scholarly journals In vivo T cell depleted unrelated allogeneic stem cell transplantation with a reduced intensity regimen in patients with advanced hematologic malignancies

2005 ◽  
Vol 11 (2) ◽  
pp. 22-23
Author(s):  
M. Magalhaes-Silverman ◽  
T. Carter ◽  
R. Gingrich ◽  
R. Hohl ◽  
A. Schlueter
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Hematologic Malignancies ◽  
Reduced Intensity

Sustained Engraftment Using Fludarabine, Melphalan and Thiotepa Conditioning for Haploidentical Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5081-5081 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Suhail Qureshi ◽  
Gabriela Rondon ◽  
Susana Pesoa ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Platelet Recovery ◽  
Haploidentical Stem Cell Transplantation ◽  
Cd34 Cells ◽  
Reduced Intensity

Abstract BACKGROUND: Haploidentical stem cell transplantation (HaploSCT) using mega-doses of CD34 cells and a T-cell depleted allograft has generally been performed in advanced hematologic malignancies using a fractionated TBI-based conditioning regimen (CR) with very high toxicity. Here we evaluated the results of a reduced intensity chemotherapy-only conditioning regimen (RIC) with fludarabine (F), melphalan (M) and thiotepa (T) for HaploSCT. METHODS: 24 patients (pts) with advanced hematologic malignancies (18 with AML/MDS, 3 with ALL, 2 with CML and 1 with T-cell lymphoma underwent HaploSCT from related donors at MDACC between 10/2001 and 04/2007. The median age was 36 years. At the time of transplantation 15/24 pts (63%) had relapsed or primary refractory disease and 37% were in remission. Pts received a median of 10.8x10e6 CD34 cells. The median number of CD3 cells infused was 1x10e4/kg. The number of allele mismatch was 3/10 in 4 pts, 4/10 in 10 pts, 5/10 in 9 pts and 6/10 in 1 pt. HLA antibody (AB) specificity was determined using fluorescent beads coated with single antigens and detected in a Luminex platform. The CR consisted of M 140 mg/m2 on day −8, T 10 mg/m2 on day −7, F 160 mg/m2 over 4 days on days −6, −5, −4, −3, and 1.5 mg/kg of rabbit ATG a day x 4 on days −6, −5, −4, and −3 (FMT). No GVHD prophylaxis and no growth factors were administered. The pts were evaluated for engraftment and 100-day transplant-related mortality (TRM). RESULTS: 23 pts were evaluable for engraftment. 1 pt died on day 27 due to respiratory failure. 19/23 pts (83%) engrafted with hematopoietic recovery with donor-derived cells. 18 pts achieved a full donor chimerism while 1 had progressive leukemia. Neutrophil recovery to ANC >0.5 x 10e9/l occurred after a median of 13 days and platelet recovery to >20 x 10e9/l occurred after a median of 13.5 days. 4 pts failed to achieve primary engraftment, presumably due to rejection. No statistically significant correlation was found between graft failure (GF) and KIR-ligand mismatch (KIR-LM). In fact KIR-LM were more common in the group of pts who engrafted (7/19) than in pts with GF (1/4). After 09/2005 when anti HLA AB were started to be done, 3/14 pts had GF, 2 of which had donor directed AB. The regimen was relatively well tolerated; 4 pts experienced grade 4 nonhematologic, organ toxicities. Cumulative day 100 TRM was 25%. 19/24 pts (79%) were in CR after transplant with 6 surviving at the last follow-up (OS 25%). Only 1 pt developed aGVHD (4.1%) and 5 pts developed cGVHD (20.8%) with 3 experiencing extensive GVHD. 9 pts (37.5%) relapsed after a median of 71.5 days post transplant. The distribution of KIR-LM in the GVH direction was similar in pts with and without relapse (3/9 pts with relapse and 5/15 pts without relapse). Causes of death were disease relapse in 9 pts, infections in 3 pts, pulmonary failure/MOF in 4 pts and cGVHD in 1 pt. CONCLUSIONS: The reduced intensity FMT regimen was sufficiently immunosuppressive to support rapid engraftment after HaploSCT in 83% of pts with advanced hematologic malignancies. In this small series, KIR-LM in the HVG or GVH direction were not associated with graft rejection or malignancy relapse. The role of anti-HLA AB need further evaluation. The rate of toxicity and 100-day TRM appears lower as compared with published studies of TBI-based CR. The FMT RIC merits further evaluation in studies of HaploSCT.

Clinical Predictors of Transplant Related Mortality after Reduced Intensity Allogeneic Stem Cell Transplantation (RIST).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1145-1145 ◽  
Author(s):  
Daniel A. Pollyea ◽  
Andrew S. Artz ◽  
Wendy Stock ◽  
Sonali M. Smith ◽  
Christopher Daugherty ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
P Value ◽  
Clinical Predictors ◽  
Reduced Intensity ◽  
Related Mortality

Abstract Reduced intensity conditioning regimens and improvements in supportive care have allowed for the expansion of allogeneic stem cell transplantation to those previously ineligble. However, such patients remain at significant risk for regimen related toxicity. We examined whether clinical predictors that influence toxicity after standard chemotherapy, such as age, comorbidity and functional status similarly predict increased transplant related mortality (TRM) and decreased survival after a RIST with in-vivo T-cell depletion. We analyzed 81 consecutive patients on a single protocol with high-risk and refractory hematologic malignancies transplanted at our institution from 2002 to 2004. The conditioning regimen consisted of fludarabine 30 mg/m2/d (D-7 to D-3), Campath-1H 20 mg/d (D-7 to D-3), and melphalan 140 mg/m2 (D-2) with tacrolimus given for post-transplant immunosuppression. Comorbidity was scored from a retrospective chart review using the Charlson Comorbidity Index (CC) and the Kaplan-Feinstein scale (KF). Eastern Cooperative Oncology Group performance status (PS) and age at transplant were tabulated. TRM was defined as any death occurring without disease progression. Median age was 51 years (range 17–68). Fifty-five percent had HLA-identical sibling donors, 5% had mismatched related donors, 35% had matched unrelated donors and 5% had mismatched unrelated donors. KF served as a more sensitive indicator of comorbidity than CC. Fifty-three percent of patients scored at least one point for a comorbid condition by KF, as opposed to 25% by CC (P<.001 by Chi square), and 28% scored at least 2 points by KF versus 8% by CC (P<.001 by Chi square). PS was 0, 1, and >1 for 61%, 28% and 11% of patients, respectively. The cumulative incidence of 100 and 180 day TRM was 21% and 30%, respectively, with an overall survival (OS) of 15.4 months. Comorbidity, PS, and age greater than 50 predicted increased TRM and decreased OS. In a multivariable model incorporating these predictors (using either CC or KF), age and PS were significant for TRM, while comorbidity and PS were significant for OS. Simple measures of comorbidity, functional status and age predict adverse outcomes after transplantation for hematologic malignancies, even with a reduced intensity regimen. Prospective studies could provide a more accurate estimation of regimen tolerability, particularly in older or sicker patients. Clinical Predictors for Mortality After Allogeneic Stem Cell Transplantation Transplant Related Mortality (TRM) Overall Survival (OS) Predictor Incidence at Day 180 Univariate Hazard Ratio Univariate P Value Multivariate P Value* Univariate Hazard Ratio Univariate P Value Multivariate P Value* CC= Charlson Comorbidity Index, KF= Kaplan-Feinstein Scale; *Multivariate analyses include only one comorbidity measure, either KF or CC. Age and PS determined using KF. **Comorbidity scores exclude underlying hematologic malignancies Performance Status PS=0 0.86 4.2 0.002 0.007 2.78 0.003 0.016 PS>0 0.53 Comorbidity** CC, no comorbidity 0.76 2.3 0.042 0.089 2.25 0.014 0.03 CC, ≥1 comorbidity 0.52 KF, no comorbidity 0.85 2.7 0.027 0.183 2.74 0.004 0.03 KF, ≥1 comorbidity 0.56 Age Age<50 0.80 3.5 0.13 0.47 1.73 0.98 0.34 Age>50 0.63

Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4771-4779 ◽  
Author(s):  
Anna Dodero ◽  
Cristiana Carniti ◽  
Anna Raganato ◽  
Antonio Vendramin ◽  
Lucia Farina ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity ◽  
Donor Lymphocyte Infusions

Abstract Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34+ cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution.

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