Influence Of Killer Immunoglobulin-Like Receptor (KIR) and HLA Genotypes On Outcomes After Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation For Patients With AML and MDS: A Report From The Center For International Blood and Marrow Transplant Research Immunobiology Working Committee

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 159-159 ◽  
Author(s):  
Ronald M. Sobecks ◽  
Meighan M. Gallagher ◽  
Medhat Askar ◽  
Michael D. Haagenson ◽  
Tao Wang ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Lower Risk ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Hla Genotypes ◽  
Grade 3 ◽  
Reduced Intensity

Abstract Disease relapse is a significant cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). In the setting of reduced-intensity conditioning (RIC), a graft-versus-leukemia (GVL) effect is critical for successful outcomes in patients with advanced myeloid malignancies. A GVL effect has been attributed in part to donor-derived alloreactive natural killer (NK) cells, which are regulated by interaction of KIRs with their HLA-class I ligands. Several models of NK reactivity (missing KIR ligand, centromeric haplotype-B content, non-tolerized KIR2DS1) have been associated with improved outcomes following HLA-matched, HLA-mismatched, related, and unrelated donor HCT, particularly for AML patients given myeloablative conditioning. The effect of KIR-HLA combinations on outcomes after RIC HCT, however, is not known. We retrospectively analyzed donor-recipient KIR/HLA genotypes from 929 URD HCTs facilitated by the National Marrow Donor Program for patients with AML (n=624) or MDS (n=305) treated with RIC between 1990 and 2007. 664 donor-recipient pairs were 10/10 HLA-matched and 265 were 9/10 HLA-matched. 332 (37%) patients received ATG and 73 (8%) received alemtuzumab. P-values less than 0.01 were considered significant. We hypothesized that donor-recipient KIR-HLA interactions may be associated with improved post-transplant outcomes following RIC HCT for AML and MDS. Patients lacking the HLA-Bw4 ligand for donor inhibitory KIR3DL1 experienced lower relapse following HCT at 1 year (27 vs 36%, p=0.002) and 5 years (31 vs 42%, p=0.003) compared to patients with the Bw4 ligand (Figure). The lower risk for relapse was confirmed in multivariate analysis (HR 0.71, p=0.005). However, there was no significant association of Bw4 ligand with disease-free survival (HR 0.84, p=0.05) and overall survival (HR=0.97, p=0.70). Risk for acute GVHD was higher among patients lacking KIR ligands after adjusting for other clinical factors. In particular, patients lacking HLA-C2 for donor KIR2DL1 experienced higher grade 2-4 (HR 1.3, p=0.005) and 3-4 acute GVHD (HR 1.5, p=0.002), and patients lacking multiple KIR ligands experienced higher grade 3-4 acute GVHD (HR 1.5, p=0.007). The analysis was then restricted to AML patients, the patient population with greatest reported KIR-HLA effects. Patients whose donors were KIR2DS1+ and HLA-C2C2 (n=33) had higher transplant-related mortality (TRM) (HR, 2.4, p=0.002) compared to all other patients. There was no significant effect of KIR2DS1 with HLA on relapse. In a multivariate analysis, lack of HLA-C2 in AML patients was associated with higher grade 2-4 (HR 1.4, p=0.002) and 3-4 acute GVHD (HR 1.5, p=0.01), and risk for grade 3-4 acute GVHD was higher in patients lacking multiple KIR ligands (HR 1.6, p=0.005). There were no significant associations between donor homozygosity for the centromeric B-haplotype (cenBB) or overall B-haplotype KIR content and RIC HCT outcomes. Overall, these results suggest that in the RIC HCT setting, lack of Bw4 ligand for KIR3DL1 is associated with a lower risk of relapse for AML/MDS. This observation corroborates previous findings in myeloablative HCT transplants. Furthermore, tolerance of donor KIR2DS1 by HLA-C2C2 was associated with worse outcome, as manifested by higher TRM, in AML patients. In contrast, it appears that in RIC HCT homozygosity for the centromeric B-haplotype does not have a significant role in leukemia relapse. The associations of KIR ligands with acute GVHD were not previously observed suggesting that NK cell alloreactivity depends on multiple variables, including RIC. Further elucidation of the biology of NK cell alloreactivity in the RIC setting may provide guidance for future approaches to help optimize conditions for generating GVL reactions without GVHD and less TRM in this transplant population.FigureFigure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Fludarabine Melphalan Versus Fludarabine Treosulfan As Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplant - a Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4493-4493
Author(s):  
Akanksha Chichra ◽  
Lingaraj Nayak ◽  
Rushabh Kothari ◽  
Siddhesh Arun Kalantri ◽  
Avinash Bonda ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Patient Characteristics ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Entire Cohort ◽  
Conditioning Regimens ◽  
Grade 3 ◽  
Haplo Group ◽  
Very High

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as > 5% to < 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.

Impact of ATG Dose on the Outcome of Patients Undergoing Reduced Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

2016 ◽  
Vol 136 (4) ◽  
pp. 193-200 ◽  
Author(s):  
Jérôme Cornillon ◽  
Marie Balsat ◽  
Aurélie Cabrespine ◽  
Emmanuelle Tavernier-Tardy ◽  
Eric Hermet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often proposed for patients with comorbidities. To enhance engraftment and limit graft-versus-host disease (GVHD), antithymoglobulin (ATG) is usually used. However, the dose needed remains unclear unlike myeloablative conditioning. In order to clarify this point, we conducted a retrospective study on patients who received a reduced intensity conditioning allo-HSCT based on a 2-day fludarabine and busulfan treatment with either 1 or 2 days of ATG treatment. One hundred and eight patients received 2.5 mg/kg (ATG2.5) and another 60 patients 5 mg/kg (ATG5). The median follow-up was 36 months. The median overall survival was 39 months and the median disease-free survival 45 months. In multivariate analysis, overall nonrelapse mortality (NRM) was independently influenced by the acute GVHD grade III-IV (p < 0.001) and ATG dose (30 vs. 21% for ATG5; p = 0.008). Despite heterogeneity of populations, using proportional-hazard assumptions, we have been able to observe in multivariate analysis a lower NRM in the ATG5 group. This leads to a statistically higher overall survival for the ATG5 group. In conclusion, 2 days of ATG decrease NRM independently without increasing the risk of relapse or infectious disease.

Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5311-5311
Author(s):  
Xiaohua Chen ◽  
Gregory A. Hale ◽  
Raymond C. Barfield ◽  
Ely Benaim ◽  
Wing H. Leung ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

Natural Killer (NK) Cell Reconstitution After Haploidentical Unmanipulated Bone Marrow Transplantation with Reduced Intensity Conditioning

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4557-4557 ◽  
Author(s):  
Isabel Gonzalez-Gascon y Marin ◽  
Ana Maria Perez-Corral ◽  
Jorge Gayoso ◽  
Javier Anguita ◽  
Cristina Pascual ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Median Number ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Abstract 4557 BACKGROUND: Natural killer (NK) cells are innate immune effectors that directly lyse virally infected or malignant cells. There are 2 different subsets of NK cells with distinct phenotypic and functional characteristics: the CD56dim subset, which composes 90% of peripheral blood NK cells and has a cytotoxic function, and the CD56bright subset, which cooperates with dendritic cells and T cells in lymph nodes to secrete interferon and promote adaptive immune responses. NK cells are the first donor-derived lymphocyte subset to reconstitute after hematopoietic stem cell transplantation, reaching normal levels after 1 month. Nearly all phenotyping studies of NK subsets after haploidentical hematopoietic stem cell transplantation (HHSCT) reveal a rapid reconstitution of NK cells towards the CD56bright subset. In addition, Y.-J. Chang et al found the highest 2-year survival in patients with a high number of CD56bright NK cells after unmanipulated HHSCT. We analyzed reconstitution of the NK compartment between days 90 and 180 after unmanipulated bone marrow HHSCT with reduced intensity conditioning (RIC). METHODS: Six adults received unmanipulated bone marrow HHSCT after RIC (fludarabine 30 mg/m2 [day –6 to –2], cyclophosphamide 14.5 mg/kg [day –6 and –5], and busulfan i.v. 3.2mg/kg [day –3]) at our institution between July 2007 and July 2010. Prophylaxis for acute graft-versus-host disease (GvHD) consisted of cyclophosphamide 50mg/kg (days +3 and +4) and cyclosporine A and mycophenolate mofetil from day +5 onwards. We monitored the reconstitution kinetics of circulating NK cells (CD56+, CD3–), and the CD56bright and CD56dim subsets by multiparametric flow cytometry (FC 500 Beckman® Coulter) at day +90 and day +180 after transplantation. Patient characteristics and clinical outcomes are shown in Table 1. 6 patients who underwent allogeneic HLA-identical sibling HSCT with RIC during the same period were used as controls. RESULTS: After HHSCT, NK cells reached normal levels in all patients but one at day +90, with a median number of NK cells of 111/mm3 (range, 25–195/mm3). At day +180 the median number of NK cells was 92/mm3 (range, 4–272/mm3). When we analyzed the absolute number of CD56bright and CD56dim subsets at day +90, we observed 2 patterns: Two patients showed skewed NK cell reconstitution towards CD56bright (Patient no. 3: 54 CD56bright/mm3; 11 CD56dim/mm3. Patient no. 4: 70 CD56bright/mm3; 17 CD56dim/mm3). Three patients reconstituted with a CD56dim/CD56bright ratio towards the CD56dim cell subset, similar to that of healthy adults (Patient no. 1: 17 CD56bright/mm3; 178 CD56dim/mm3. Patient no. 5: 9 CD56brigh/mm3; 135 CD56dim/mm3. Patient no. 6: 20 CD56bright/mm3; 116 CD56dim/mm3). One patient did not achieve adequate NK cell reconstitution (Patient no. 2: 15 CD56bright/mm3; 10 CD56dim/mm3). In contrast, in the control group, an increase in the CD56bright NK cell subset was not observed in any of the patients at any point. It is worth noting that 2 of the 3 patients with better clinical outcome (no GvHD, no relapse), namely patients no. 3 and no. 4 were the ones with skewed NK cell reconstitution towards the CD56bright NK cell subset. The other patient with a better clinical outcome (patient no. 6) had a normal CD56dim/CD56bright ratio at day +90. However, he showed an early CD56bright reconstitution (363 CD56bright/mm3; 34 CD56dim/mm3) in an additional determination on day +30. NK cell subsets reconstitution kinetics is shown in Figure 1. CONCLUSIONS: In our experience, NK cell reconstitution is adequate after RIC unmanipulated bone marrow HHSCT. Some patients recovered with a high proportion of CD56bright NK cells, as previously reported in other studies on HHSCT. Although limited by the sample size, our results are consistent with the previously observed survival advantage of patients with high early levels of CD56bright NK cells after unmanipulated haploidentical transplantation. Disclosures: No relevant conflicts of interest to declare.

The Impact of Anti-HLA Antibodies on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes After Reduced-Intensity Conditioning Regimens

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2038-2038
Author(s):  
Marie Y. Detrait ◽  
Valerie Dubois ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Nathalie Tedone ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Univariate Analysis ◽  
Reduced Intensity Conditioning ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Abstract 2038 Introduction: Anti-HLA antibodies are associated with several complications in solid organ transplantations but their impact after allogeneic hematopoietic stem cell transplantation (HSCT) is not very well defined yet. Patients and methods: To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allogeneic HSCT after reduced-intensity conditioning (RIC) regimen between 2005 and 2010. Acute myeloid leukaemia (n=52,48.5%) and multiple myeloma (n=18,17%) were the most common diagnosis in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation. Results: We found in 24 patients (22%) the presence of anti-HLA antibodies. There was no association between the presence of anti-HLA antibodies and engraftment, incidence of relapse or acute GvHD. The presence of anti-HLA antibodies was associated with worse survival in univariate analysis (HR 2.04; [95%CI,1.21–3.44], p=0.0056) and in multivariate analysis (HR 2.63; [95%CI, 1.32–5.25], p=0.006). The 3-year probability of OS was 34% (95%CI, 24–49) without anti-HLA antibodies and 16% (95%CI, 6–41) in their presence (Figure 1). The other significant factors on survival were the disease status at transplantation, the age, minor and major ABO incompatibilities between donor and recipient, the sex-mismatching and the CMV status. Moreover, the positive anti-HLA antibodies group showed a trend of higher TRM in univariate analysis (p=0.07) and in multivariate analysis (HR= 1.9; [95%CI, 0.94 – 3.9], p=0.076). The TRM at 3 years after transplantation were 31% (95%CI, 26–37) without anti-HLA antibodies and 46% (95%CI, 36–57) in their presence (figure 2). The causes of the pejorative effect of the anti-HLA antibodies were not defined yet but we observed microangiopathy associated with vascular endothelium damage which could be related to the presence of anti-HLA antibodies. Conclusion: Our study suggests that anti-HLA antibodies should be tested and considered as an important prognostic factor for transplant outcomes after RIC HSCT. Disclosures: No relevant conflicts of interest to declare.

Identification Of Patients At High Risk Of Chronic Graft-Versus-Host Disease: Gvhd Prophylaxis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4611-4611
Author(s):  
Gabriel Afram ◽  
Jose Antonio Pérez Simón ◽  
Mats Remberger ◽  
Teresa Caballero-Velázquez ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Reduced Intensity Conditioning ◽  
Host Disease ◽  
Graft Versus Host ◽  
Female Donor ◽  
Reduced Intensity

Introduction Chronic Graft-versus-Host disease (cGVHD) remains a major cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (ASCT). Among the major risk factors previously noted is sex-mismatch, acute GVHD and peripheral hematopoietic blood stem cell grafts (PBSC). Our aim in this study was to determine risk factors for cGVHD and evaluate the impact of ATG on cGVHD in a multi-centre setting. Methods Patients from three centers (Stockholm, Sant Pau, Barcelona and Salamanca) were included. Retrospective data analysis was conducted for all patients (n=820) transplanted between 2000 and 2006. In our cohort 91% had malignant disease, 57% received HLA-identical sibling donor grafts, 13% received grafts with one HLA-A, -B or –DR antigen mismatch and 30% received grafts from HLA-A, -B and –DR matched unrelated donors. Reduced intensity conditioning was given to 65% of the patients. Chronic GVHD was classified according the National Institute of Health consensus criteria. Results Overall incidence of cGVHD was 46% for patients surviving more than three months after ASCT (n=747). Older patient age HR 1.15 (95% CI 1.07-1.24), p<0.001, acute GVHD HR 1.30 (95% CI: 1.04-1.63), p=0.024, and reduced intensity conditioning (RIC) HR 1.36 (95% CI 1.04-1.79) p=0.028 were shown to significantly increase the risk of overall cGVHD in multivariate analysis. In addition, female donor to male recipient HR 1.43 (95% CI 1.07-1.92), p=0.02, RIC HR 1.65 (95% CI 1.18-2.30) p=0.003, and PBSC HR 1.90 (95% CI 1.14-3.16), p=0.01 significantly influenced the risk of moderate-to-severe cGVHD in multivariate analysis. For both overall and moderate-to-severe cGVHD, ATG had a protective effect with HR 0.41 (95% CI 0.32-0.52) p<0.001 and HR 0.32 (95% CI 0.23-0.46) p<0.00, respectively. Accordingly, we developed a scoring system including all variables influencing the risk of cGVHD in multivariate analysis allowing us to distinguish patient cohorts with 12% to 71% incidence of cGVHD (figure 1). Relapse free survival (RFS) was significantly impaired in the group with severe cGVHD. RFS was not affected significantly by the addition of ATG. All three centers had similar overall survival for patients with cGVHD. Conclusion RIC increases the risk for both overall and moderate to severe cGVHD. Acute GVHD and older recipient age are significant risk-factors for overall cGVHD and female donor to male recipient and PBSC for moderate to severe cGVHD. ATG significantly reduces the risk of all grades of cGVHD without having a negative outcome on RFS. Therefore, in order to prevent overall and moderate-extensive cGVHD it should be added to the RIC regimen in older patients and in male patients with female donors after PBSC grafts. Disclosures: Ringden: Gilead : Invited to Gilead on July 28, 2011, to participate in an Advisory Board Meeting on Treatment of invasive fungal infection. Other. San Miguel:Jansen, Celgene, Onyx, Novartis, Millenium: Consultancy, Membership on an entity’s Board of Directors or advisory committees.

Multiple CMV Reactivations Are Associated with Lower Risk of Relapse Following Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3955-3955
Author(s):  
Feras Alfraih ◽  
Naheed Alam ◽  
Vikas Gupta ◽  
Dennis Dong Hwan Kim ◽  
John Kuruvilla ◽  
...  
Keyword(s):  
Stem Cell ◽  
Lower Risk ◽  
Independent Risk Factor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Group Versus ◽  
Transplant Outcomes ◽  
Grade 3 ◽  
Reduced Intensity ◽  
Risk Of Relapse

Abstract Introduction : Cytomegalovirus (CMV) is a major infectious complication following allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we attempted to evaluate the impact of multiple versus single CMV viremia (CMV-V) events on transplantÕs outcomes especially with respect to relapse, non-relapse mortality (NRM) and overall survival (OS). Methods : A total of 548 patients were evaluated for the occurrence of CMV-V after receiving HSCT between 2005 and 2012 at Princess Margaret Cancer Centre. CMV-V was diagnosed in peripheral blood samples obtained on two occasions either by PCR (³ 200 IU/ml) or antigenemia testing (³2 positive cells/100000). A total of 246 patients developed CMV-V and were included in the analysis. Patients were stratified into two groups, multiple CMV-V (³ 2) versus single CMV-V. Median age for all patients is 52 (range 17-71) and 125 (51%) were female. Matched related donors were used for one hundred twenty-five patients (57%). One hundred fifty-six patients (64%) were transplanted for myeloid and 70 (29%) for lymphoid malignancies. Ninety-seven patients (30%) were CMV sero-positive with a negative donor (R+D-) while 138 (51%) were recipient and donor CMV sero-positive (R+D+). Graft versus host disease (GVHD) prophylaxis included CSA/MMF (n=131, 53%) and CSA/MTX (n=115, 47%). Myeloablative conditioning regimens were administered to 143 patients (58%), 103 patients (42%) were treated with a reduced intensity regimen (RIC). Two hundred-fifteen patients (89%) received peripheral blood stem cells as a stem cell source. In- vivo T-cell depletion (TCD) with alemtuzumab was used in 103 (53%). Results: With a median follow-up duration of 27 months among survivors (range 6-92), overall CMV-V occurred in 64% (n=246). Multiple CMV-V occurred in 61% (n=151) versus 39% (n=95) in single CMV-V. The cumulative incidence of grades 1-4 acute GVHD, grades 2-4, grades 3-4 at day 120 and overall chronic GVHD at 2 years was 78%, 61%, 27% and 60% in the multiple CMV-V group versus 54%, 43%, 18% and 39% in single CMV-V group, suggesting higher incidence of acute & chronic GVHD in multiple CMV-V group versus single-CMV-V. The OS, NRM and relapse rate at 2 years were 47%, 41% and 14% in the multiple CMV-V versus 41%, 36% and 24% (p=0.06) in single CMV-V group, suggesting no differences on transplant outcomes between both groups. Sub-analyses based on preparative regimen administered showed, in RIC patients there were significant differences on relapse and NRM between multiple CMV-V versus single CMV-V (table 1) while in myeloablative set, these differences were not seen. The higher incidences of acute and chronic GVHD in patients with multiple CMV-V versus single-CMV-V events were similar on both RIC and myeloablative sets. Table 1. Transplant outcomes according to the occurrence of CMV infection following RIC allogeneic HSCT Overall Multiple CMV-V Single CMV-V (n=103, 100%) (n=57, 55%) (n=46, 45%) p-value Acute GVHD Grades 1-4 64 (62%) 39 (68%) 25 (54%) 0.158 Grades 2-4 46 (45%) 31 (54%) 15 (33%) 0.030 Grades 3-4 14 (14%) 11 (19%) 3 (7%) 0.083 CGVHD, overall 52 (50%) 34 (60%) 18 (39%) 0.048 Transplant outcomes Death 55 (53%) 30 (53%) 25 (54%) 1.000 Non-relapse mortality 33 (32%) 23 (40%) 10 (22%) 0.057 Relapse 23 (22%) 7 (12%) 16 (35%) 0.009 A multivariate analysis in patients conditioned with RIC for transplant outcomes, confirmed multiple CMV-V as an independent protective factor for relapse (p=0.03, Hazard ratio [HR] 0.32) together with chronic GVHD (p< 0.01, HR 0.27) and myeloid disease (p=0.02, HR 2.46). For NRM, multiple CMV-V was not confirmed as an independent risk factor, but acute GVHD grade 3-4 (p< 0.01, HR 5.33) and chronic GVHD (p <0.01, HR 0.34) were found to be significant factors. For OS, chronic GVHD (p<0.01, HR 0.27), grade 3-4 (<0.01, HR 3.52) and age (P<0.01, HR 1.06) were independent prognostic factors. Conclusion: 1) Multiple CMV-V after RIC allogeneic HSCT is associated with significantly lower risk of relapse mortality, which might be affected in part by the occurrence of severe acute and chronic GVHD, and by other unknown independent mechanisms related to CMV infections. 2) CMV sero-status was not an independent risk factor for transplant outcomes in patients with CMV-V. 3) Further studies in larger populations are warranted to confirm and further explore a possible anti-tumor effect of cytomegalovirus infections especially in patients prepared with RIC. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Patients Older Than 60 Years.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5134-5134
Author(s):  
Alessandro Busca ◽  
Franco Locatelli ◽  
Stella Santarone ◽  
Franco Narni ◽  
Enrico Morello ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with hematological malignancies but its use is limited to young patients without comorbidities. The aim of present study was to evaluate the efficacy of a reduced-intensity conditioning (RIC) consisting of fludarabine and TBI in older patients aged 60 to 70 years. Methods: between March 2000 and May 2003, 22 patients (median age 62 years; range 59–70) with hematological malignancies (n=18 AML/MDS; n=1 ALL; n=1 CLL; n=1 myelofibrosis) and solid tumor (n=1 renal cell carcinoma) were treated with a RIC regimen based on fludarabine (30 mg/m2 x 3–5 days) and 200 cCy TBI followed by alloHSCT from a matched-sibling donor. GVHD prophylaxis consisted of cyclosporine and mycophenolate. The source of stem cell was blood in all patients. The median CD34+ content of the grafts was 5.7 x 106/kg (range 3.1–8.7). Three patients had received a prior allograft. Eleven patients had active disease at transplantation, 5 patients were untreated and 6 were allografted in complete remission (CR). Results: neutrophil recovery occurred in 15 patients (68%) at a median time of 16 days (range 8–33). One patient who died early after transplantation (day +5) and 4 patients who experienced an autologous reconstitution, failed to reach this threshold; 2 patients did not become granulocytopenic. Fifty-eight percent of the patients had &gt; 90% donor chimerism on day +30. Twelve of 17 evaluable patients (70%) developed acute GVHD (n=5 grade I; n=6 grade II; n=1 grade III), whereas chronic GVHD was observed in 11 of 13 patients (85%) surviving more than 100 days (limited in 7 cases and extensive in 4 cases). The probability of acute GVHD grades II–IV and extensive chronic GVHD was 43% and 31% respectively. Two patients died of treatment-related complications: 1 patient died of toxic encephalopathy on day 5 after transplantation and 1 patient of thrombotic thrombocytopenic purpura on day 915. The 100-day nonrelapse mortality for the whole population was 5%.Ten patients (45%) died as a result of relapse. With a median follow-up of 586 days (range 50–1128) 10 patients are alive (9 with CR and 1 with relapsed disease).The probability of overall survival at 2 years was 86% for patients treated in CR or at diagnosis and 9% for patients transplanted in advanced phase of disease (p= 0.0008). Conclusion: Our analysis would suggest that for patients older than 60, this RIC regimen is well tolerated and associated with a low incidence of transplant-related mortality and serious acute and chronic GVHD. The leukemic burden at time of transplant has proven to be the most important risk factor for the outcome.

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