Prolonged Duration of Systemic Immunosuppression after Allogeneic Hematopoietic Cell Transplantation Associates with the Use of Peripheral Blood Stem Cells, Severe Grade of Chronic Gvhd, Progressive Type Onset of Chronic Gvhd, Grade 2-4 Acute Gvhd and Older Age, but Not with T-Cell Depletion or Conditioning Regimen

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1948-1948
Author(s):  
Sita D. Bhella ◽  
Elizabeth Shin ◽  
Marc Poch Martell ◽  
Jieun Uhm ◽  
Fotios V. Michelis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Risk Score ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Stem Cell Source ◽  
Progressive Type ◽  
Cell Source ◽  
Related Donor ◽  
Nih Consensus Criteria

Abstract Background: Prolongedsystemic immunosuppression (SIS) post allogeneic hematopoietic cell transplantation (HCT) results in increased unnecessary complications. In our previous study of avascular necrosis (AVN; ASBMT 2015), one of common complications occurring after allogeneic HCT related to the use of prolonged immunosuppression including corticosteroids, we demonstrated a strong correlation between the duration of SIS and the risk of AVN. The probability of remaining on SIS was higher in the group developed AVN than those without episode of AVN (46.4% vs 11.7% at 4 years post-HCT). The question remains what are the risk factors related to prolonged SIS after allogeneic HCT. The present study attempted to evaluate potential risk factors for prolonged SIS. Methods: A retrospective review of 845 consecutive patients ≥18 years of age who underwent alloHCT at Princess Margaret Cancer Centre from 2002 to 2013 was conducted to determine the probability of SIS discontinuation considering death and relapse as competing risks. Univariate and multivariate analyses were conducted using cumulative incidence method considering competing risk to identify the risk factors for failure from SIS discontinuation. Results: Out of 845 patients, the probability of remaining on SIS, SIS discontinuation and death at 4 years is 19.6%, 30.5%, 49.9%, respectively. The median follow up duration among survivors was 3.5 years. Univariate analysis for successful SIS cessation revealed following risk factors: aGVHD grade 2-4 (p<0.001, HR 0.53), cGVHD by NIH consensus criteria (p<0.001, HR 0.52), cGVHD severity (p<0.001,HR 0.44), progressive type onset of cGVHD (p<0.001, HR 0.62), stem cell source (p<0.001,HR 0.54 for PBSC), T cell depletion (p<0.001, HR 1.42), donor type (p=0.0028, HR 1.45 for matched related donor), HLA match (p=0.0039, HR 0.30 for mismatched) and age (p<0.001, HR 0.98). Multivariate analysis confirmed that younger age (p<0.001, HR 0.97), aGVHD grade 2-4 (p<0.001, HR 0.51), progressive type of cGVHD (p<0.001, HR 0.53), cGVHD by NIH consensus criteria (p<0.001, HR 0.53), stem cell source (p<0.001, HR 0.51 for PBSC) and use of matched related donor (p<0.001, HR 1.68) were significant risk factors. ROC analysis was performed which revealed an age ≤ 50 to be a categorical risk factor for SIS discontinuation. A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to aGVHD grade 2-4, younger patient of age ≤50 years, progressive type of cGVHD, cGVHD by NIH consensus criteria, PBSC stem cell source and the use of matched related donor. Total score was calculated with risk score 0 (n=16, 2%), risk score 1 (n=55, 7%), risk score 2 (n=109, 14%), risk score 3 (n=215, 28%), risk score 4 (n=232, 30 %), risk score 5 (n=119, 16%), risk score 6 (n=14, 1%). Three risk groups were created: low (score 0-2, n=181, 21.4%), intermediate (score 3, n=216, 25.6%) and high (score 4-6, n=365, 47%). This risk score group could stratify the patients according to their success rate of SIS cessation (p<0.0001): 48.0% in low vs. 40.8% in intermediate vs. 28.5% in high risk group for SIS discontinuation rate at 4 yrs. Conclusions: Younger age, aGVHD grade 2-4, progressive type of cGVHD, cGVHD by NIH consensus criteria, peripheral stem cell source and use of matched sibling donor predicts for prolonged immunosuppression use post allogeneic transplant. Figure 1. Figure 1. Disclosures Kim: Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

scholarly journals Monocyte Subpopulation Recovery and Outcomes Following Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2232-2232 ◽  
Author(s):  
Lucie M. Turcotte ◽  
Qing Cao ◽  
Elias Krahn ◽  
Julie Curtsinger ◽  
Ashley M. Yingst ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Monocyte Count ◽  
Stem Cell Source ◽  
Cell Source ◽  
Cell Sources ◽  
Monocyte Subpopulations ◽  
Multivariable Models ◽  
Classical Monocytes

Abstract Introduction: Monocyte recovery following allogeneic hematopoietic cell transplantation (allo-HCT) has previously been correlated with improved overall survival (OS). Three distinct monocyte subpopulations have been identified based on CD14 and CD16 surface expression, including: CD14+CD16++ (non-classical), CD14+CD16+ (intermediate), and CD14++CD16- (classical). Among these subpopulations, non-classical monocytes have greater capacity to produce inflammatory cytokines, whereas classical monocytes have phagocytic activity, are less inflammatory and produce counter regulatory cytokines (i.e., IL-10), and intermediate monocytes are a transitionary population sharing features of both non-classical and classical monocytes. To date, there has not been a direct comparison between stem cell source and monocyte recovery, nor has there been an analysis of monocyte subpopulation recovery and HCT outcomes. We hypothesized that recovery of monocytes and their subpopulations would vary based on stem cell source and that recovery of the monocyte subpopulations would be associated with clinical outcomes. Methods: This analysis included individuals who underwent a first allo-HCT at the University of Minnesota between 2010-2014 and who enrolled onto an institutional immune reconstitution protocol. Absolute monocyte count (AMC), as well as the absolute counts of non-classical, intermediate and classical monocyte subpopulations were assessed at days 28, 60, 100 and 365 post-HCT. Optimal cut points of each monocyte subpopulation at day 28 were calculated using the Contal and OQuigley method and were used for analysis. This time point was selected because the outcomes of interest were unlikely to have occurred prior to this time. Individuals who experienced acute graft versus host disease (aGVHD) prior to day 28 were excluded from the aGVHD analysis (n=39). Patient demographics, disease and treatment characteristics were included in univariable analyses to determine associations between monocyte subpopulations and transplant outcomes, including 2-year OS, 1-year transplant related mortality (TRM), 2-year disease free survival (DFS), 2-year relapse, 180-day aGVHD and chronic GVHD. Factors with P-values <0.15 were included in multivariable models. Results: Among 318 individuals with available day 28 data, median age at HCT was 38 years, and median follow up was 531 days. Conditioning was myeloablative for 45% and reduced intensity for 55%. Stem cell source was: BM (n=80), PBSC (n=79), single UCB (SUCB) (n=54) and double UCB (DUCB) (n=105). Although monocyte subpopulation recovery did not differ across stem cell sources at day 28, AMC, classical and intermediate monocyte recovery was greater among UCB recipients compared to other stem cell sources at days 60, 100 and 365 (Table). In multivariable models, after controlling for each monocyte subpopulation, stem cell source, disease and treatment characteristics, an absolute classical monocyte count of >/= 0.25x 109/L at day 28 was associated with improved OS (HR=0.33, 95% CI 0.12-0.86, P=0.02) (Figure) and DFS (HR=0.36, 95% CI 0.15-0.85, P=0.02). Absolute numbers of non-classical monocytes >/=0.02 x 109/L at day 28 was associated with decreased rates of grade II-IV aGVHD (HR=0.58, 95% CI 0.34-0.99, P=0.04) and decreased cGVHD (HR=0.48, 95% CI 0.26-0.90, P=0.02). None of the day 28 monocyte subpopulation counts were associated with TRM or relapse. Conclusions: Monocyte recovery differs among stem cell sources. UCB recipients experience more robust monocyte recovery, specifically within the intermediate and classical monocyte subpopulations, at day 60 and at all measured time points beyond, compared to other stem cell sources. Early monocyte recovery is associated with HCT outcomes. Increased classical monocyte count at day 28 is independently associated with improved OS and DFS. Paradoxically, despite their inflammatory properties, increased non-classical monocyte count predicts decreased acute and chronic GVHD within this large series of patients. If reproduced, these findings could allow for enhanced outcome prediction models and could lead to novel interventions to improve transplant outcomes. Disclosures Cooley: Fate Therapeutics: Research Funding. Miller:Oxis Biotech Scientific Advisory Board: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Outcome of 673 Patients with Hematologic Malignancies Surviving at Least 8 YEARS Post- Allogeneic Transplants: Risk Factors and Quality of Life

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4601-4601
Author(s):  
Giuseppe Sapienza ◽  
Teresa Lamparelli ◽  
Alida Dominietto ◽  
Anna Maria Raiola ◽  
Carmen Di Grazia ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Risk Factors ◽  
Stem Cell ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Advisory Board ◽  
Actuarial Survival ◽  
Stem Cell Source ◽  
Cell Source

Background : Allogeneic hemopoietic stem cell transplantation (HSCT) has been widely used in hematologic malignancies for over 4 decades. One important question is the longterm outcome of these patients, in terms of leukemia control and quality of life. Aim of the study. Assess the outcome of patients surviving at least 3000 days post allogeneic HSCT, and identify risk factors for failure. Methods. We used our transplant relational database, in which patients' clinical and laboratory data are prospectively recorded during each outpatient visit or during admission. We identified 673 patients who were seen between 8 and 30 years post-transplant. The median follow up was 17.5 years (range 8.2-36.6), median age was 34 years (range1-65). The diagnosis was AML (n=205), ALL (n=97) CML (n=208), MDS (n=51), Lymphoma (n=45), Myelofibrosis (n=19), other (n=48). The stem cell source was bone marrow (BM)(n= 488), peripheral blood (PB) (n=154), cord blood (CB) (n=31). The disease was in remission (n=553) or in relapse (n=120). Result . The overall actuarial survival at 20 years was 86% (95%CI 83%-89%). The CI of TRM at 20 years was 9.4% and the CI of relapse related death (RRD) was 4.6% . Leading causes of death were second tumours (3.2%), chronic GvHD (2.8%) relapse (2.8%). In univariate analysis negative predictors of survival were the following : severe cGvHD (RR 5.0, p=0.002) compared to n0 cGvHD, the use of PB compared to BM as a stem cells source (RR 2.6, p<0.00001), patients age over 40 (RR 3.1, p<0.0001), donors age over 40 (RR 2.4, p=0.0001), advanced disease (RR 2.0, p=0.005), conditioning without TBI (RR 2.1, p=0.0007). The actuarial survival at 20 years of patients grafted from BM or PB was 89% vs 75% (p<0.0001), with a CI of TRM at 20 years of 7% vs 17% respectively (p=0.001) and a CI of RRD of 3% vs 7% (p=0.008). The actuarial 20 year survival for patients </> 40 years was 91% vs 80% (p<0.0001). Survival according to the severity of cGvHD is shown in Figure 1. Multivariate analysis. In a multivariate Cox analysis, negative predictors of survival, were severe cGvHD (RR 5.0, p=0.0003), patients age over 40 (RR 2.4, p=0.001) , PB grafts versus BM (RR 1.8, p=0.002). Conclusions. Patients surviving 8 years post HSCT have a 9% risk of transplant related death and a 4% risk of relapse related death. Chronic GvHD remains the strongest negative predictor of survival , together with patients age , and PB as a stem cell source. The impact of cGvHD 10-20 years post transplant strongly calls for preventing meaures to be adopted early in the transplant course, and or with a preferential use of BM as a stem cell source. Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC.

Risk Factors to Develop Sclerotic Chronic GvHD After Allogeneic HSCT: Preliminary Results of a Multicentre Retrospective study From the Société Française De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1947-1947
Author(s):  
Marie Y. Detrait ◽  
Roberto Crocchiolo ◽  
Stephane Vigouroux ◽  
Jacques-Olivier Bay ◽  
Mohamad Sobh ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Cord Blood ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Allogeneic Hsct ◽  
Factors Associated ◽  
Stem Cell Source ◽  
Cell Source ◽  
Unrelated Donors

Abstract Abstract 1947 Introduction Sclerotic cGvHD is one of the most severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). The sclerotic skin manifestations of cGvHD result from inflammation and fibrosis of the dermis, subcutaneous tissue, or muscular fascia, leading to functional disability. Risk factors associated with sclerotic cGvHD remain not well studied. TBI, PBSC, female recipient, and prior severe skin acute GvHD were identified as factors associated with an increased risk of sclerotic cGvHD in a large previous retrospective study from Seattle (n=986 patients) which was presented at the ASH 2011 meeting. Objective In the aim to validate the previous risk factors in France, we have conducted this retrospective multicentric analysis. We present here the preliminary results from four centers, seven are expected in the next months. Between 2005 and 2010, 437 consecutive patients who received systemic therapy for chronic GvHD after a first allogeneic HSCT were included. Chronic GvHD was diagnosed by the NIH consensus criteria. Sclerotic GvHD was defined by manifestations of cutaneous sclerosis, fasciitis or joint contracture in the medical record. Analyses to determine risk factors included as variable patient and donor age, kind of donor, HLA matching, diagnosis, stem cell source, patient and donor gender, intensity of conditioning regimen, use of total body irradiation (TBI) or antithymocyte globulin (ATG) in the conditioning regimen, and prior acute GvHD. Results All patients had hematological malignancies, the median age is 45 (17–65), 227 patients (52%) had HLA-matched related donors, 125 (29%) had HLA-matched unrelated donors, 48 (11%) had HLA- 9/10 unrelated donors and 37 (8%) had one or two cord blood unit (HLA-4/6 or 5/6 matched). The median time from allogeneic HSCT to chronic GvHD was 6.5 (1.8–41.5) months; 69 patients (15.7%) presented sclerotic features at initial diagnosis or after the onset of chronic GvHD. The cumulative incidence of sclerotic cGvHD was 12% (95%CI, 11–13.5) at 5 years after onset of chronic GvHD (Figure). From the 69 patients who experienced sclerotic cGvHD, 49 patients (71%) had HLA-matched related donors, 19 patients (27.5%) had HLA-matched unrelated donors, and 1 patient (1.5%) had HLA-mismatched unrelated donor. In univariate analysis, we found more sclerotic cGvHD in patients who had multiple myeloma (p=0.018); this effect seems to be associated with the prophylaxis for GvHD with CsA alone. There was no effect of TBI or intensity of conditioning. There was more sclerotic GvHD in female recipient (p=0.032) and for patients who had an unrelated donor (p=0.0028). In multivariate analysis (Table), factors associated with an increased risk of sclerotic cGvHD were female recipient, patients with unrelated donor, and patients with previous aGvHD. Cord blood as stem cell source was associated with a lower risk of sclerotic GvHD. Prophylaxis of GvHD with CsA alone showed a trend to a higher risk. At the last follow-up, of the 69 patients, 51 (74%) were alive and 10 (14.5%) died from cGvHD. Conclusion In this intermediate analysis, we found that female recipient, unrelated donor, previous aGvHD are risk factors for developing sclerotic cGvHD. Moreover, we found that cord blood as stem cell source is a protector factor. Study of GvHD prophylaxis, ABO matching, type of HLA-mismatching, acute skin GvHD is ongoing on the whole cohort (n= 1587 patients from 7 centers) and results will be communicated later. After the final analysis on the whole cohort we would like to establish a score risk of sclerotic cGvHD in the goal to conduct a prospective study in France with a prophylactic treatment for high risk patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4655-4655 ◽  
Author(s):  
Kavita Raj ◽  
Eduardo Olavarria ◽  
Diderik-Jan Eikema ◽  
Liesbeth C de Wreede ◽  
Linda Koster ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Treatment of Acute Lymphocytic Leukemia (ALL) in 126 Adults: Impact of Donor Source on Leukemia Free Survival (LFS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2064-2064 ◽  
Author(s):  
Priya Kumar ◽  
Todd E. Defor ◽  
Claudio Brunstein ◽  
Juliet Barker ◽  
John E. Wagner ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Growth Factor ◽  
Disease Status ◽  
Lymphocytic Leukemia ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Cell Source ◽  
Donor Source

Abstract White blood cell (WBC) count and specific cytogenetic abnormalities at diagnosis, patient age and disease status at HSCT have previously been identified as risk factors associated with LFS in patients with ALL. As the use of umbilical cord blood (UCB) is relatively new, particularly for adults, we sought to evaluate the relative impact of donor source. In this single center study, 126 adults aged 18–61 (median 31) years (yrs) underwent myeloablative conditioning (cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy based regimen in 92%) followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 85, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14 and HLA 0–2 (A, B, DRB1) mismatched UCB in 12. At the time of HSCT, 64 patients were in CR1, 51 in CR2, and 11 patients in ≥ CR3; 20 pts had T-lineage disease; 38 pts (30%) had either t(9;22)(n=28), t(4;11) or t(1,19) (n=10) with the remainder (70%) having normal cytogenetics. WBC ≥ 30 x 109/l at diagnosis was documented in 50%. Demographics, disease characteristics at initial diagnosis and transplant variables were similar in all 4 groups except: year of transplant after 1996 and use of growth factor for all UCB recipients. Outcomes by donor source: MRD URD:M URD:MM UCB P N 85 15 14 12 Median follow up in yrs 9.3 3.5 7.2 1.2 OS 1 yr % (95% CI) 41 (31–52) 33 (9–57) 14 (0–33) 75 (51–100) 0.02 LFS 1 yr % (95% CI) 35 (25–45) 27 (4–49) 14 (0–33) 67 (40–93) 0.03 Relapse 1 yr % (95% CI) 21 (12–30) 20 (0–40) 0 8 (0–23) 0.22 TRM 1 yr % (95% CI) 44 (33–55) 53 (27–79) 86 (57–100) 25 (1–49) <0.01 As a consequence of low TRM, OS and LFS were superior after UCB transplants. In multiple regression analysis, 5 independent risk factors were significantly associated with poorer OS: use of URD:M (RR 3.8, 95% CI 1.1–13.8, p= 0.04) and URD:MM (RR 4.9, 95% CI, 1.3–19.1, p= 0.02), ≥ CR3 at HSCT (RR 3.0, 95% CI, 1.1–8.8, p= 0.04), WBC >30 x 109/l (RR 2.4, 95% CI, 1.4–4.1, p<0.01), cytomegalovirus (CMV) seropositive recipient and donor (RR 4.0, 95% CI, 2.0–7.9, p<0.01), and ≥ 2 induction regimens to achieve initial CR (RR 2.7, 95% CI, 1.2–5.9, p= 0.01). Patients who developed grade II–IV acute graft versus host disease (GVHD) had significantly lower mortality rates (RR 0.4, 95% CI, 0.2–0.7, p<0.01). There was no impact on OS by year of transplant or use of growth factor. Variables associated with poor LFS were identical to those for OS, and GVHD was again associated with improved LFS. These results support the use of UCB as an alternative stem cell source for adults with ALL with results comparable to outcomes observed with MRDs. In addition, GVHD is associated with improved LFS suggesting a significant graft versus leukemia effect with all donor graft sources.

Allogeneic Stem Cell Transplantation (allo-SCT) in 192 Acute Myeloid Leukemias (AML): A Single Center Experience From 1982 to 2010

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4498-4498
Author(s):  
Carmen Montes-Gaisan ◽  
Jorge Monge ◽  
Clara Martin ◽  
Zurie Diez ◽  
Johny Alberto Hinostroza ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
The Other ◽  
Univariable Analysis ◽  
Stem Cell Source ◽  
Significant Difference ◽  
Cell Source

Abstract Abstract 4498 Background: Giving the fact that allo- SCT currently offers patients with high risk AML the best chance of cure, we`ve aimed to investigate the outcome of AML patients who have undergone allo-SCT in our center, considered as one of spanish reference hospital in SCT, and the parameters that have been able to influence in relapse rate (RR), overall survival (OS) and relapse free survival (RFS). Methods: Retrospective study in 192 AML patients who have undergone allo-SCT between 1982 and 2010. The analysis has been performed in 171 patients (85 male and 86 female) by excluding 21 acute promyelocitic leukemias (APL): 65 patients until 1999 and 106 since 2000. Median age was 37 1874 and median lecocyte count, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(13400/\hbox{ L }\frac{470}{250000}\) \end{document}. 82 were de novo AML and 87 were in morfologic complete remission (70 in first CR). 14 patients had received a previous SCT. Cytogenetic risk was as follows: 55 intermediate, 34 high and 11 low. Conditioning regimen was ablative in 162 patients: CyTBI (36), BuCy (31), BuFlu (30) and others (3). 130 patients (76) underwent a related allo-SCT (95 of them were matched) and 41 patients (24), an unrelated allo-SCT (64 of them were matched). Stem cell source was bone marrow (BM) in 146 patients (85) and only 3 patients received umbilical cord (UC). Graft versus host disease (GvHD) prophilaxis was based on Ciclosporine in 150 patients (88). Median time from last treatment was 73 days 12268. Results: The median follow-up of this study was 61 months 1317. OS at 1, 3 and 5 years were 57, 44 and 40. RFS at 1, 3 and 5 years were 62, 50 and 45. Early mortality (before day 100) was 26 (43 until 1999 and 15 since 2000, p0,0001): 18 patients because of infections, 10 because of toxicity, 9 because of disease and 7 because of EICH. Late mortality was 27 (more than the half because of relapse, with no significant difference between 19881999 and 20002010). Cumulative relapse incidence at 5 years was 35, with a median time of relapse of 4 months. Secondary malignancies incidence was 5. Multivariable analysis showed that Transplantation Related Mortality (TRM) was influenced by: year of allo-SCT (OS at 5 years of 49 if 20002010 vs 28 if 19821999, p0,0001), late engraftment (p0,002) and severe acute GvHD (OS at 5 years of 45 if no evidence/grade I-II vs 25 if grade III-IV, p0,071). The other important parameters which lost its univariable analysis significance were donor type, recipient age and conditioning regimen. No difference was found in case of HLA and ABO discordance or donor/recipient CMV status. Multivariable analysis also showed that RR and RFS at 5 years was influenced by: disease status at allo-SCT (50 if 1CR vs 0 if 2CR/PR/refractory disease, p0,002), chronic GvHD (67 if present vs 41 if absent, p0,035) and leucocyte count at diagnosis (54 if 20000/ L vs 37 if 20000/ L, p0,038). The other important parameters which lost its univariable analysis significance were cytogenetic risk, initial induction response and positive minimal residual disease (MRD) before allo-SCT. No diference was found in case of ethiologic classification or stem cell source. Conclusions: Allo-SCT is a curative procedure in AML patients (global RFS of 50 at 3 years), specially when disease is under control and patient develops chronic GvHD. In the last decade, there have been important improvements in the procedure which have led to a significant decrease in TRM, and consequently, a significant increase in OS. Disclosures: No relevant conflicts of interest to declare.

Post Transplant Cyclophosphamide (PTCy) with Anti-Thymocyte Globulin (ATG) Effectively Reduces the Severe (Grade III-IV) Acute Graft-Versus-Host Disease (GVHD) When Compared to ATG Alone in Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplants

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3430-3430 ◽  
Author(s):  
Uday Deotare ◽  
David Loach ◽  
Fotios V. Michelis ◽  
Dennis D. Kim ◽  
Santhosh Thyagu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Historical Cohort ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Grade Iii ◽  
Severe Grade

Abstract Introduction: Acute Graft-versus-Host Disease (aGVHD) is a frequent complication of Allogeneic Hematopoietic cell transplants (allo-HCT). It can be lethal with increased morbidity and mortality and can occur in upto 40-50% of allo-HCT. Various agents such as calcineurin inhibitors, anti-metabolites and anti T cell antibodies, have been variably used for GVHD prophylaxis. Use of Post-transplant Cyclophosphamide (PTCy) has recently been used extensively in haplo-identical transplant setting with promising results, but has mainly been used in patients with BM as a stem cell source. In those patients receiving PBSC as a stem cell source, PTCy alone could reduce the risk of acute and chronic GVHD significantly. Anti-Thymocyte Globulin (ATG) has been associated with decrease in chronic but not acute GVHD. As most of our patients use PBSC as a graft source, we hypothesized that combination of ATG and PTCy can reduce the incidence of both acute and chronic GVHD. Since we had also used ATG for GVHD prophylaxis in a historical cohort, we compared the results of this approach with the current GVHD prophylaxis regimen. Methods: A total of 28 patients with hematological malignancies, who had an unrelated donor underwent allo-HCT at our center from 1 Oct 2015 to 31 Mar 2016. After interim analysis, when increased non-hematological toxicity was observed with myeloablative conditioning, all patients subsequently received reduced intensity conditioning. Peripheral blood was used as a stem cell source in all patients. The GVHD prophylaxis consisted of a combination of ATG-PTCy-CsA, with rabbit ATG administered on Days -3 (0.5 mg/Kg), -2 (2 mg/Kg) and -1 (2 mg/Kg), PTCy at dose of 50 mg/kg on Days +3 and +4 and CsA from Day+5 onwards. Filgrastim was used from day +7 onwards for 13 patients. Emphasis was given to incidence of acute GVHD, especially Steroid Refractory (SR-GVHD). Results: Out of total of 28 patients, aGVHD was seen in 6 (21.4%) patients, five of which had skin involvement (Grade I- II) and one suspected liver involvement (Grade III), all of which responded rapidly to steroids with no cases of SR-GVHD. Secondary graft failure and EBV reactivations; each were seen in 10% of cases. Primary disease relapse was seen in 3 patients, two of which had minimal residual disease prior to transplantation. These results were then compared to the historical cohort of 27 patients who received a combination of ATG-CsA plus Mycophenolate Mofetil (MMf) (Table 1). The incidence of acute GVHD was 26% vs 22% (p=0.99), with severe Grade III-IV aGVHD of 4% vs 20% (p=0.085) in the ATG-PTCy-CsA and ATG-CsA-MMf cohorts, respectively; both were statistically not signifcant. There were five patients with SR-GVHD in the ATG-CsA-MMf cohort and none in the current GVHD prophylaxis arm. In the historical cohort, the main cause of death in 7 out of 11 patients was severe GVHD as compared to 1 out of 9 in the ATG-PTCy-CsA cohort. Conclusions: Combination of ATG-PTCy-CsA is an effective strategy to reduce aGVHD; especially severe Grade III-IV and doesnot increase the risk of SR-GVHD, in unrelated donor transplants as compared to ATG-CsA-MMf. However, a long term follow up is needed to assess relapse and cGVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Low Incidence of Chronic Gvhd after Haploidentical T-Cell Replete Peripheral Blood Stem Cell Transplantation with Post Transplantation Cyclophosphamide (PT-Cy)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4594-4594
Author(s):  
Angela Granata ◽  
Sabine Furst ◽  
Jean marie Boher ◽  
Luca Castagna ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Neutrophil Recovery ◽  
Stem Cell Source ◽  
Cell Source ◽  
Low Incidence

Abstract Background: Since the first publication at the John Hopkins Hospital, (Luznik et al. BBMT 2008), Haploidentical T-cell replete Stem Cell Transplantation (HaploSCT) with post transplantation cyclophosphamide (PT-Cy) has become a reproducible and feasibility therapeutic option for many patients (pts) with hematologic malignancies , notably because of the low incidence of GVHD and infections, without increased graft failure. Initially, bone marrow (BM) was considered as the favorite source of hematopoietic stem cells in order to minimize the risk of GVHD. In a retrospective study, we previously showed no difference in terms of increased events (GVHD, NRM), regardless of the hematopoietic stem cell source (PBSC or BM) (Castagna et al. BMT 2014). Some recent publication seems to confirm this observation (Sugita J. BBMT 2015 , Solomon R. Adv in Hem. 2016), although no randomized study so far has been conducted. Here, we retrospectively analyze the incidence and the characteristics of GVHD in the setting of HaploSCT using PT-Cy, after infusion of PBSC. Methods: Inclusion criteria were: adult pts with hematologic malignancies receiving a PBSC HaploSCT from 2012 to 2015 in 4 centers (3 in France and 1 in Italy) with PT-Cy as part of the GVHD prophylaxis. PBSC infusion at day 0 was followed by PT-Cy 50 mg/kg on days +3 and +4 in association with calcineurin inhibitors (cyclosporine A or Tacrolimus) and mycophenolate mofetil (MMF), started at day +5. All patients received G-CSF support from day+5 until neutrophil recovery. Study end points were the cumulative incidences of acute (a) and chronic (c) GVHD, with a specific organ grading evaluation, non-relapse mortality (NRM), relapse (CIR) as well as progression free (PFS) and overall survival (OS). Additionally, we analyzed the composite endpoint "GVHD and relapse free survival" (GFRS) for which the occurrence of relapse, death or severe chronic GVHD was considered as relevant events. Correlation between CD 34+ and CD 3+ and the incidence of aGVHD and cGVHD was studied by a linear continuous variable. Results: Between March 2012 and December 2015, 192 pts with a median age of 57 years (range: 16-73) received T-cell replete PBSC HaploSCT for hematologic malignancies (myeloid: n= 55%; lymphoid: n=45%) in 4 centers. Patient's characteristics are shown in table 1. Pts received non myeloablative (according to Baltimore regimen) or busulfan-based reduced intensity conditioning, in 56% and 44% of cases, respectively. All, but 3 pts, engrafted, with a median time of 19 days (range, 14-47) to neutrophil recovery (ANC >500 x106/L) and 22 days (range, 14-252) to platelet recovery (PLT > 20 G x 109/L). The median CD34+ x 106/Kg and CD3+ x 106/Kg cells infused were 5.5 (range, 1.5-14.8) and 404 (range, 38-704), respectively. No relevant correlation was observed between the CD34+ and CD3+ infused cells and the incidence of GVHD, studied by linear continues variable. We noted only a trend to develop severe cGVHD with an increasing number of CD3+ cells infused. This result has to be considered with caution, because of the small events (6 pts affected by severe cGVHD). Complete donor T cell chimerisme was evaluable in 162 pts (83%) and achieved by day +30. The incidence of aGVHD was 38% at 100 days (all grades), whereas grade II-IV and III-IV were 24% and 10%, respectively. Concerning patients with aGVHD grade 2-4, the most affected organ was skin (19%), followed by gut (9%) and liver (2%). The incidence of 3-year cGVHD according to NIH classification was 15% (all grades). Three percent of pts developed severe cGVHD (lung n=1; liver, n=1). The most frequent involved organs were skin and mucosae (70%). No patient showed gut cGVHD. Finally, in univariate analysis, busulfan-based conditioning seems to negatively impact on severe cGVHD (p = 0.03; HR=3.37 [1.09 -10.46]) After a median follow up of 20 (range, 4 - 52) months, NRM at 100 days and 1 year was 10% and 20%, respectively. Three-year OS, PFS, CIR and GRFS were 63%, 55%, 25% and 49%, respectively. Conclusion: This retrospective study shows a very low incidence of severe cGVHD after HaploSCT even with PBSC as stem cell source, suggesting that the use of PT-Cy may overcome the anticipated increased incidence of cGVHD, contrary to as previously reported in the HLA identical setting (Mohty et al. Leukemia 2003). Similar to HLA identical sibling and unrelated donor transplantation, the most frequent organs involved are skin and mucosae Disclosures No relevant conflicts of interest to declare.

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