However the differences were not statistically significant (p=0.77). The source of stem cells did not influence the occurrence of molecular/cytogenetic remissions after DLI (80% vs. 77%) grade II-IV acute GVHD (16% vs. 16%), chronic GVHD (23% vs. 30%) and myelosuppression (10% vs. 16%). In order to search for factors having impact on survival of analyzed patients, we performed both univariate and multivariate survival analyses. The univariate analysis revealed that interval from SCT to DLI longer than 2 years (p=0.001), date of DLI after 2000 (p=0.026) and molecular/cytogenetic stage of relapse at DLI (p<0.001) were associated with favorable survival. Similarly, the multivariate Cox analysis identified interval between SCT and DLI (HR= 0.50, CI: 0.3-0.8; p=0.01 for after 2 years), date of DLI (HR=0.63, CI:0.4-1.0; p=0.07 for after 1999), and stage of relapse (HR=2.8, CI:1.2-6.5; p=0.02 for HemCR and HR=3.6, CI:1.8-7.0; p<0.001 for missing data group), but not for stem cell source (HR=0.95, CI 0.56-1.6 ;p=0.86) as independent factors affecting survival. Based on our retrospective data from EBMT registry covering a period of 14 years of SCT and DLI, it seems that the PBSCT does not affect the efficiency of DLI compared to BMT. Therefore, keeping all limitations of a retrospective analysis in mind, it seems that differences in efficacy of DLI do not influence the decision whether PBSC or BM should be used as stem cell source for allogeneic SCT in CML in first chronic phase. Disclosures No relevant conflicts of interest to declare.

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