HCT-CI Has Prognostic Value in Acute, but Not Chronic Gvhd Specific Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3915-3915
Author(s):  
Marc Poch Martell ◽  
Nada Hamad ◽  
Fotios V. Michelis ◽  
Jieun Uhm ◽  
Feras Alfraih ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Immunosuppressive Treatment ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Allogeneic Hct

Abstract Introduction : Graft-versus-host disease (GVHD) is a major cause of treatment failure in allogeneic hematopoietic cell transplantation (HCT). The hematopoietic cell transplant-specific comorbidity index (HCT-CI) predicts transplant-related mortality (Sorror, et al: Blood, 2005; Raimondi, et al: Blood, 2012), but its prognostic value has not been well explored in the setting of GVHD. It is hypothesized that patients with a high HCT-CI score would have worse outcomes after developing GVHD compared to those with a low HCT-CI score. In this retrospective study we calculated the pre-transplant HCT-CI and analysed its relationship with GVHD specific survival (GSS). Methods : A total of 541 patients who received allogeneic HCT at Princess Margaret Cancer Centre between 2000 and 2012 were included in this retrospective cohort study. The GSS was defined as the time from diagnosis of GVHD (for acute and chronic GVHD separately) until death from a GVHD-related cause, including organ dysfunction directly related to GVHD and infection in the setting of GVHD and immunosuppressive treatment. The GSS in relation to the HCT-CI was analysed using the Cox proportional hazard regression model. The GSS was plotted using the Kaplan-Meier method and the Log-rank test was used for comparison. Results : The incidence of all grades of acute GVHD and grade 2-4 acute GVHD was 68.7±2.1% and 54.9±2.3%, respectively. The incidence of chronic GVHD by the NIH consensus criteria was 72.9±2.8%. With a median follow-up duration of 24 months among survivors after a diagnosis of GVHD, the 2-year rates of acute GSS (aGSS) and chronic GSS (cGSS) were 60.7±2.9 and 74.6±2.7%, respectively. Univariate analysis demonstrated that the HCT-CI score as a continuous variable was prognostic for aGSS (p=0.001, HR 1.198, 95% CI [1.082-1.325]), showing that an increase in the HCT-CI score by 1 resulted in an increase in mortality by 20%. However, for cGSS, there was only borderline statistical significance with a p-value of 0.068 (HR 1.130 95% CI [0.991-1.289]). Patients were divided into 3 groups according to their HCT-CI score: 0-1(n=232, 42.9%), 2-4 (n=267, 49.4%) and ≥5 (n=42, 7.8%). The HCT-CI was able to stratify patients in relation to aGSS (p=0.001): The 2 year aGSS rate was 72.0±3.9% in those with an HCT-CI of 0-1 (n=148), 53.6±4.4% with an HCT-CI of 2-4 (n=173), and 35.6±11.5% with an HCT-CI of ≥5 (n=25). In contrast, no correlation was found with cGSS among the 3 groups (p=0.355). The 2 year cGSS rate was 79.5±3.6% in patients with an HCT-CI of 0-1 (n=141), 70.5±4.3% with an HCT-CI of 2-4 (n=149), and 63.2±14.0% with an HCT-CI of ≥5 (n=24). A multivariable analysis was performed to confirm the HCT-CI score as an independent prognostic factor for GSS, accounting for the following covariates: age, donor type, source of stem cells, and severity of acute GVHD (grade 3-4 vs others) and chronic GVHD (NIH global score mild, moderate and severe). The HCT-CI was found to be an independent risk factor for aGSS (p=0.016, HR 1.15, 95% CI [1.03-1.3]), but not for cGSS (p=0.80, HR 1.02, 95% CI [0.84-1.2]). Conclusion : Patients undergoing allogeneic HCT with significant comorbidities prior to transplant demonstrated by a higher HCT-CI have a shorter GSS. This finding is only significant for survival following acute GVHD (i.e. acute GSS), but not for chronic GVHD. This study suggests that the HCT-CI score may provide additional prognostic information in the assessment of the risk of acute GVHD related outcomes but not chronic GVHD outcomes, and that the assessment of HCT-CI score prior to HCT may be useful in risk adaptive preventive and treatment strategies for GVHD. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcome Following Second Allogeneic Hematopoietic Cell Transplantation: A Single Centre Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5838-5838
Author(s):  
Hassan A. Aljasem ◽  
Hans A. Messner ◽  
Jeffrey H. Lipton ◽  
Dennis Dong Hwan Kim ◽  
Auro Viswabandya ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Graft Failure ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Single Centre ◽  
Platelet Recovery ◽  
Allogeneic Hct

Abstract Second allogeneic hematopoietic cell transplant (HCT) may be indicated for relapsed hematological malignancies or graft failure. However, there are limited data in the literature concerning outcome post second allogeneic HCT. The purpose of the presented study was to investigate parameters that may influence outcome post second allogeneic HCT. This single centre retrospective study at the Princess Margaret Cancer Centre examined 92 patients that underwent second HCT from 1980-2015. First HCT was done for patients with median age 35 years (range 9-68), for various hematological diseases (AML 26 patients, CML 28 patients, aplastic anemia 14 patients, ALL 11 patients, other diseases 13 patients). Donors were related for 78 patients (85%) versus unrelated for 14 (15%). Graft was bone marrow for 71 patients (77%) versus peripheral blood stem cells (PBSC) for 21 (23%). For the second HCT, median age was 40 years (range 16-69, age ≤40 n=46, >40 n=46). The indication for second HCT was either relapsed hematologic malignancy for 59 patients (64%, 12 patients relapsed ≤6 months post first HCT), versus graft failure for 33 patients (36%). The median time from first HCT until relapse or graft failure was 11 months (1-206 months). The median time from first HCT until second HCT was 18 months (range 1-212). Year second HCT was performed was grouped into 1980-1995 (n=28), 1996-2005 (n=42), 2006-2015 (n= 22). Fifty-two patients (57%) had ECOG 0-1 versus 40 patients (43%) with ECOG 2-3. Preparative regimen was myeloablative (MA) for 47 (51%) versus 45 with other regimens (49%). Calcineurin inhibitor-based GVHD prophylaxis was used in 75 patients (82%). Eighty-three patients (90%) used the same donor versus only 9 patients (10%) which had a different donor. The type of graft at second HCT was PBSC in 54 patients (59%) versus BM for 38 patients (41%). Among the 82 patients with count recovery data, median neutrophil count ≥0.5/µL was 18 days (range 8-54), and platelet recovery ≥20/µL was 16 days (range 10-88). Among the 66 patients that died, cause of death was relapse in 17 patients (26%), infection in 18 patients (27%), GVHD in 6 patients (9%), graft failure in 6 patients (9%) and other complications in 19 patients (29%). Median follow up of survivors was 120 months (range 5-286). Three-year overall survival (OS) of the entire cohort was 35% (95% CI=25-45) (Figure 1). Univariate analysis for OS examined second HCT indication (3-year OS 43% for relapse versus 20% for graft failure, p=0.02), ECOG score (3-year OS 48% for ECOG 0-1 versus 18% for ECOG ≥2, p=0.0006, Figure 2), time from first HCT to relapse/graft failure (3-year OS for <12 months 21% versus ≥12 months 46%, p=0.009), preparative regimens (3-year OS for MA 42% versus other regimens 23%, p=0.08). Age at second HCT (≤40 versus >40 years, p=0.2), time period second HCT was performed (p=0.7), use of different donor (p=0.3) and graft source for second HCT (p=1.0) were not significant. Multivariable analysis for OS demonstrated ECOG score at second HCT (HR=2.15 for ECOG ≥2, 95% CI=1.32-3.51, p=0.002) and indication for second HCT (HR=1.67 for graft failure, 95%CI=1.02-2.75, p=0.04) to be the only independent prognostic variables influencing survival in this cohort. In conclusion, second HCT may provide prolonged survival, particularly for patients transplanted for relapsed disease following first HCT, and with a favorable performance status. Disclosures Lipton: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Serious Acute or Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplantation: A Comparison of Myeloablative and Non-Myeloablative Conditioning Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 755-755
Author(s):  
Olga Sala-Torra ◽  
Paul J. Martin ◽  
Barry Storer ◽  
Mohamed Sorror ◽  
Rainer F. Storb ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Co Morbidity

Abstract We have previously described serious graft-versus-host disease (GVHD) as a highly undesirable outcome after allogeneic hematopoietic cell transplantation (HCT). Serious GVHD encompasses death, lengthy hospitalization, major disability, or recurrent major infections related to either acute or chronic GVHD. In a previous study, we found a 25% incidence of serious GVHD among 171 consecutive patients who had HCT after non-myeloablative (NMA) conditioning between January 1998 and May 2002. To put this observation into perspective, we applied the same criteria for serious GVHD in a cohort of 264 consecutive patients who had HCT after myeloablative (MA) conditioning during the same period of time and compared results with those of the previous study. The overall incidence of serious GVHD was 17% (44/264) in the MA group, compared to 25% (43/171) in the NMA group. There were no statistically significant differences in the incidence of grades III–IV GVHD, extensive chronic GVHD or nonrelapse mortality between the two groups (Table). Patients in the NMA group were older and had higher comorbidity scores than those in the MA group. In the univariate analysis, the hazard ratio (HR) of serious GVHD for the NMA group compared to the MA group was 1.71 (95% C.I., 1.1–2.6) (p = 0.01). After adjusting for patient age, patient and donor gender, donor type, HLA-mismatch, aggressive versus indolent malignancy at HCT, remission versus relapse at HCT, myeloid versus non–myeloid malignancy, HCT co–morbidity index, and prior donor lymphocyte infusion, the HR of serious GVHD was 1.50 (95% C.I., 0.8–2.7) (p = 0.17). After censoring for recurrent or progressive malignancy after HCT, the cumulative incidence of serious GVHD at 3 years was 21% for the NMA group and 14% for the MA group, and the HR was 1.33 (95% C.I., 0.7–2.6) (p = 0.40). Reasons for categorization of GVHD as serious (i.e., death, lengthy hospitalization, major disability, or recurrent major infections) were similar between the MA and NMA cohorts. Among the 44 patients with serious GVHD in the MA group, 19 (43%) had serious acute GVHD, and 25 (57%) had serious chronic GVHD. Among the 43 patients with serious GVHD in the NMA group, 20 (46%) had serious acute GVHD, and 30 (70%) had serious chronic GVHD. Among the 264 MA patients, 28 (11%) had grade III–IV acute GVHD and 147 (56%) had extensive chronic GVHD that did not meet the criteria for serious GVHD, compared to 7 (4%) and 84 (49%) of the 171 NMA patients, respectively. We conclude that the type of pretransplant conditioning regimen does not have a large effect on the incidence of serious GVHD after HCT. Assessment of serious GVHD provides additional useful information to acute GVHD grades and the classification of limited and extensive chronic GVHD in describing overall GVHD-related outcomes after HCT. MA NMA Outcome, n (%) n = 264 n = 171 Serious GVHD 44 (17) 43 (25) Grades III–IV acute GVHD 54 (20) 27 (16) Extensive chronic GVHD 174 (66) 114 (68) 2-year nonrelapse mortality 66 (25) 43 (25)

Association Between Genetic Variants in Immune Response Genes and Outcomes After Hematopoietic Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3049-3049
Author(s):  
Bharat Thyagarajan ◽  
Scott Jackson ◽  
Saonli Basu ◽  
Pamala A. Jacobson ◽  
Myron D Gross ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Genetic Variants ◽  
Acute Gvhd ◽  
Cytokine Response ◽  
Innate Immune ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Allogeneic Hct ◽  
Increased Risk

Abstract Abstract 3049 Background: Despite rapid advances in allogeneic hematopoietic cell transplant (HCT) techniques, the procedure continues to be associated with a high morbidity and mortality with transplant related mortality (TRM) ranging from 15% to as high as 50%. Acute graft versus host disease (GvHD) remains a major cause of morbidity and an important cause of early TRM in patients undergoing allogeneic HCT. Though variations in major histocompatibiliy (MHC) genes are well known determinants of acute GvHD, there is increasing evidence that genetic variation in immune/cytokine response pathways also contributes significantly to the pathogenesis of acute GvHD. Methods: We evaluated the association of single nucleotide polymorphisms (SNPs) in non-MHC dependent immune/cytokine response pathways (n= 77 SNPs in recipients and donors) with acute GvHD and TRM at one year in a cohort of 425 recipient-donor pairs who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota between 1998 and 2007. We used a Fine and Gray proportional hazards model adjusted for competing risk to evaluate the association between the genetic variants and time to acute GvHD and time to TRM. Results: After adjustment for recipient age at transplant, race, diagnosis, disease status at transplant, gender mismatch, CMV serostatus of recipient and donor, recipient and donor sex, donor type, conditioning regimen (myeloablative or reduced intensity) and year of transplant, one recipient SNP, rs646005 in the TIRAP gene and one donor SNP, rs2232596 in the LBP gene were marginally associated with increased risk for grade II-IV acute GvHD (Hazard ratio (HR) = 1.33 (95% Confidence interval (CI): 1.07 – 1.62) and 1.32 (1.07 – 1.66) respectively; p =0.01). Similar analyses for TRM showed recipient SNP rs5498 in the ICAM1 gene was associated with a decreased risk of TRM (HR: 0.67(95% CI: 0.50 – 0.89); p=0.0006) while recipient SNPs rs1739654 in the LBP gene and rs3804100 in the TLR2 gene were associated with an increased TRM risk (HR: 1.86 (95% CI: 1.16 – 2.97) and 1.66 (95% CI: 1.11 – 2.48) respectively; p =0.01). Conclusions: These findings are consistent with previous reports that support a role for genetic variants in the innate immune response pathways among both recipients and donors can influence the risk of acute GvHD and TRM among patients undergoing allogeneic HCT. These findings indicate that a systematic search for genetic variants in the innate immune response pathways may identify novel biomarkers that can be used to identify patients at high risk for acute GvHD and TRM. Disclosures: Weisdorf: Genzyme: Consultancy, Research Funding.

Significance of Busulfan Dose Intensity On Outcomes of Hematopoietic Cell Allografting for AML in Second Complete Remission or Beyond: A Report From the EBMT Acute Leukemia Working Party

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1929-1929
Author(s):  
Ali Bazarbachi ◽  
Myriam Labopin ◽  
Mohamed A. Kharfan-Dabaja ◽  
Gérard Socié ◽  
Nicolaus Kröger ◽  
...  
Keyword(s):  
Complete Remission ◽  
Cumulative Dose ◽  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Number Of Patients ◽  
Donor Source

Abstract Abstract 1929 Background: Allogeneic hematopoietic cell transplantation (HCT) is associated with inferior outcomes in patients with more advanced stage AML. In such cases, reducing the ablative intensity of the preparative regimen could potentially compromise its efficacy. We hereby compare transplant outcomes of two preparative regimens, known as FB2 and FB4, in patients (pts) with AML transplanted in second complete remission (CR2) or beyond at EBMT participating centers. Materials and methods: Between 2003 and 2010, 128 (FB2=88 (69%), FB4=40 (31%)) pts with a median age of (FB2=60 (22–70) years, FB4=42 (19–65) years, p<0.0001), with AML in ≥CR2 (FB2 (CR2=85 (97%), CR3=3 (3%)); FB4 (CR2=38 (95%), CR3=2 (5%)), p=0.67, underwent allogeneic HCT. FB2 comprised intravenous (IV) busulfan cumulative dose of 6.4 ± 10% mg/kg, while FB4 cumulative dose was 12.8 ± 10% mg/kg. Cytogenetic risks groups were similar: FB2 (good=17, int=31, poor=6) and FB4 (good=6, int=7, poor=0), p=0.35. For pts treated with FB2, donor source consisted of matched-related donors (MRD)=32, matched unrelated donor (MUD)=39, mismatched unrelated donors (MMUD)=8, unknown=9. For FB4, donor source consisted of MRD=17, MUD=15, MMUD=6, unknown=2. Use of peripheral blood stem cells (PBSC) was higher in the FB2 group (92% vs. 70%, p=0.001). Administration of anti-thymocyte globulin (ATG) was also higher in FB2 conditioned patients (89% vs. 45%, p<0.0001). Results: Median follow-up time was 24 (3–76) months. Median time to absolute neutrophil count engraftment (days) was 16 (5–38) and 16 (9–29) days, for FB2 and FB4, respectively (p=0.45). The 2-year leukemia-free survival (LFS), cumulative incidence of relapse (CI-R), and of non-relapse mortality (NRM) was: LFS (FB2=47±5% vs. FB4=70±8%, p=0.01), CI-R (FB2=27±5% vs. FB4=19±7%, p=0.24), and NRM (FB2=25±5% vs. FB4=10±5%, p=0.06). The 2-year cumulative incidence of chronic GVHD was similar (FB2=41±6% vs. FB4=43±8%, p=0.8). On multivariable analysis, favorable impact on 2-year LFS was observed with FB4 conditioning (HR 0.66 (95%CI: 0.46–0.97), p=0.03) and with longer interval from diagnosis to transplantation (> median) (HR=0.49 (95%CI: 0.29,0.85), p=0.01). When the analysis was performed by age groups, the statistical advantage of FB4 on LFS was lost, likely because of small numbers in each subgroup. Indeed, for pts <50 yrs. (n=43; FB2=16, FB4=27), LFS was (FB2=50±13% vs. FB4=72±9%, p=0.11), whereas for pts ≥50 yrs. (n=85, FB2=72, FB4=13), LFS was (FB2=47±6% vs. FB4=67±13%, p=0.18). Conclusion: Although limited by the small number of patients, these results suggest that FB4 is a reasonable preferred conditioning in patients with AML in ≥CR2. Disclosures: No relevant conflicts of interest to declare.

Impact Of Total Nucleated Cell and CD34+ Cell Dose On Transplant Related Outcomes In Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplants

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2048-2048 ◽  
Author(s):  
Paul Martin ◽  
Shuli Li ◽  
Edwin P. Alyea ◽  
Vincent T. Ho ◽  
Corey S. Cutler ◽  
...  
Keyword(s):  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Reduced Intensity Conditioning ◽  
Allogeneic Hct ◽  
Cell Dose ◽  
The Impact ◽  
Reduced Intensity

Abstract Background Mobilized peripheral blood (PB) is the most common graft source for allogeneic hematopoietic transplantation (HCT) following reduced intensity conditioning (RIC). The impact, if any, of donor PB graft composition on major transplant outcomes in the RIC allogeneic HCT setting remains incompletely understood. Existing studies have focused primarily on CD34+ cell dose and report conflicting results, especially in relation to survival. The impact of total nucleated cell (TNC) dose has been less frequently evaluated, but limited studies with relatively small cohort sizes have reported higher TNC dose to be associated with improved survival. Methods In order to further explore the relationship between PB donor CD34+ cell dose, TNC dose and RIC HCT outcomes, we assessed 705 adult patients with hematological malignancies who underwent RIC allogeneic HCT at Dana Farber Cancer Institute/ Brigham and Women's Hospital (DFCI/BWH) between 2000 and 2010. The vast majority received a RIC regimen of fludarabine and busulfan (n=698). GVHD prophylaxis was tacrolimus based with or without sirolimus (524 vs. 171, respectively). Recipients of in vivo T-cell depletion (TCD) with antithymocyte globulin or ex-vivo TCD were excluded. The median age was 57 years (range,18-74). Patient's disease risk index (DRI) was categorized as low (n=164), intermediate (n=350), high (n=170) or very high (n=21) per Armand, et al (Blood, 2012). Transplants were categorized as matched (MRD n=273, MUD n=374) or mismatched (MMRD n=4, MMUD n=58). Results There was weak correlation between CD34+ cell dose and TNC (Spearman coefficient 0.25 [0.18-0.32]), and between CD34+/kg and TNC/kg with coefficient 0.25 [0.26, 0.39]. Cell doses for TNC effects were evaluated by quartiles. On multivariable analysis including age, DRI, donor source, gender, and CMV serostatus, higher TNC dose (top quartile, ≥10.8 x 10^10 cells) was independently associated with increased chronic GVHD (HR 1.33 [1.06-1.67], p=0.015) as well as decreased relapse (HR 0.74 [0.58-0.94], p=0.015). There was no effect on acute GVHD, engraftment, or non-relapse mortality. Importantly, higher TNC dose was associated with improved overall survival (HR 0.74 [0.59-0.94], p=0.014, Figure 1) and progression free survival, PFS (HR 0.76 [0.61-0.94], p=0.014). In contrast, although higher doses of CD34+ cells (> 10 x 10^6/kg vs. < 5 x10^6/kg) resulted in faster engraftment for both platelets and neutrophils (data not shown) and a decrease in non-relapse mortality ( HR 0.53 [0.30-0.93], p=0.027), there was no significant effect on acute or chronic GVHD incidence, relapse, PFS or survival. Conclusions These data suggest TNC dose is an important prognostic variable in T-replete RIC HCT with significant impact on survival and should, like CD34+ cell dose, be taken into consideration when planning donor graft infusions. Further studies are needed to confirm these data, and characterize the components of the PB graft that influence survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Risks and Benefits of Sex-Mismatched Hematopoietic Cell Transplantation Differ By Conditioning Intensity

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2537-2537
Author(s):  
Hideki Nakasone ◽  
Mats Remberger ◽  
Lu Tian ◽  
Petter Brodin ◽  
Bita Sahaf ◽  
...  
Keyword(s):  
Multivariate Analyses ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Lymphocytic Leukemia ◽  
Hematopoietic Cell ◽  
University Hospital ◽  
Cell Transplant ◽  
Increased Risk ◽  
Conditioning Intensity

Abstract Backgrounds: Sex-mismatched hematopoietic cell transplant (HCT), especially HCT of male recipients with female donors (F->M) is known to be associated with a higher incidence of graft-versus-host disease (GVHD) and inferior survival. Total lymphoid irradiation with anti-thymocyte globulin (TLI-ATG) has been reported to reduce GVHD incidences and non-relapse mortality (NRM). We hypothesized that TLI-ATG could reduce adverse effects of sex-mismatched HCT without reducing graft-versus leukemia/lymphoma (GVL) effect. Methods: We reviewed clinical charts of 1041 adult recipients who received peripheral blood stem cell transplant between 2006 and 2013 at Stanford University (n=749) and Karolinska University Hospital (n=292). Primary diseases included acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), lymphoma, chronic lymphocytic leukemia (CLL) and others. Our study excluded indications for which TLI-ATG is not used such as acute lymphoblastic leukemia. Haplo-identical HCT and recipients who received GVHD prophylaxis other than cyclosporine and tacrolimus were also excluded. Impacts of sex-mismatch on clinical outcomes were separately assessed in TLI-ATG (n=437), reduced-intensity conditioning (RIC, n=266), and myeloablative conditioning (MAC, n=345). We also measured allo-antibodies (HY-Ab) against 5 HY-antigens encoded on the Y-chromosome (DBY, UTY, ZFY, EIF1AY, and RPS4Y) at 3 months (3m) post F->M HCT in the Stanford cohort. Results: F->M HCT was significantly associated with an increased risk of acute GVHD grade 2-4 in the RIC group (HR 1.96, P<0.01) and an increased risk of chronic GVHD in the MAC group (HR 1.83, P<0.01), while no impact of sex-mismatch on GVHD was observed in the TLI-ATG group. F->M HCT was also associated with an increased risk of NRM only in the MAC group (HR 1.84, P=0.022), while there was no difference in the TLI-ATG or RIC group. In the TLI-ATG group, relapse incidences of sex-mismatched HCT at 2 years post-HCT (40% in F->M HCT and 33 % in M->F HCT) were significantly lower than that of sex-matched HCT (52%, P<0.01, Fig1). Multivariate analyses revealed that sex-mismatch was significantly associated with reduced relapse in the TLI-ATG group (HR 0.64 in F->M and 0.59 in M->F, P<0.01 in each), while no difference was observed in the RIC or MAC group. The GVL benefit of sex-mismatch in TLI-ATG was observed in AML and lymphoma patients other than CLL. In MDS and CLL patients, the GVL benefit by sex-mismatch was not observed. We found that the overall survival (OS) of sex-mismatch recipients (69% in F->M and 70% in M->F HCT at 2 years post-HCT) was higher than that of sex-matched HCT (56%, P<0.01, Fig 1) in the TLI-ATG group. In contrast, for MAC recipients, OS of F->M HCT (49%) was significantly inferior to those of sex-matched HCT (60%) and M->F HCT (58%, P=0.01). Multivariate analyses confirmed that sex-mismatch was significantly associated with superior OS in the TLI-ATG group (HR 0.69 in F->M, P=0.037; HR 0.61 in M->F, P=0.014), while F->M HCT was significantly associated with inferior OS in the MAC group (HR 1.59, P=0.018). In the TLI-ATG group, the benefit of sex-mismatched HCT on OS seems due to the reduced relapse rate. We previously reported HY-Ab response post-HCT was associated with chronic GVHD as a representative of allo-Ab response (Nakasone et al. ASH 2013). We then hypothesized that HY-Ab response 3m post-HCT could predict reduced relapse in F->M HCT with TLI-ATG. Excluding patients with MDS and CLL because of the absence of GVL benefit by sex-mismatch in TLI-ATG (above), relapse incidence at 2 years post-HCT was higher in the recipients who had no HY-Ab response at 3m post-HCT vs. those who did (49% vs. 26%, P=0.037, Fig 2). Multivariate analysis corroberated that the detection of HY-Ab 3m post-HCT was significantly associated with reduced relapse in F->M HCT with TLI-ATG (HR 0.29, P=0.039). On the other hand, in the MAC group, HY-Ab 3m post-HCT was not significantly associated with reduced relapse. Conclusion: Benefits and risks of sex-mismatch differ according to conditioning intensity. Recipients of TLI-ATG conditioning preferentially benefit from sex-mismatched HCT with significantly reduced relapse rates and improved OS. HY-Ab 3m post-HCT as a representative of allo-Ab demonstrated the association with reduced relapse in the TLI-ATG group. We believe that sex-mismatched HCT should be selected in TLI-ATG, while F->M HCT should be avoided in MAC. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Risk Factors and Outcome of Children with Relapsed/Refractory Acute Leukemia after T-Cell-Rich Haploidentical Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4604-4604
Author(s):  
Atsushi Kikuta ◽  
Hideki Sano ◽  
Kazuhiro Mochizuki ◽  
Shogo Kobayashi ◽  
Mitsuko Akaihata ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
T Cell Therapy ◽  
Gvhd Prophylaxis ◽  
Significant Difference

Abstract Background: T-cell rich (TCR) HLA-haploidentical SCT (haplo-SCT) is a form of T-cell therapy that has a high degree of efficacy in hematologic malignancies. Previously we reported the safety profile assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate (MTX) and prednisolone (PSL) in unmanipulated haplo-SCT (Clin Transplant 2010, Transfus Med 2014). We evaluated efficacy and toxicity of TCR haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL). Methods: VHR-R/R AL were defined as: relapse after SCT, very early or early relapse, induction failure(2 or more) and relapse of risk factor with MLL rearrangement, Ph+, Mo7 and 5q-. From Aug 2000 to April 2014, consecutive 38 patients (pts) with VHR-R/R AL who underwent TCR-haplo-SCT were included. The median age of pts was 8.2(0.3-19.1) years old. The diagnosis included ALL (n=27), AML (n=8), M/NKL (n=3). The disease status at TCR-haplo-SCT were 18 in CR (positive MRD: 8 pts), 20 in non-CR. HLA disparities were 2/8 in 1pt, 3/8 in 9 pts, 4/8 in 28 pts. Donors included fathers (n=21), mothers (n=14), and siblings (n=3). Thirty one pts received myeloablative conditioning (TBI based: 20 pts, Bu based: 11 pts) and 34 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus, MTX and PSL. Thirty four pts received peripheral blood stem cells and 4 pts received BM. Results: Neutrophil engraftment (defined as >0.5x109/L) was 95% with a median day of 13 (range, 10-15). With a median 1640 days follow-up (range, 320-5510 days) in pts without events, the actuarial 3-year overall survival (OS) and disease-free survival (DFS) were 57% and 39%, respectively. On competing-risk analysis, 1-year cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 71% and 63%, respectively; 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 40% and 20%. On univariate analysis, 3-year OS in pts with acute GVHD vs. without acute GVHD were 70% vs. 22% (p=.0006), in pts CR vs. non-CR at TCR-SCT were 83% vs. 32% (p=.007), in pts infused CD3 cell doses >=5 x 108/kg vs. <5 x 108/kg were 83% vs. 25% (p=.005), according to age at TCR-SCT <9 vs. >=9 were 79% vs. 34% (.008), respectively. In contrast, the occurrence of acute GVHD had no significant difference in infused CD3 cell doses. Conclusions: These data suggest that TCR haplo-SCT following low-dose ATG containing conditioning combined with our GVHD prophylaxis is well tolerated, facilitates engraftment, and has significant anti-leukemic activity, particularly in pediatric patients with refractory/ relapsed population. Disclosures No relevant conflicts of interest to declare.

scholarly journals Venetoclax and DLI for Patients with Early Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation. a Historical Prospective Multicenter Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2018-2018
Author(s):  
Odelia Amit ◽  
Yael Bar-On ◽  
Galit Perets ◽  
Lena Atlas ◽  
Liat Shargian ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Tumor Lysis Syndrome ◽  
Median Number ◽  
Eligibility Criteria ◽  
Hematopoietic Stem ◽  
Early Relapse ◽  
Allogeneic Hct ◽  
Overall Response

Introduction: Prognosis in patients with post allogeneic HCT-early relapse of AML is dismal and response to salvage treatment is less than 20%. Venetoclax has been shown to be safe and efficacious in frail/elderly patients with AML. Treatment results in an increase of pro-apoptotic function, thus the addition of alloreactive T cells may augment the anti-leukemic potency. We hypothesized that the combination of donor lymphocyte infusion may further enhance this response. Methods: Eligibility criteria for this protocol were - age>18 y, early (<6 months post allogeneic HCT) relapse and no concurrent GVHD. Venetoclax was administered at a daily dose of 400 mg for up to 6 cycles with DLI in escalating doses for up to 4 doses. Additional chemotherapy was allowed according to physician discretion. Primary endpoint of study included assessment Overall response (CR/CRi/CRp) rate at 3 months post treatment. Secondary endpoints included 1-year OS, rate of acute and chronic GVHD, documented infections, hematological complications, and other safety measures. Results: From January 2017 until May 2019, 19 patients were given the study protocol. Median age was 60 (43-75) years, Table. There were no cases of tumor lysis syndrome. Microbiology documented infections occurred in 5 patients (26%) and 2 patients were admitted during protocol (10%). No cases of significant bleeding were observed, and majority of patients were able to tolerate the protocol without any admissions. Acute GVHD was observed in 2 (10%) patients and chronic GVHD was observed in 4 (21%) patients. Overall response was observed in 8 (47%) patients (CR, n=3; CRi, n=2; CRp, n=3). Median time to response was 28 (18-67) days (median number of courses 2 (1-6)) and duration of response was 106 (31-395) days. Survival at 6 months was 3.5 months (95% CI 1.5-5.5). Median survival of patients achieving complete remission was 16.2 months (CI not det.), Figure. On univariate analysis there was no association between patients and disease's characteristics and overall survival, however any type of GVHD (entered to the model as a time dependent variable) was associated with a lower rate of mortality (HR=0.2, p= .03). Conclusions: These results may endorse the hypothesis that enhancing alloreactivity as a therapy may lead to a chemotherapy free approach to relapsed AML. A phase 2 study is under preparation with a larger sample size and a standardized approach to additional salvage chemotherapy added versus Venetoclax + DLI regimen only for a more robust analysis of this therapeutic approach. 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.

Prognostic Factors Identifiable at the Time of Onset of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1247-1247
Author(s):  
Kyoo Hyung Lee ◽  
Seong-Jun Choi ◽  
Jung-Hee Lee ◽  
Soon-Ja Shin ◽  
Miee Seol ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Lymphocyte Count ◽  
Initial Treatment ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Immunosuppressive Agents ◽  
Immunosuppressive Treatment ◽  
Absolute Lymphocyte Count ◽  
Independent Variables ◽  
Allogeneic Hct

Abstract Existing grading systems of acute GVHD, based on the overall degrees of skin, liver, and gut involvement, may not identify patients who are likely to have poor outcome at the time of onset of acute GVHD due to the subjective nature of determining the extent of skin involvement and wide variation of daily amount of diarrhea. This retrospective analysis was to identify prognostic factors for acute GVHD, with an emphasis given to the factors available at the time of onset. Among 303 adult patients who were given allogeneic HCT between Jan 1996 and Aug 2003, 83 patients (27.4%, 50 males and 33 females) developed ≥ grade II acute GVHD, received systemic immunosuppressive treatment, and were included in the analysis. The median age of the patients was 32 years (range, 15–59). The indications for HCT were acute leukemia in 34 patients, CML in 20, MDS in 13, SAA/PNH in 8, and others in 8. Initial treatment for acute GVHD was corticosteroids in 81 and mycophenolate mofetil in 2. Of those, 40 (48.2%) required additional immunosuppressive agents on median day 10 (range, 3–48) of onset of acute GVHD (time to initial treatment failure, TITF). Overall, 52 patients (62.7%) discontinued immunosuppressive treatment successfully except for the prophylactic dose of cyclosporine or tacrolimus on median day 44 (range, 7–800, time to completion of treatment, TCT). After median follow-up of surviving patients of 805 days (range, 302–2290), 42 patients died. Of 42 deaths, 27 died due to complications related uncontrolled acute or chronic GVHD within 1 year of onset of acute GVHD and these deaths were considered as GVHD-related death (GVHD-specific survival). Two died due to complications of chronic GVHD beyond 1 year and were not considered as an event related to acute GVHD. Thirteen died due to relapse of malignancie (6) or other causes (7). Multivariate analysis with variables of P < 0.05 on univariate analysis showed that GVHD prophylaxis (cyclosporine plus methotrexate vs. cyclosporine alone; P=0.005; odd ratio, 0.282; 95% CI, 0.117–0. 677), HLA match (full vs. 1 ag mismatch; P=0.023; odd ratio, 2.591, 95% CI, 1.142–5.878), lower G-I involvement (no vs. yes; P=0.000; odd ratio, 4.868; 95% CI, 2.501–9.475), and absolute lymphocyte count (> 100 vs. < 100/ul; P=0.003; odd ratio, 2.786; 95% CI, 1.418–5.473) were significant independent variables predicting TITF. HLA match (P=0.037; odd ratio, 0.218; 95% CI, 0.052–0.909), lower G-I involvement (P=0.020; odd ratio, 0.420; 95% CI, 0.202–0.874), and absolute lymphocyte count (P=0.040; odd ratio, 0.448; 95% CI, 0.208–0.963) were significant independent variables predicting TCT. For the prediction of GVHD-specific survival, type of cell donor (sibling vs. unrelated; P=0.042; odd ratio, 0.420; 95% CI, 0.182–0.969), HLA match (P=0.014; odd ratio, 0.286; 95% CI, 0.105–0.779), skin vs. visceral initiation (P=0.033; odd ratio, 0.287, 95% CI, 0.091–0.903), upper G-I involvement (P=0.015; odd ratio, 0.213; 95% CI, 0.061–0.739), and absolute lymphocyte count (P=0.003; odd ratio, 0.260; 95% CI, 0.106–0.641) were significant independent variables. Our study showed that, at the time of onset of acute GVHD, peripheral blood lymphocytopenia was an independent variable that predicted shorter TITF, longer TCT, and shorter GVHD-specific survival, in addition to visceral organ involvement. Early aggressive treatment for acute GVHD in this population of patients may improve overall outcome of acute GVHD after allogeneic HCT.

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