Cytomegalovirus (CMV) Serostatus: High Importance of Choosing Seropositive Donors for Seropositive Patients When Using Rabbit Antithymocyte Globulin (ATG)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4402-4402
Author(s):  
Amit Kalra ◽  
Andrew Daly ◽  
Jan Storek
Keyword(s):  
Unrelated Donor ◽  
Seropositive Patient ◽  
Transplant Recipients ◽  
Matched Unrelated Donor ◽  
Lower Survival ◽  
R And D ◽  
Survival Difference ◽  
Pp65 Antigenemia ◽  
Matched Sibling ◽  
Cmv Dnaemia

Abstract Introduction: In published studies that included mostly hematopoietic cell transplants (HCTs) not using in vivo T cell depletion by ATG, there is a substantial survival difference between D-R- and D+R- patients, and a very small or no survival difference between D-R+ and D+R+ patients. We set out to determine the impact of donor CMV serostatus on survival after HCTs using ATG. Methods: A total of 919 patients underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014, with a uniform graft versus host disease (GVHD) prophylaxis using ATG (4.5 mg/kg given between day -2 and 0) in addition to methotrexate and cyclosporine. Monitoring for CMV reactivation was performed until at least day 100 after transplant using pp65 antigenemia (before 2008) or CMV DNAemia by quantitative polymerase chain reaction (since 2008). Preemptive therapy typically with ganciclovir was started whenever pp65 antigenemia exceeded 10 to 20 positive cells/200,000 granulocytes or CMV DNAemia exceeded 25,000 IU/mL plasma. Significance of survival difference between patient groups was tested using Cox proportional hazards analysis. Significance of difference in nonrelapse mortality (NRM) or cumulative incidence of relapse (CIR) was tested using Fine-Gray analysis (nonrelapse death was a competing risk of relapse and vice versa, in addition to graft failure and second malignancy). In all analyses, covariates included patient age (>45 vs ≤45), disease stage (acute leukemia in first remission, chronic myeloid leukemia in first chronic phase and myelodysplasia with <5% marrow blasts were considered good risk, all others poor risk), graft type (marrow vs PBSCs) and donor type (human leucocyte antigen [HLA] matched sibling vs other [typically matched unrelated]). Results: D-R- and D+R- patients had similar survival (no significant difference) (blue vs orange curve, figure 1). D-R+ patients had a substantially lower survival than D+R+ patients with an estimated 5 year survival of 41% versus 60% respectively (Hazard Ratio [HR], 1.6; P = 0.001; 95% confidence interval[CI], 1.22-2.09) (red vs green curve, figure 1). This was due to higher NRM (sub hazard ratio [SHR], 1.76; P = 0.003; 95% CI, 1.212-2.58), not CIR. This appeared to be due to higher GVHD-associated mortality. We then compared D-R+ HLA matched sibling transplants with D+R+ HLA matched unrelated donor transplants to assess whether for a CMV seropositive patient with a CMV seronegative HLA matched sibling, search for a CMV seropositive HLA matched unrelated donor could be justified. D-R+ HLA matched sibling transplant recipients had a substantially lower survival than D+R+ 8/8 HLA allele matched unrelated donor transplant recipients with an estimated 5 year survival of 45% versus 66% respectively (HR, 1.7, P = 0.01, 95% CI, 1.10-2.89) (green vs orange curve, figure 2). This suggests that in the scenario of a seropositive patient with a seronegative matched sibling, unrelated donor search is justified. Conclusion: Contrary to recommendations for HCTs not using ATG, choosing a seronegative donor for a seronegative patient is unimportant, whereas choosing a seropositive donor for a seropositive patient is very important (~20% absolute 5 year survival gain). Even if a seronegative HLA matched sibling donor is available for a seropositive patient, it is better to select a seropositive HLA matched unrelated donor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease

Blood ◽  
2020 ◽  
Vol 136 (5) ◽  
pp. 623-626 ◽  
Author(s):  
Ruta Brazauskas ◽  
Graziana M. Scigliuolo ◽  
Hai-Lin Wang ◽  
Barbara Cappelli ◽  
Annalisa Ruggeri ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Risk Score ◽  
Unrelated Donor ◽  
Cell Disease ◽  
Event Free Survival ◽  
Matched Unrelated Donor ◽  
Free Survival ◽  
Matched Sibling

Abstract We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-matched sibling donor were at the lowest risk with a 3-year EFS of 92% (score, 0). Patients age 13 years or older with an HLA-matched sibling donor or age 12 years or younger with an HLA-matched unrelated donor were at intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with a haploidentical relative or HLA-mismatched unrelated donor and patients age 13 years or older with an HLA-matched unrelated donor were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in the validation cohort. This simple risk score may guide patients with sickle cell disease and hematologists who are considering allogeneic transplantation as a curative treatment relative to other available contemporary treatments.

A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2313-2313
Author(s):  
Lun-Wei Chiou ◽  
Junya Kanda ◽  
Paul Szabolcs ◽  
Gregory E. Sempowski ◽  
Jeffrey Hale ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Peripheral Blood ◽  
Nkt Cells ◽  
Unrelated Donor ◽  
Immune Recovery ◽  
Transplant Recipients ◽  
Cell Recovery ◽  
Matched Sibling

Abstract Abstract 2313 Immunologic reconstitution following stem cell transplantation (SCT) arises from thymic-independent peripheral expansion of memory T-cells transplanted with the stem cell graft, and thymic-dependent maturation of stem cell derived lymphoid progenitor cells. As a consequence of thymic involution, adult stem cell transplant recipients rely largely upon the thymic-independent pathway. This process is facilitated by a plentiful supply of mature T-cells contained within peripheral blood or bone marrow grafts. Umbilical cord blood (UCB) grafts contain predominantly naive T-cells thereby limiting the potential for thymic-independent immune recovery. Recent reports have documented slow immune recovery in adult UCB recipients, however it has yet to be described in the context of a comparable population of adult allogeneic matched sibling or unrelated donor SCT. Methods: Between 2007 and 2009, we characterized cellular immune reconstitution in a consecutive cohort of adult patients undergoing myeloablative SCT using either matched sibling (MSD), matched unrelated donor (MUD) peripheral blood stem cell (PBSC) or dual UCB donor grafts. Dual UCB transplant recipients were conditioned with TBI 1350cGy and fludarabine 160mg/m2 (Flu). PBSC recipients were conditioned with either TBI 1350cGy or IV busulfan 12.8mg/kg (Bu) and cyclophosphamide 120mg/kg, or Bu/Flu. PBSC grafts were allele-level matched at HLA-A, B, C and DRB1. UCB grafts were mismatched at no more than 2 class I or class II loci. Both cohorts received GvHD prophylaxis with Tacrolimus for at least 6 months. UCB recipients received mycophenolate mofetil 2g/day for at least 60 days instead of standard dose methotrexate GvHD prophylaxis for PBSC recipients. Quantification of the following lymphoid subsets were performed by flow cytometry on fresh peripheral blood prior to, and then at approximately 45, 100, 180, and 360 days following transplantation: NK and NKT cells, B-cells, plasmacytoid dendritic cells, CD3+, CD4+, CD8+, regulatory and na•ve T-cells. T-cell receptor excision circles (sjTREC) were quantified by real time PCR on DNA collected from an isolated fraction of CD3+ T-cells. Cumulative corticosteroid usage prior to day 100 (as determined by area under the curve) was determined as a method for comparing acute GvHD severity. The Kruskal-Wallis test with adjustments for multiple comparisons was used compare immune recovery values at 45, 100, 180 and 360 days post transplantation. The PearsonÕs Chi-square test was used to compare the CMV reactivation rate of UCB to MSD/MUD. Results: Forty-two recipients of allogeneic SCT (MSD-13, MUD-14, UCB-15) with successful donor engraftment and who survived a minimum of 6 months were evaluated. The MSD, MUD and UCB recipients had a median age of 41, 42 and 31 years, respectively (p = 0.13). There was no significant difference in corticosteroid administration before day 100 or chronic GvHD in the three cohorts (p=0.74). There were no differences in the kinetics of immune recovery between MSD and MUD recipients. At 45 days following transplantation, UCB recipients had significantly lower levels of CD4+ (figure), CD8+ and NKT-cells. By day 100, UCB recipients had similar numbers of CD4+ T-cells, but remained lower in the other major T-cell subsets. By day 180 however, all T-cell subsets except NKT cells (p=0.033) were similar to the MSD/MUD recipients. NK cell recovery was faster in the UCB recipients (figure). There was also no difference in B-cell recovery among the 3 cohorts. TREC levels were not significantly different in recipients of all graft types, but were uniformly low (figure). The slow recovery of T-cells in the UCB cohort corresponds with a higher Kaplan-Meier estimate of CMV reactivation compared to the MSD/MUD cohort (90% vs. 36%; p = 0.0078). Conclusion: Compared to HLA-identical MSD and MUD adult SCT recipients, quantitative lymphoid recovery in UCB transplant recipients is slower in the first two months, but these differences are erased by 4–6 months following transplantation. NK reconstitution is more rapid in UCB recipients. Reduction of early opportunistic infections affecting UCB transplant recipients may arise from effective techniques to boost early T-cell recovery. Disclosures: No relevant conflicts of interest to declare.

Matched Unrelated Donor Transplantation Is Curative In Selected Patients with Diffuse Large B Cell Lymphoma: A Report of the Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 363-363 ◽  
Author(s):  
Irit Avivi ◽  
Carmen Canals ◽  
Jian Jian Luan ◽  
Gerald. G. Wulf ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Conditioning Regimen ◽  
Poor Performance ◽  
Poor Performance Status ◽  
Unrelated Donor ◽  
Refractory Disease ◽  
Matched Unrelated Donor ◽  
Matched Sibling

Abstract Abstract 363 Matched unrelated donor stem cell transplantation (MUD-SCT) has recently become a therapeutic option for patients with B cell diffuse large cell lymphoma (DLBCL) who fail other conventional therapies and do not have a matched sibling donor available. We present retrospective data of 473 DLBCL patients, 285 males and 188 females, aged 18 to 69 years (median 46 years), treated with matched sibling (n=301) or matched unrelated (n=172) SCT between January 2000 and December 2007 and reported to the EBMT registry. Median time from diagnosis to allograft was 25 months (range 2 – 203). Fifty-seven percent of the patients had failed previous autologous SCT, and 12% were transplanted in chemorefractory disease. After a median follow up of 41 months, the estimated 3-year non-relapse mortality (NRM), relapse rate (RR), progression free survival (PFS) and overall survival (OS) for the whole series were 37%, 32%, 31% and 40%, respectively. There were no statistically significant differences in patient age, disease status at transplantation, stem cell source and intensity of conditioning regimen between the Sib and the MUD cohorts (summarized in Table 1).However, a higher number of patients undergoing MUD have already failed an autograft (66% vs 52%, p=0.004), and T cell depleted grafts were more frequently used in the MUD cohort. Acute GvHD occurred in 48% of patients treated with a sib allograft vs 54% in those receiving a MUD (p=n.s). Interestingly, there were no statistically significant differences in NRM and RR between the Sib and the MUD groups (3 yr NRM=38% vs 37%, RR approached 38% vs 34%), resulting in a similar 3-year PFS and OS (32% vs 29% and 42% vs 35%, respectively). Multivariate analysis identified refractory disease (p = 0.001, RR 3.2; CI=1.3-3.5), poor performance status (p = 0.017, RR 1.9; CI=1.1-3.4) and age at transplantation > 50 years (p = 0.015, RR1.5; CI=1.1-2.1) as independent adverse prognostic factors for NRM and time from diagnosis to SCT < 36 months (p = 0.02, RR 1.5; CI=1.1-2.1), a previously failed autologous SCT (p = 0.026, RR .4; CI=1.1-1.9), refractory disease (p = 0.003, RR 2; CI=1.3-3.1), poor performance status (p = 0.0001, RR 3.5; CI=2.1-5.6) and T cell depletion (p = 0.001, RR 2; CI=1.3-2.9) as adverse prognostic factors for RR. A previous autologous SCT, poor performance status and refractory disease at transplantation were found to be significantly associated with a shorter PFS (p=0.04, RR 1.3; CI=1-1.6; p=0.0001, RR 2.4; CI=1.6-3.4; p=0.000,RR 2.1; CI=1.5-2.9, respectively) and refractory disease (p=0.0001, RR 2.2; CI=1.6-3.1) and poor performance status at the time of SCT (p=0.0001, RR 2.5; CI=1.7-3.6) with a shorter OS. Patients allografted from MUD tended to have a slightly increased risk of overall mortality in multivariate analysis, but this was not statistically significant (p=0.06, RR 1.2; CI=0.95-1.6). In conclusion, MUD SCT provides a curative option, not significantly inferior to that obtained with a matched sibling transplant, for selected patients with DLBCL who have failed conventional therapies, including autograft. Similarly, the type of conditioning regimen was not found to have a significant impact on patient outcome. Table 1. Clinical characteristics Sib vs MUD Sib (n = 301) MUD (n= 172) p Age (median, years) 46 45 N.S. Previous ASCT 48% 33% 0.004 Refractory disease 12% 12% N.S. Poor P.S. 13% 7% 0.06 RIC/CC 57%/43% 56%/42% N.S. SC source BM/PB 20%/80% 22%/78% N.S. ATG/ALG 15% 46% <0.001 in vivoüT-cellüdepletion 12% 20% 0.03 ex vivoüT-cellüdepletion 5% 12% 0.03 ASCT. Autologous stem cell transplantation; PS. Performance status; RIC. Reduced intensity conditioning; CC. Conventional conditioning; SC. Stem cell; BM. Bone marrow; PB. Peripheral blood; ATG/ALG. Anti-thymocyte globulin/ALG. Anti-lymphocyte globulin. Disclosures: No relevant conflicts of interest to declare.

Genoidentical Donor Versus A, B, Cw, DR, DQ, HLA Allelic-Matched Unrelated Donor for Stem Cell Transplantation in Patients with Standard Risk Haematological Malignancy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 976-976 ◽  
Author(s):  
Ibrahim Yakoub-Agha ◽  
Jean-Michel Boiron ◽  
Mauricette Michallet ◽  
Noel Milpied ◽  
Jean-Henri Bourhis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Sibling Donor ◽  
Significant Difference ◽  
Matched Sibling ◽  
Standard Risk

Abstract To compare outcome of pts with standard risk hematological malignancy undergoing allogeneic stem cell transplantation (allo-SCT) from either allelic A, B, Cw, DR and DQ HLA-matched unrelated (so called 10/10) or HLA-matched sibling donor, we conducted a prospective study including 12 French BMT centres. Between 01/2000 and 12/2002, 236 consecutive pts were enrolled. Fifty five pts received unrelated allo-SCT (pheno-group) and 181 received genoidentical allo-SCT (geno-group). Conditioning regimen associated TBI and Cy in all pts. Pts who received ATG with conditioning were excluded. GVHD prophylaxis consisted on Cs-A plus MTX. Diagnoses of the underlying disease were, AL (n=175) of whom 47 were in CR > 1; CML (n=43) of whom 4 were with accelerated phase and myelodysplastic syndrome (n=18) of whom 11 with untreated disease. The analyses were performed at the reference date of december 31th 2003. The two groups were comparable in terms of patients’ initial characteristics. However, pts of pheno-group were slightly younger and had more often CML whereas those belonging to geno-group had more often acute leukemia in 1st remission . At the date of analysis, the median follow-up was 955d (373–1398). The overall survival was 63% and 52,5% (p=NS) for geno and pheno-group, respectively. Furthermore, the statistical power was insufficient to demonstrate an equivalence of the two survival curves.. Although, the occurrence of acute GVHD of grade ≥2 was statistically higher in pheno-group (67% vs 52%, p=0.0), there was no significant difference en term of TRM between the two groups (27% vs 33% for geno and pheno-group, respectively). Relapse rates were 20% vs 26% and ultimately EFS (56% vs 52%) for geno and pheno-group. In multivariable analysis, only age (>36 years) and positive-CMV serology of recipient were found to adversely influence EFS. Finally, there was no demonstration of an independent prognostic value of the donor origin on outcome. In conclusion, although, the equivalence was not fully demonstrated between the two groups, these preliminary results of allo-SCT from 10/10 HLA-matched unrelated donor compare favourably to those obtained with HLA-matched sibling donor in patients with standard risk haematological malignancies.

Outcome Of Patients With IPSS Intermediate (int) Or High Risk Myelodysplastic Syndrome (MDS) According To Donor Availability: A Multicenter Prospective Non Interventional Study For The SFGM-TC and GFM

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 301-301 ◽  
Author(s):  
Marie Robin ◽  
Raphael Porcher ◽  
Lionel Ades ◽  
Emmanuel Raffoux ◽  
Mauricette Michallet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
No Donor ◽  
Matched Sibling ◽  
Mismatched Donor ◽  
Matched Donor ◽  
Bone Marrow Blasts ◽  
Related Mortality

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for MDS patients (pts). Due to transplant-related mortality, only pts with short life expectancy are referred to HSCT, usually those with IPSS int-2 or high risk. The aim of this prospective study was to compare outcome in candidates for HSCT according to donor availability: no donor, HLA-matched sibling donor, 10/10 HLA-matched unrelated donor and 9/10 HLA-mismatched unrelated donor. Method SFGM-TC and GFM centers that had agreed on general recommendations concerning the management of MDS pts participated to the study (16 centers). Transplant indications were int-2 or high IPSS, int-1 with refractory thrombocytopenia or proliferative CMML. Pts were registered in this study if older than 50 years, when they acquired an indication for HSCT and in the absence of comorbidity contraindicating HSCT. A donor research was initiated at registration including HLA-matched sibling donor, HLA-matched unrelated donor (10/10) or mismatched donor for one allele. Other alternative donors (mismatched unrelated cord blood or > 1 mismatched donor) were not accepted. Transplantation was scheduled upfront if bone marrow blasts < 10% at inclusion or after treatment with AML like anthracycline-aracytine chemotherapy (CT) or azacitidine (AZA) if marrow blasts > 10% ideally within 6 months if a donor was identified. Recommended reduced intensity conditioning regimen consisted in fludarabine, busulfan and anti-thymoglobulin with peripheral stem cells (PB) as source of stem cells. Characteristics of pts and disease were compared within 3 groups: no donor, HLA-matched donor (sibling or 10/10), HLA-one mismatched donor (9/10). Overall and disease free survivals (OS, DFS) were compared using Kaplan Meier estimates. Cumulative incidences of complete remission and disease-related mortality were compared using Gray-test. Results From April 2007 to January 2013, 163 pts were included: 34 (21%) pts had no donor; 115 (71%) pts had an HLA-matched donor (34% sibling and 37% unrelated) and 14 (9%) pts had an HLA mismatched donor. Groups were well-balanced for age, gender, time from diagnosis to inclusion, WHO classification, bone marrow blasts at time of inclusion, cytogenetic (IPSS) and IPSS classification. WHO classification at time of inclusion was: AML post MDS in 12, RAEB1 in 29, RAEB2 in 82, CMML1 or 2 in 20, RCMD in 14 and other MDS in 6 pts. Cytogenetics were favorable in 49 (30%), intermediate in 37 (23%) and poor in 74 (45%) pts. IPSS was int-1 for 8%, int-2 for 69% and high for 23% of pts. Median follow-up was 38 months. 117 pts were treated by AZA and 40 by CT. Bone marrow blasts < 10% were achieved in 68% and 57% for pts without and with donor, respectively. 69% of pts with HLA-identical donor and 57% of those with HLA-mismatched donor were transplanted. Some pts with donors were not transplantation because of excess of marrow blasts in most pts (> 10% in 3, > 20% in 20 pts), comorbidities contraindicating the transplantation acquired after inclusion (9 pts), early deaths (7 pts) and other causes in 3 pts. Four other pts scheduled for transplantation have not been transplanted yet. Probability of complete remission 12 months after inclusion was: 39% (95% CI: 22-55), 49% (95%CI: 40-58) and 46% (95%CI: 17-71) for pts without a donor, with an HLA-compatible donor and with HLA-mismatched donor. Disease-related mortality at 48 months was not significantly different in the 3 groups: 50 % (95%CI: 29-68), 38% (95%CI: 27-49), 51% (95%CI: 17-77). DFS was also not different in 3 groups: 18% (95%CI: 7-44), 25% (95%CI: 16-37) and 9% (95%CI: 1-57). In contrast, OS at 48 months was better in pts with HLA-compatible donor than in pts without donor or those with HLA-mismatched donor: 35% (26-49), 17% (6-43) and 8% (1-55), respectively, p=0.011 (Figure 1). The poor survival observed in pts transplanted with an HLA-mismatched donor may be due to their small number and requires further analysis in a larger cohort. Outcome was not different in pts receiving PB from HLA-matched sibling or from HLA 10/10 matched unrelated donor. Conclusion In a prospective study, we observed that int-2 or high risk MDS pts with a HLA-matched donor have an improved life expectancy as compared to pts without donor. This study confirmed that they should be referred to the transplantation before acquisition of comorbidity contraindicating HSCT. Disclosures: No relevant conflicts of interest to declare.

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