Impact of Targeted Immunotherapies and Novel Cytogenetic and Clinical Risk Groups on Outcome after Allogeneic Hematopoietic Stem Cell Transplant (AlloHCT) for Acute Lymphoblastic Leukemia (ALL): The Mayo Clinic Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2588-2588
Author(s):  
Zaid Abdel Rahman ◽  
Michael G. Heckman ◽  
Kevin C. Miller ◽  
Patricia Greipp ◽  
Matthew R Spiegel ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Targeted Therapies ◽  
Mayo Clinic ◽  
Lower Risk ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Risk Groups ◽  
Increased Risk ◽  
The Impact

Introduction Novel high-risk groups have been identified in adult ALL, including secondary (sALL) and Philadelphia-like ALL (Ph-like, based on CRLF2, IgH, ABL2, JAK2 and other tyrosine kinase translocations), and those with minimal residual disease >0.1% (MRD+) after induction therapy. Novel targeted therapies are now routinely incorporated into 1st line regimens, including tyrosine kinase inhibitors (BCR-ABL1-pos), rituximab (CD20+) and blinatumomab (Blina) for MRD+. The impact of these novel high risk groups and therapies after alloHCT is unknown; therefore, we evaluated their impact on overall survival (OS), relapse rate (REL), non-relapse mortality (NRM) and acute and chronic GVHD. Methods We evaluated pts receiving 1st Allo-HCT for ALL at Mayo Clinic (Rochester, Phoenix, and Jacksonville) from 2008-2018 for outcomes of interest, specifically the impact of novel therapies and risk groups. Associations of patient factors with outcomes were examined using univariable (UVA) and multivariable (MVA) Cox proportional hazards regression models, where the cause-specific hazard of the given outcome was modeled to account for the competing risk of death. Results We identified 261 consecutive AlloHCT recipients during the study period. Median age at transplant was 48 years (18-72) and 147 (56.3%) were male. The median comorbidity (HCT-CI) score was 2 (0-8). 213 pts (81.6%) had B-lineage ALL, of which 85 (32.6%) were BCR-ABL-pos, 17 (6.5%) Ph-like (identified by FISH), 16 (6.1%) hypoploidy/near triploidy (Hy/Tri), and 67 (25.7%) pre-B ALL NOS. The remaining 48 (18.4%) had T-ALL. 30 pts (11.5%) had sALL (i.e. prior chemo/radiotherapy for another malignancy). HyperCVAD was the most common 1st line regimen (68.2%). 243 (93.1%) pts achieved Complete Remission (CR1) after induction therapy, and 203 (77.8%) were in CR1 at the time of alloHCT. Blina was administered for MRD+ in 14 pts (5.4%), and for relapsed/refractory ALL (R/R) in 13 (27% of R/R pts), 7 of whom received Blina as initial therapy for R/R. Donors were matched unrelated in 149 (57.1%), matched related in 98 (37.5%), and haploidentical in 14 (5.4%). Peripheral blood (PB) grafts were used in 233 (89.3%). 103 (54.5%) were donor:recipient (D:R) sex-matched, and 86 D:R mismatched [47 (24.9%) M:F; and 39 (20.6%) F:M]. Myeloablative conditioning was used for the majority (78.5%) mostly with Cy/TBI (60.5%). Standard GVHD prophylaxis regimens were used. Outcomes Median follow-up after transplant was 22.4 months (0.5-135), and 51 (19.5%) had REL. The 1, 2 and 5-year survival rates were 71.9%, 64.9%, and 54.1%, respectively (Figure 1). Acute GVHD developed in 144 (55.2%) and chronic GVHD in 100 (38.3%). Ph-like ALL, Blina for MRD+, Blina for R/R, sALL and CD20-pos had no independent impact on OS. In contrast, age>60, Hy/Tri, and >CR1 at alloHCT were associated with worse OS in UVA, however, in MVA only pre-B ALL NOS was associated with better OS. Female:male D:R status was associated with inferior OS. Blina for R/R disease was associated with increased risk of REL in UVA [HR 5.26 95% CI (1.33, 20.00), p=0.017], whereas other novel high risk groups had no impact on REL. In contrast, T-ALL, Hy/Tri and >CR1 at AlloHCT were associated with increased REL in UVA, but only T-ALL and Hy/Tri continued to predict for increased REL in MVA. Secondary ALL was associated with increased NRM in UVA [HR 1.96 95% CI (1.07, 3.57), p=0.028], whereas other novel high risk groups had no impact on NRM. In contrast, age>60, >CR1 at AlloHCT and D:R sex mismatch were associated with higher NRM in UVA, but only sex mismatch and >CR1 at AlloHCT were associated with higher NRM in MVA. TBI use was associated with higher risk of acute GvHD (p=0.008) and ATG use with lower risk chronic GVHD (p<0.001). Similarly non-PB grafts were associated with a lower risk of chronic GVHD (p=0.005). Results for OS, REL, NRM, acute and chronic GVHD analysis are shown in Table 1. Conclusion Novel high risk groups (CD20+, Ph-like and sALL) do not appear to adversely impact OS after alloHCT, although sALL was associated with increased risk of NRM. Interestingly, pre-B-ALL NOS appear to be associated with favorable OS. Novel targeted therapies also do not independently predict outcome, with the exception of Blina for R/R ALL which may be associated with REL after subsequent alloHCT (a subgroup for whom novel maintenance strategies should be explored). Our analysis highlights the importance of allo-HCT for novel high risk ALL subgroups. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Foran:Agios: Honoraria, Research Funding.

Graft-Versus-Leukemia (GVL) Effect After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) as Treatment for Acute Myeloid Leukemia (AML): a Survey From the Acute Leukemia Working Party of the EBMT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3313-3313
Author(s):  
Frederic Baron ◽  
Myriam Labopin ◽  
Mohamad Mohty ◽  
Nadezda Basara ◽  
Dietger Niederwieser ◽  
...  
Keyword(s):  
High Risk ◽  
Lower Risk ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Working Party ◽  
Cox Models ◽  
Landmark Analysis ◽  
Factors Associated ◽  
The Impact ◽  
Risk Of Relapse

Abstract Abstract 3313 Poster Board III-201 RIC allo-SCT has been increasingly used as treatment for AML patients (pts) ineligible for myeloablative allo-SCT. Previous studies have observed a lower risk of relapse in pts who experienced chronic GVHD after RIC allo-SCT versus in those who did not. The objective of the current study was to further investigate the association between chronic GVHD and relapse in a large cohort of pts given RIC allo-SCT as treatment for AML. Data from 1188 AML pts in first or second CR transplanted between 2000 and 2008 following a RIC regimen at EBMT affiliated centers were analyzed. Patients were given PBSC from HLA-identical sibling (MRD, n=879), or from HLA-matched unrelated donors (MUD, n=309). RIC was defined as Busulfan conditioning regimens containing ≤ 8mg/kg total dose, or TBI <6 Gy. Median pt age at transplantation was 55 (range, 18-76) yrs in pts given grafts from MRD, versus 57 (range, 19-72) yrs in those given grafts from MUD. 54 pts had good risk (4.5%), 564 standard-risk (47.5%), and 116 high-risk (9.8%) cytogenetics, while cytogenetic was unknown in 454 pts (38.2%). The impact of chronic GVHD on relapse risk, non-relapse mortality (NRM) and leukemia-free survival (LFS) was assessed by time-dependent multivariate Cox models and in a landmark analysis. Three-yr incidences of relapse, NRM and LFS were 35 ± 2%, 14 ± 2%, and 50 ± 2%, respectively, while 2-yr incidence of chronic GVHD was 49 ± 2%. In a landmark analysis at 18 months after allo-SCT, 5-year relapse rates were 10 ± 2% versus 19 ± 3% for patients with or without chronic GVHD (P=0.04), respectively. In multivariate Cox models, CR2 versus CR1 (P=.003), pt age > 55 yrs (P=.008), alemtuzumab use in the RIC (P=.048), TBI-based RIC (P=.006), high-risk cytogenetics (P=.001), and absence of chronic GVHD (P=.015) were each associated with higher risk of relapse. Factors associated with high NRM were MUD versus MRD (P=.003), grade II-IV acute GVHD (P<.001), and chronic GVHD (P=.002). Factors associated with lower LFS were CR2 versus CR1 (P=.003), pt age > 55 yrs (P=.007), alemtuzumab use in the RIC (P=.012), and high-risk cytogenetics (P=.003). In conclusion, in this cohort of AML patients transplanted in remission, chronic GVHD was associated with a lower risk of relapse while profound in-vivo T cell depletion with alemtuzumab was associated with higher relapse rate suggesting that GVL effects play a role in preventing AML relapse in patients given RIC allo-SCT. Therefore, closed surveillance of patients in this setting not presenting chronic GVHD such as decreasing of immunosuppression should be further investigated. Disclosures No relevant conflicts of interest to declare.

Outcome of Patients Aged ≥60 After Allogeneic Hematopoietec Cell Transplantation: Age Has No Impact on Survival

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3540-3540 ◽  
Author(s):  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
Wolfgang A. Bethge
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Allogeneic Hct ◽  
Kaplan Meier ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract Abstract 3540 Historically, allogeneic hematopoietic cell transplantation (HCT) has been offered only to patients with good performance status and below the age of 60. However, the peak incidence of most hematologic malignancies is above 60 years of age. The introduction of reduced intensity conditioning (RIC) regimens enabled successful allogeneic HCT in patients with considerable comorbidities and older than 60 years. The impact of age on outcome of allogeneic HCT in patients ≥60 years has not been evaluated extensively. We retrospectively analyzed 109 consecutive patients (f=43, m=66) aged≥60 who received allogeneic HCT 2000–2010 at our institution. Median age of the patients was 65 years (range, 60–76). Patients were grouped in two cohorts depending on age: group 1 aged 60–65 years (n=60, median age=63) and group 2 aged 66–76 years (n=49, median age=68). Diagnoses were acute leukemia (AML n=65, ALL n=1), myelodysplastic syndrome (n=14), osteomyelofibrosis (n=7), non-Hodgkin lymphoma (n=9), multiple myeloma (n=8), aplastic anemia (n=1), chronic myeloid leukemia (n=2) and chronic lymphatic leukemia (n=2). At time of HCT, 41 of the patients were in complete remission (CR), 68 in partial remission (PR) (group 1: CR 21, PR 39; group 2: CR 20, PR 29) and 18 patients had a preceding HCT, 14 in group 1. Conditioning regimens were grouped in high (TBI/Bu+Cy, n=5, all group 1), intermediate (FLAMSA, Flu/Mel/BCNU, n=28, group 1=11, group 2=17), low (FLU+alkylans, n=48, group 1=32, group 2=16) and minimal (2GyTBI/Flu, n=28, group 1=12, group 2=16) intensity. Intermediate intensity conditioning was particularly used for high risk patients in PR (25/28). 22 patients were transplanted from matched related (MRD), 46 from matched unrelated (MUD) and 41 from mismatched unrelated donors (MMUD). Kaplan-Meier-estimated 3-year overall survival (OS) was 45% for all patients, 32% for group 1 and 62%, for group 2, respectively (p=0.02), with more patients with high risk constellation in group 1. 3-year OS for patients transplanted with MUD was 57%, with MMUD 46% vs. with MRD 0% (p=0.01). Non-relapse-mortality was 28% for all patients, 40% in group 1 and 12% in group 2, probably due to the higher intensity in conditioning in group 1. The outcomes with intermediate, low and minimal intensity conditioning were comparable, while all patients after high intensity conditioning died. Table 1 describes Kaplan-Meier estimated 3-year-OS and statistical univariate analysis by log-rank test in the different subgroups. Table 1. 3-year OS (in%) All Group 1 Age 60–65 Group 2 Age 66–76 Remission CR 52 p=0.25 31 p=0.76 77 p=0.15 PR 40 32 50 Conditioning high 0 p=0.5 0 p=0.08 – p=0.38 intermediate 52 50 53 low 48 43 57 minimal 45 17 67 Donor MRD 0 p=0.01 0 p=0.06 73 p=0.45 MUD 57 53 65 MMUD 46 40 33 GVHD acute no 18 p=0.003 13 p=0.008 33 p=0.27 ≥II 43 53 58 chronic no 39 p=0.25 36 p=0.70 52 p=0.08 limited 52 30 100 extensive 50 30 67 In group 1 the outcome of minimal conditioning was inferior compared to intermediate and low conditioning while patients in group 2 had a better outcome with minimal vs. low and intermediate conditioning. Incidences of acute GVHD ≥II, limited and extensive chronic GVHD (cGVHD) were 10%, 28% and 13%, respectively. In group 1, acute GVHD ≥II occurred in 13% and cGVHD in 35%, in group 2 in 5% and 41% of the patients, respectively. Acute GVHD ≥II was associated with inferior outcome (3-year OS of 18% vs. 43%, p=0.003) while cGVHD had a positive impact on OS. In group 2 patients with limited cGVHD showed better 3-year OS than patients without cGVHD (67% vs. 52%, p=0.12). Age alone had no major impact on outcome of allogeneic HCT. Patients aged ≥60 seemed to benefit from the use of MUD rather than an older MRD. Chronic GVHD had a positive influence on survival. Our data indicate that the regimen used should be tailored to disease risk and patient performance status. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Non-Infectious Pulmonary Toxicity after Allogeneic Hematopoietic Cell Transplantation (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Sagar S. Patel ◽  
Kwang Woo Ahn ◽  
Manoj Khanal ◽  
Caitrin Fretham ◽  
Celalettin Ustun ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lower Risk ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Marrow Transplant ◽  
Smoking History ◽  
Platelet Recovery ◽  
Increased Risk

Introduction Early non-infectious pulmonary toxicity (NIPT) is a significant HCT complication and comprises diffuse alveolar hemorrhage (DAH), idiopathic pneumonia syndrome (IPS), and cryptogenic organizing pneumonia (COP) with an overall incidence ranging 1-10%. Treatment options are primarily immunosuppressive therapy and supportive care with limited efficacy. Mortality in IPS, for example, approaches 60-80% (PMID: 21531955). Therefore, to better identify potentially high-risk patients (pts) we performed a registry-based analysis of the incidence, risk factors, and outcomes of early NIPT after HCT. Methods This retrospective study included adult pts undergoing allogenic HCT for hematologic malignancies and non-malignant disorders as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2017). Data analyses were divided into four common disease categories (AML/ALL, CML/MDS/MPN, NHL/CLL/PCD, and non-malignant diseases) to minimize statistical interactions in the multivariate model. The primary outcome was the incidence of and risk factors for individual NIPT and a composite of the three NIPT (IPS, DAH, COP); the secondary outcome was overall survival (OS). Multivariable Cox proportional hazards regression models were developed to identify the risk factors for NIPT and OS. In addition to baseline pre-transplant covariates, post-transplant neutrophil recovery (&gt;500/mcL x 3 consecutive days), platelet recovery (&gt;20k/mcL x 3 consecutive days, without transfusion in 7 previous days) and grade 2-4 acute GVHD were included as time-dependent covariates in the multivariable models. Results Characteristics of 21,587 adult pts are shown in Table 1. Median age at HCT was 54 years, 59% were male, and 39% had KPS &lt;90. Median follow-up was 49 months. Per the HCT-Comorbidity Index (HCT-CI), 15% and 24% of pts had a severe (FEV1 and/or DLCO≤65%, dyspnea at rest, requiring supplemental oxygen) and moderate (FEV1 and/or DLCO 66-80%, dyspnea on slight activity) pulmonary comorbidity, respectively. Pre-transplant, 3% of pts had a history of mechanical ventilation, 5% had a history of pulmonary fungal infection, and 40% reported a smoking history. Most pts had a matched sibling or unrelated donor (68%) and received peripheral blood graft (71%). Myeloablative conditioning was used in 49% pts, and 39% received total body irradiation (TBI). Table 2 shows the cumulative incidence of early NIPT amongst pts in the four disease categories. Multivariable analysis in the AML/ALL group identified TBI-based conditioning, grade 2-4 acute GVHD, HCT-CI score of 1-3, and prior autologous HCT were associated with increased risk of NIPT, while platelet recovery decreased the risk of NIPT. In the CML/MDS/MPN group, smoking history, grade 2-4 acute GVHD and HCT-CI scores of 2-5+ were associated with increased risk of NIPT, while non-TBI and non-myeloablative TBI conditioning and platelet recovery were associated with a lower risk. In the NHL/HD/CLL/PCD group, a higher risk of NIPT was seen with severe pulmonary comorbidity pre-HCT and chronic GVHD, while platelet recovery and non-TBI regimens were associated with a lower risk. In the non-malignant disease group, both neutrophil and platelet recovery were associated with a lower risk of NIPT. Furthermore, the multivariable analysis for OS (Table 2) showed across all disease groups, NIPT increased the risk of mortality (vs. no NIPT; HR of 4.3 in AML/ALL, 4.1 in CML/MDS/MPN, 3.5 in NHL/CLL/PCD, 6.8 in non-malignant diseases; p&lt;0.0001). Conclusions This large registry-based analysis of allogeneic HCT pts highlights several risk factors for the development of early NIPT including smoking history, severe pulmonary comorbidity, myeloablative TBI conditioning, and acute and/or chronic GVHD. Identification of these risk factors can enhance appropriate selection of pts prior to HCT. We also found that post-transplant, platelet and neutrophil recovery was associated with a reduced risk of NIPT. Furthermore, early NIPT is associated with a several-fold higher mortality risk in the current era despite significant advances in supportive care. Future studies are needed to optimize risk factors such as conditioning regimen and graft source selection to reduce the risk of early NIPT. Disclosures Ustun: Kadmon: Honoraria. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Mallinckrodt: Honoraria. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. . Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding.

scholarly journals Validation of Minnesota Acute GVHD Risk Score and Identification of New Factors Associated with Initial Response to Steroids: Not All GVHD Is Created Equal

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 67-67
Author(s):  
Margaret L. MacMillan ◽  
Shernan G. Holtan ◽  
Armin Rashidi ◽  
Todd E. DeFor ◽  
Claudio G Brunstein ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Steroid Therapy ◽  
Early Onset ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Risk Scores ◽  
Increased Risk ◽  
Better Than

Abstract Introduction: We recently reported on the Minnesota acute GVHD Risk Score that is based on the number of involved organs and severity of GVHD at onset. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. Patients with HR GVHD were 3 times less likely to respond to steroid therapy and had >2 fold increased risk of mortality and transplant-related mortality (TRM) than patients in the standard risk (SR) GVHD group. This GVHD Risk Score more accurately predicts response, survival and TRM than other published GVHD risk scores based upon clinical grading criteria (BBMT.2015,21:761). Methods: To validate this Risk Score, we examined a new cohort (2008-2016) of 355 patients (median age 49 years, range <1-75) at the University of Minnesota diagnosed with acute GVHD and treated with prednisone 60 mg/m2/d for 14 days, followed by an 8-week taper. Results: All patients had >6 months follow-up after steroid initiation (median 3.2 years). 79 (22%) patients had HR GVHD and 276 (78%) had SR GVHD. Demographics were similar in the two groups (Table). Overall response [complete response (CR)+partial response (PR)] was significantly higher in the 276 SR vs 79 HR GVHD patients at day 14 (71% vs 56%, p<0.01), day 28 (74% vs 59%, p=0.02) and day 56 (68% vs. 49%, p<0.01) after steroid initiation (Figure A). Day 28 CR/PR did not differ by initial GVHD grade being 64%, 77%, 65% and 50% for grade I, II, III and IV (p=0.07). HR GVHD was observed in 31% single UCBT recipients, 19% double UCBT recipients and 22% BMT/PBSCT recipients. Notably, Day 28 responses were significantly higher in UCB recipients than others (Figure B). In multiple regression analysis, the odds of day 28 CR/PR were lower in HR vs SR GVHD patients (OR 0.5, 95% CI 0.3-0.8) and in HLA matched URD donor vs other recipients (OR 0.5, 95% CI,0.3-1.1, p<0.01). OR of response was 2 fold higher in UCB (OR 2.2, 95% CI,1.3-3.7, p=0.01) vs. BM/PBSC recipients. Factors significantly associated with greater 2 year TRM included HR GVHD (HR 1.4, 95% CI,1.0-1.9, p=0.05), age ≥60 years (HR 1.7, 95% CI,1.1-2.8, p=0.02) and high risk HCT-comorbidity index (HCT-CI; HR 1.6, 95% CI,1.1-2.2, p=0.01). Similarly, mortality at 2 years was higher in HR GVHD (HR 1.7, 95% CI,1.2-2.4, p<0.01), high risk HCT-CI (HR 1.8, 95% CI,1.3-2.5, p<0.01), and recipients of URD grafts HR 1.9, 95% CI,1.1-3.1, p=0.01). Mortality was lower in early onset GVHD (HR 0.95, 95% CI,0.92-0.99, p=0.04). Two years after initiation of steroid therapy, 92 patients developed chronic GVHD for a cumulative incidence of 26% (95% CI 21-31%). No differences in the incidence of chronic GVHD were observed in those with SR and HR acute GVHD (28% vs 20%, p=0.54). Risks of chronic GVHD however were significantly lower in UCB recipients (HR 0.6, 95% CI,0.5-0.9, p=0.01) and in early onset GVHD (HR 0.95, 95% CI,0.92-0.98, p<0.01), but were higher in patients with high risk HCT-CI (HR 1.7, 95% CI,1.2-2.3, p<0.01). Conclusions: This analysis confirms that the Minnesota GVHD Risk Score is a valuable, immediately available bedside tool to define risk in patients with acute GVHD and predicts outcomes better than GVHD clinical grades. These results also demonstrate the importance of age, HCT-CI, graft source, and time to onset of GVHD on outcomes after GVHD therapy. Notably, UCB recipients have better responses to steroid therapy and lower subsequent risk for chronic GVHD than other donor sources. These data suggest that a tailored approach to upfront GVHD therapy based upon the Minnesota acute GVHD Risk Score and other risk factors should be considered in order to improve outcomes in patients with acute GVHD. Further studies are needed to explore why cord blood recipients with acute GVHD respond better than BM/PBSC recipients with a similar severity of GVHD. Disclosures MacMillan: Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Holtan:Incyte: Consultancy. Brunstein:Gamidacell: Research Funding. Wagner:Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Weisdorf:SL Behring: Consultancy; Equillium: Consultancy; FATE: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy.

A Comparison of Stem Cell Source in Recipients of T-Cell Depleted Myeloablative Transplants for Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 46-46
Author(s):  
B.E. Shaw ◽  
Nigel H. Russell ◽  
A. Pagliuca ◽  
J. Apperley ◽  
G. Cook ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Increased Risk ◽  
Significant Difference ◽  
Cell Source ◽  
The Impact

Abstract The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in >90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.

scholarly journals Perinatal Cat and Dog Exposure and the Risk of Asthma and Allergy in the Urban Environment: A Systematic Review of Longitudinal Studies

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Caroline J. Lodge ◽  
Katrina J. Allen ◽  
Adrian J. Lowe ◽  
David J. Hill ◽  
Cliff S. Hosking ◽  
...  
Keyword(s):  
High Risk ◽  
Longitudinal Studies ◽  
Allergic Disease ◽  
Allergic Diseases ◽  
Risk Groups ◽  
Perinatal Period ◽  
Perinatal Exposure ◽  
Increased Risk ◽  
History Of ◽  
The Impact

Background. The literature is contradictory concerning pet exposure and the risk of development of asthma and other allergic diseases. Using longitudinal studies, we aimed to systematically review the impact of pet ownership in the critical perinatal period as a risk factor for allergies in childhood.Methods. Medline database was searched for urban cohort studies with perinatal exposure to cats and/or dogs and subsequent asthma or allergic disease.Results. Nine articles, comprising 6498 participants, met inclusion criteria. Six found a reduction in allergic disease associated with perinatal exposure to dogs or, cats or dogs. One study found no association. Two found increased risk only in high-risk groups.Conclusion. Longitudinal studies in urban populations suggest that perinatal pets, especially dogs, may reduce the development of allergic disease in those without a family history of allergy. Other unmeasured factors such as pet-keeping choices in allergic families may be confounding the association seen in these high-risk families, and further study is required.

scholarly journals Impact of Chronic Graft-Versus-Host disease (GVHD) After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) As Treatment for Acute Myeloid Leukemia (AML): A Survey From the Acute Leukemia Working Party of the EBMT

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 321-321
Author(s):  
Frederic Baron ◽  
Myriam Labopin ◽  
Dietger Niederwieser ◽  
noel-Jean Milpied ◽  
Jan J Cornelissen ◽  
...  
Keyword(s):  
Lower Risk ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Time Dependent ◽  
Graft Versus Leukemia ◽  
Grade Ii ◽  
The Impact ◽  
Risk Of Relapse ◽  
Time Point

Abstract Abstract 321 The goal of RIC allo-SCT is to harness the graft-versus-leukemia (GVL) effect, while minimizing toxicities and the risk of GVHD. However, prior studies have shown a lower risk of relapse in AML patients (pts) who experienced chronic GVHD after RIC allo-SCT versus in those who did not. Here, we investigated the impact of occurrence of GVHD on transplantation outcomes in a large cohort of AML pts given allogeneic PBSC after RIC conditioning. Data from 1859 AML pts in first (n=1439) or second (n=420) CR transplanted between 2000 and 2009 following a RIC regimen at EBMT affiliated centres were analyzed. Pts were given PBSC from HLA-identical sibling (MRD, n=1208), or from HLA-matched unrelated donors (MUD, n=651). Median pt age at transplantation was 56 y (range, 18–77). 338 male pts were given grafts from female donors. RIC was based on low-dose TBI in 520 (28%) pts, while the remaining pts received chemotherapy-based RIC. ATG was given in 269 (22%) MRD and in 267 (41%) MUD recipients, respectively, while 151 (13%) MRD and 165 (25%) MUD recipients received in-vivo T cell depletion with alemtuzumab. The impact of chronic GVHD on relapse risk, non-relapse mortality (NRM), leukemia-free survival (LFS), and overall survival (OS) was assessed using time-dependent multivariate Cox models and in a landmark analysis at 18 months after transplant. Three-year incidences of relapse, NRM, LFS and OS were 34±1%, 15±1%, 51±2% and 60±2% in MRD recipients, respectively, and 34±2% (p=NS), 24±2% (P<0.001), 42±2% (P=0.001) and 47±2% (P=0.001) in MUD recipients, respectively. Grade II, III and IV acute GVHD were observed in 133 (11%), 61 (5%) and 30 (2%) MRD recipients and in 119 (18%), 41 (6%) and 24 (4%) MUD recipients, respectively. The 3-y cumulative incidence of chronic GVHD was 47%. Fifty-three percent of patients with chronic GVHD had extensive chronic GVHD, while the remaining 47% had limited chronic GVHD. In multivariate analyses, occurrence of grade II-IV acute GVHD was associated with a lower risk of relapse (HR=0.8; P=0.04), a higher risk of chronic (HR=2.2; P<0.001) and extensive chronic GVHD (HR=2.8; P<0.001), a higher risk of NRM (HR=2.4 P<0.001), a worsened LFS (HR=1.3; P=0.01), and a worsened OS (HR=1.5; P<0.001). In multivariate time-dependent analyses, occurrence of limited chronic GVHD was associated with a lower risk of relapse (HR=0.7; P=0.05), comparable NRM (HR=1.4; P=0.16), comparable LFS (HR=0.9; P=0.29) and better OS (HR=0.5; P<0.001), while occurrence of extensive chronic GVHD was associated with a lower risk of relapse (HR=0.6; P=0.01), higher NRM (HR=3.2; P<0.001), a trend for worsened LFS (HR=1.3; P=0.06) and comparable OS (HR=0.9; P=0.34). The median interval from transplantation to occurrence of chronic GVHD was 163 (range, 100–1545) days. To further assess the graft-versus-leukemia effect of chronic GVHD, we performed a landmark analysis in patients who were leukemia-free at 18 months after transplantation (n=776). Median follow-up from this landmark time-point was 24 (range, 0.1–112) months. Two-year relapse, NRM, LFS and OS were 16±2%, 2.5±1%, 82±2%, and 89±2%, respectively, in patients without chronic GVHD before the landmark time-point, versus 9±1% (P=0.001), 8±1% (P<0.001), 83±2% (P=0.65), and 86±2% (P=0.38), respectively, in patients with chronic GVHD before the landmark time-point.In conclusion, in this cohort of AML patients transplanted in remission, occurrence of chronic GVHD was associated with a lower risk of relapse that translated to better OS in patients with limited chronic GVHD but not in those with extensive chronic GVHD who experienced higher long term NRM, highlighting the need for long term prospective assessment of long term effects and quality of life in patients receiving RIC allo-SCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pre-transplant Marital status and Hematopoietic Cell Transplantation Outcomes

2020 ◽  
Vol 27 (6) ◽  
Author(s):  
J. Tay ◽  
S. Beattie ◽  
C. Bredeson ◽  
R. Brazauskas ◽  
N. He ◽  
...  
Keyword(s):  
Social Support ◽  
Marital Status ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Increased Risk ◽  
The Impact

Background Evidence regarding the impact of pre-hematopoietic cell transplantation (HCT) marital status on post-HCT outcomes is conflicting. Methods We identified patients, ≥40-years within the Center for International Blood and Marrow Transplant Research registry who received a HCT between January 2008 and December 2015. Pre-HCT marital status was declared as either 1) Married/living with a partner, 2) Single/never married, 3) Separated/divorced, and 4) Widowed. We performed multivariable analysis to determine the association of marital stsatus with post-HCT outcomes. Results We identified 10,226 allogeneic and 5,714 autologous HCT patients with a median follow-up of 37 months (range 1-102) and 40 months (range 1-106) respectively. There was no association between marital status and OS in both allogeneic (p=0.58) and autologous (p=0.17) settings. However, marital status was associated with grade 2-4 acute GVHD (p<0.001) and chronic GVHD (p=0.04). There was an increased risk of grade 2-4 acute GVHD in separated patients compared with married patients [HR 1.13, 95%CI (1.03-1.24)], while single patients had a reduced risk of grade 2-4 acute GVHD [HR 0.87, 95%CI (0.77-0.98)]. The risk of chronic GVHD was lower in widowed patients [HR 0.82, 95%CI (0.67-0.99)] compared with married patients. Conclusions OS post-HCT is not influenced by marital status, but there are associations between marital status and grade 2-4 acute and chronic GVHD. Future research should consider measuring social support using validated scales, patient and caregiver reports of caregiver commitment, and assess health-related quality of life together with health-care utilization to better appreciate the impact of marital status and social support.

SNP12 and SNP13 Variants of NOD2/CARD15 Gene of Donor and Recipient as Independent Risk Factors for Severe Intestinal and Pulmonary GVHD after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3242-3242
Author(s):  
Alexandra Holowiecka-Goral ◽  
Jerzy Wojnar ◽  
Sebastian Giebel ◽  
Elzbieta Grudziecka ◽  
Malgorzata Oczko ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Card15 Gene ◽  
The Impact ◽  
Grade Iii

Abstract Background: Presence of any of single nucleotide polymorphism (SNPs) of the NOD2/CARD15 gene have been recently proven to correlate with higher rate of GvHD after allogeneic hematopoietic stem cell transplantation - alloHSCT (Holler E et al; Blood2006,107,4189). Mutated variants lead to impaired antibacterial response. As NOD2/CARD15 is expressed not only in monocytets/macrophages but also in both intestinal and bronchial epithelial cells these organs seem to be a major target for developing advanced GvHD. Patients and methods: The impact of each single donor (D) and recipient (R) SNPs (8,12,13) of NOD2/CARD15 gene on the incidence of acute GvHD (grade II-IV, grade III-IV, intestinal), chronic GvHD (overall, extensive, pulmonary), survival, and non-relapse mortality was evaluated in a setting of 72 patients treated with alloHSCT in single BMT center in Katowice between Jan 2000 and Jun 2005. Median patient age was 33 (11–52) years. In 70/72 cases hematological malignancies were indication for alloHSCT. Conditioning regimen was myeloablative in all cases, bone marrow was used as the only source of stem cells in 74% of patients. GVHD prophylaxis consisted of CsA, Mtx and, in case of URD-HSCT - antithymocyte globulin. Results: In univariate and multivariate analysis, including other potential risk factors, the presence of SNP12 in the recipient was associated with increased incidence of intestinal acute GVHD (75% vs. 29%; RR 4,37, p=0,03), overall chronic GVHD (100% vs. 50%, RR 4,72; p=0,003), extensive chronic GVHD (80% vs. 24%; RR 5,12; p=0,02), and pulmonary chronic GVHD (47% vs. 9%; RR 5,97; p=0,02). SNP13 in the recipient resulted in increased incidence of grade III–IV acute GVHD (45% vs. 12%; RR 4,66; p=0,01), intestinal acute GVHD (64% vs. 24%; RR 4,21, p=0,005), and extensive chronic GVHD (55% vs. 25%; RR 3,59; p=0,03). SNP13D in the donor contributed to increased risk of pulmonary chronic GVHD (36% vs. 8%; RR 6,58; p=0,01). In this single centre analysis we were not able to demonstrate the impact of NOD2/CARD15 SNPs on survival. Conclusion: The presence of particular mutations of NOD2/CARD15 in the recipient and/or the donor is associated with increased risk of severe acute and chronic GVHD. In particular, intestines and lungs appear to be target organs of these complications. Our findings may contribute to optimization of immunosuppressive and gastrointestinal decontamination regimens based on individual risk assessment for GVHD.

scholarly journals The Impact of Marital Status on Hematopoietic Stem Cell Transplant (HCT) Recipient Outcomes: A Surrogate for Consistent Caregiver. a CIBMTR Registry Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4788-4788 ◽  
Author(s):  
Jason Tay ◽  
Ruta Brazauskas ◽  
Naya He ◽  
Sara Beattie ◽  
Christopher Bredeson ◽  
...  
Keyword(s):  
Social Support ◽  
Overall Survival ◽  
Marital Status ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Allogeneic Hct ◽  
Increased Risk ◽  
The Impact

Abstract Background Current literature suggests that the presence and quality of social support may provide meaningful benefits in overall survival of HCT recipients. Further, studies in general oncology and renal transplantation population suggest that married patients have favorable outcomes. Caregivers of HCT recipients are an important source of both instrumental and emotional support, and a reasonable surrogate for presence of social support. Using data from Center for International Blood and Marrow Transplant Research (CIBMTR), we examined the potential influence of marital status (surrogate for caregiver) at the time of HCT on outcomes of HCT. Methods Patients, >40 years of age who underwent either autologous or allogeneic-HCT from 2008 to 2015 were included. Marital status was defined as either 1) Married, 2) Single, never married, 3) Separated/divorced, and 4) Widowed. The probability of OS at 5 years, Grade 2-4 acute GVHD at 100 days and chronic GVHD at 2 years were estimated as appropriate using the Kaplan-Meier method with the log-rank test used for univariate comparisons. Multivariate analysis was performed to determine the association of marital status with these outcomes, while adjusting for clinical and sociodemographic variables. Results We identified 10,226 allogeneic and 5,714 autologous HCT patients; the median follow-up of survivors was 37 months (range 1-102 months) and 40 months (range 1-106 months) respectively. In the allogeneic population, there were n=7,999 married, n=741 single, n=1,175 separated/divorced and n=311 widowed patients. There were n=4,308, n=478, n=695 and n=233 respectively in the autologous population. The baseline characteristics amongst the 4 groups of marital status were comparable. In the allogeneic population, the 5-year probability of OS, 100-day Grade 2-4 acute GVHD, 2-year probability of chronic GVHD were 38% [95%CI (36-39%)], 16% [95%CI (15-17%)]and 46% [95%CI (45-47%)] respectively; while the 5-year probability of OS in the autologous population was 63% [95%CI (61-64%)]. When compared with married patients, single, separated/divorced and widowed patients were not at an increased risk of death [HR 1.09, 95%CI (0.98-1.2); HR 1.01, 95%CI (0.93-1.09); HR 1.09, 95%CI (0.98-1.2)] in the allogeneic setting. Similarly, there was no association of marital status and OS in the autologous setting [HR 1.10, 95%CI (0.92-1.33); HR 1.17, 95%CI (1.01-1.36); HR 1.08, 95%CI (0.86-1.37)] respectively. In contrast, marital status in the allogeneic setting was associated with an increased risk of grade 2-4 acute GVHD in patients who are divorced/separated as compared to married patients [HR 1.13, 95%CI (1.03-1.24)] but not chronic GVHD [HR 0.90, 95%CI (0.80-1.02); HR 0.94, 95%CI (0.86-1.04); HR 0.82, 95%CI (0.68-0.99)] respectively. We did not identify an interaction between marital status and gender. Conclusions Our data suggest the marital status in patients undergoing either autologous or allogeneic HCT is not associated with overall survival or chronic GVHD, while the risk of acute GVHD maybe increased in patients who are divorced/separated. Taken together, the effect of marital status on post-HCT outcomes is negligible when other patient, disease and transplant variables are considered. Alternatively, marital status maybe an imperfect marker for positive social support. Future research should consider measuring social support using validated scales and assess health related quality of life together with health care utilization outcomes to better appreciate the potential impact of social support. Disclosures No relevant conflicts of interest to declare.

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