Development of BK Virus-Associated Hemorrhagic Cystitis (HC) Is Associated with Decreased Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1933-1933
Author(s):  
Vivien Bautzer ◽  
Fernanda NC Santos ◽  
Erika AF Oliveira ◽  
Erika Maria Macedo ◽  
Fabio R. Kerbauy ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Bk Virus ◽  
Pcr Assay ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
The Impact ◽  
Time Varying Covariates ◽  
Cmv Reactivation

Abstract Abstract 1933 Introduction: Infection by BK virus in the allo-HSCT setting is associated with the development of HC, which is a major cause of morbidity. There are few studies evaluating the impact of BK virus-associated HC on survival post allo-HSCT. Objectives: To evaluate the incidence of HC by BK virus in patients after allo-HSCT and its impact on survival. Methods: We retrospectively reviewed the medical charts of 107 patients who underwent allo-HSCT at Hospital Israelita Albert Einstein from July 2007 until November 2011. HC was defined by the presence of any degree of unexplained hematuria and positivity for BK virus in a urine sample by quantitative polymerase chain reaction (PCR) assay. CMV reactivation was defined as positivity in the antigenemia assay or greater than 165 copies in a quantitative PCR assay. Three patients were excluded because PCR results for BK virus were inconclusive, with 104 patients being analyzed in the final cohort. Cumulative incidence (CI) of HC, CMV reactivation and acute graft-versus-host disease (GVHD) were estimated taking into account the competing risk of death. Overall survival (OS) was estimated by the Kaplan-Meier method. Gray model was used for regression analysis of factors associated with the development of HC. Hazard ratios (HRs) were estimated by a Cox multivariable proportional hazards model, considering HC, CMV reactivation and acute GVHD as discrete time-varying covariates. Results: Median age was 28 years (range 6 months–76 years), and 60.5% of patients were male. About 37% had high-risk disease (refractory leukemia/lymphoma or 2nd-transplantation). Source of HSCs included matched related donors (37%), 10/10 HLA-matched unrelated donors (24%) and cord blood/haploidentical donors in 39%. The conditioning regimen was myeloablative in 81% of cases. The median follow-up of the whole cohort was 450 days (range 9–1624 days). At 1 year, the cumulative incidence of HC was 30.5% (95% confidence interval [CI] 21.8%–39.7%). The 1-year incidence of CMV reactivation and acute GVHD (all grades) was 57.1% and 39.7%, respectively. In a multivariate analysis taking into account age, sex, risk of disease, source of HSCs, intensity of conditioning, CMV reactivation and acute GVHD, only receiving cells from cord blood/haploidentical donors was associated with an increased incidence of HC (subhazard ratio 4.04, 95% CI 1.31–12.49, p = 0.015). The 1 year-OS of the whole cohort was 55% (95% CI 44–62%). Patients who developed HC had an inferior OS (1 year: 18% vs. 70%; HR= 4.40, p <0.0001; 95% CI 2.37–8.14). In the multivariate Cox analysis for OS, after adjusting for age, sex, disease risk, source of HSCs, intensity of conditioning, CMV reactivation and development of acute GVHD, development of HC was associated with an increased mortality (table). Conclusion: In this cohort, the development of CH was associated with an inferior OS in patients undergoing allogeneic HSCT. Even after adjusting for several variables, including development of acute GVHD and CMV reactivation, HC still remained an important factor associated with decreased survrival. It is possible that HC is not the direct cause of the increased mortality, but is rather a surrogate marker of a state of severe immunosuppression and increased risk of dying in the post-transplant setting. Nonetheless, our results suggest that the development of BK virus-associated HC in allo-HSCT patients is associated with inferior survival and future studies should confirm this finding and seek strategies to prevent this complication. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Single or Associated CMV, EBV and BK Virus Reactivation Early after Allogeneic Hematopoietic Stem Cell Transplantation on Relapse Incidence

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1428-1428
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Sandrine Leroy ◽  
Fiorenza Barraco ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Median Time ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Bk Virus ◽  
Viral Reactivation ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Cmv Reactivation ◽  
Risk Of Relapse

Abstract Background: Many recent studies have evaluated the impact of cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showing a significant association with reduced risk of relapse. On the other hand, other frequent viral infections or reactivations like Epstein-Barr virus (EBV) and BK virus (BK-V) have not been evaluated in the same context and we do not know whether their association has an impact on transplantation outcomes or not. Objective: The aim of this study is to evaluate the impact of CMV, EBV and BK-V reactivation up to 3 months after allo-HSCT whether alone or associated on the relapse incidence of patients with hematological malignancies. Patients and methods: We evaluated 359 consecutive patients with hematological malignancies who received allo-HSCT and were followed in our center between January 2008 and June 2013; there were 218 (61%) males and 141 (39%) females with a median age of 48 years (range: 18-70), 182 (51%) had acute myeloid leukemia, 44 (12%) multiple myeloma, 34 (9%) myelodysplastic syndrome, 30 (8%) Non-Hodgkin lymphoma, 7 (2%) chronic lymphocytic leukemia, 21 (6%) myeloproliferative syndrome, 14 (4%) Hodgkin disease, 13 (4%) chronic myeloid leukemia and 14 (4%) aplastic anemia. At transplantation, 227 (63%) patients were in complete response (CR) or chronic phase (CP) and 132 (37%) were in less than CR or CP. For conditioning regimen, 171 (48%) were myeloablative and 188 (52%) were reduced intensity. DNA levels of CMV, EBV and BK-V in blood were detected by quantitative real-time polymerase chain reaction (RQ-PCR) after weekly monitoring up to 3 months after allo-HSCT. CMV-DNA, EBV-DNA or BK-V-DNA was considered positive when the copies exceeded 1000 copies/ml. Results: Among 359 patients, there were 102 patients who had CMV reactivation after a median time of 1.4 months (1.1-1.8) after allo-HSCT with a cumulative incidence of 25 % (24-26) at 3 months; 222 patients had EBV reactivation after a median time of 1.3 months (0.7-2.5) after allo-HSCT with a cumulative incidence of 48 % (47-50) at 3 months; and 38 patients had BK-V reactivation after a median time of 1.1 months (0.7-1.5) after allo-HSCT with a cumulative incidence of 10 % (9-11) at 3 months. The cumulative incidence of relapse at one and two years for the whole population was 27% (26-28) and 34% (33-35) respectively and the cumulative incidence of transplant-related mortality (TRM) was 22% (21-23) and 25% (24-26) respectively. The multivariate analysis took into account the type of disease, the type of conditioning, the disease status at transplantation, the presence of acute GVHD and single or the association of viral reactivation; this analysis showed that the presence of a single viral reactivation was associated with a significant lower relapse rate, for CMV: sdHR=0.34 [0.12-0.92], p=0.03, for EBV: sdHR= 0.52 [0.35-1], p=0.05 and for BK-V: sdHR=0.58[0.24-0.7], p=0.002; and that patients who have an associated CMV and EBV reactivation had significantly higher risk of relapse, sdHR= 5 [1.59-16], p=0.006. There was no significant impact of these reactivations on TRM. Conclusion: We confirmed the positive impact of CMV reactivation on relapse incidence, in addition we demonstrated that this impact exists also for EBV and BK-V, however we showed for the first time that the association of CMV and EBV was significantly associated with a higher risk of relapse. More investigations are ongoing to evaluate the immunological status of these patients and the different administered anti-viral treatments. Disclosures No relevant conflicts of interest to declare.

Matched HLA Haplotype Contributes to Reduce Sever Acute GVHD with Conserving GVL Effect in HLA-Mismatched Cord Blood Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4140-4140
Author(s):  
Satoshi Takahashi ◽  
Jun Ooi ◽  
Seiko Kato ◽  
Toshiro Kawakita ◽  
Arinobu Tojo ◽  
...  
Keyword(s):  
Cord Blood ◽  
Acute Gvhd ◽  
Adult Patients ◽  
The Other ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Matched Group ◽  
Other Hand ◽  
The Impact

Abstract Abstract 4140 Study purpose: The cell dose of graft is the primary factor to select for cord blood (CB) unit and most of adult patients choose human leukocyte antigen (HLA)-mismatched CB graft. We have performed more than 7,500 CB transplantation (CBT) in Japan. Almost two-third of them has been using 2-loci HLA-mismatched CB unit. The degree of HLA disparity between patient and graft is known to be associated with risks of poor graft function and of graft-versus-host disease (GVHD) on allogeneic hematopoietic stem cell transplantation. On the other hand, those risks of transplant-related complications are not equivalent even among the donor-recipient pairs who have same number of mismatched HLA antigens. The mismatched HLA haplotype could be responsible for post-transplant adverse events because of incompatibility of non-HLA polymorphic genes. Recently, HLA haplotype matching effect on GVHD has been demonstrated in unrelated bone marrow transplantation (S Morishima, et al. Blood 2010). In this study, we have performed the single institutional analysis to determine the impact of HLA haplotype matching in HLA-mismatched CBT. Patients and Methods: We studied the clinical outcomes of 170 consecutive adult patients who received unrelated CBT between August 1998 and January 2011 in the institute of medical Science, University of Tokyo. Patients received previous allogeneic transplants were excluded from this study. All patients received myeloablative regimens including 12 Gy of total body irradiation, cyclosporine plus short term methotraxate for GVHD prophylaxis and almost same supportive care by the institutional protocol. By low-resolution typing method for HLA-A, -B and -DR loci, 6 patients received matched grafts, 57 received 1 antigen-mismatched and 107 received 2 antigens-mismatched grafts in the graft-versus-host (GvH) direction. We have determined the HLA haplotype based on common haplotypes in Japanese population referred from the 11th International Histocompatibility Workshop and other previous reports. We evaluated the impact of haplotype matching on cumulative incidences of hematopoietic recovery, of GVHD, of relapse and of non-relapse mortality (NRM) using the Pepe and Mori's test. Estimates of overall and disease-free survivals were calculated using the Kaplan-Meier method and analyzed by the log-rank test. Results: Thirty-three among all 170 pairs were defined as the haplotype-matched pairs sharing same haplotypes in both grafts and recipients. The age, sex, cytomegalovirus serological status, diagnosis, risk of the disease at the transplant, numbers of total nucleated cells and CD34+ cells at the cryopreserved were not significantly different between both groups with and without matched haplotypes. Engraftment of platelet after CBT tended to be earlier in haplotype-matched group compared with control group among the 1 antigen-mismatched pairs in the host-versus-graft direction (median: 38 days versus 44 days) and among the 2 antigens-mismatched pairs (median: 38 days versus 42 days), but those were not significant. The cumulative incidences of grades III and IV acute GVHD in patients with haplotype-matched (7%) were significantly lower than non-matched group (9%) among 2 antigens-mismatched pairs in the GvH direction (P=0.033). Notably, cumulative incidences of relapse tended to be lower in haplotype-matched patients among this group (3 years cumulative incidences were 7% in haplotype-matched patients versus 21% in non-matched patients, P=0.086). The haplotype matching effects were not observed in survival rates, cumulative incidences of NRM among any HLA-mismatched pairs. Conclusion: Those data suggest that untyped variation carried on the HLA haplotytpe might be better to be matched. The haplotype matching seemed to effect on lower risk of sever acute GVHD, on the other hand, graft-versus-leukemia effect was conserved in the setting of HLA-mismatched CBT. Disclosures: No relevant conflicts of interest to declare.

Negative Effect of KIR Alloreactivity in Recipients of Umbilical Cord Blood Transplantation Depends on Transplantation Conditioning Intensity

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 152-152
Author(s):  
Claudio Brunstein ◽  
John E. Wagner ◽  
Daniel Weisdorf ◽  
Sarah Cooley ◽  
Harriet Noreen ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Cord Blood Transplantation ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
Increased Risk ◽  
Reduced Intensity

Abstract Transplant strategies involving natural killer (NK) cell alloreactivity (KIR-ligand mismatch [KIR-L mismatch]) have demonstrated superior outcomes for patients receiving T cell depleted HLA haploidentical hematopoietic stem cell allografts. It is unknown whether KIR-L mismatch has a similar effect in recipients of partially HLA-matched umbilical cord blood (UCB) grafts which contain comparatively few T-cells. We examined the clinical impact of KIR-L mismatch in 257 UCB recipients treated with either a myeloablative (n=155) or reduced intensity (n=102) regimen. After myeloablative conditioning, KIR-L mismatch had no demonstrable effect on grades III–IV acute GVHD (17% [CI, 6–28%] vs. 17% [CI, 10–24], p=.97), transplant-related mortality (TRM) (27% [CI, 14–40%] vs. 18% [CI, 11–25%], p=.19), relapse at 2 yrs (18% [95%CI, 6–30%] vs. 28% [95%CI, 19–27%], p=.37) and survival at 3 yrs (50% [CI, 32–68%] vs. 57% [CI, 47–67%], p=.46). In contrast, following reduced intensity conditioning when the engrafting unit was KIR-L mismatched there was a significantly higher incidence of grades III–IV acute GVHD (42% [CI, 27–59) vs. 13% [CI, 5–21], p &lt; .01). Multivariate analysis confirmed NK cell alloreactivity as the only predictive factor associated with severe acute GVHD was (RR 1.8, CI [1.1–2.9]; p=.02). TRM was higher (27% [CI, 12–42%] vs. 12% [CI, 5–19%], p=.03) and three year survival was poorer (32% [CI, 15–59%] vs. 52% [CI, 47–67%], p=.03) when the engrafting unit was KIR-L mismatched, but relapse was unaffected (39% [95%CI, 21–57%] vs. 47% [95%CI, 34–60%], p=.72). KIR-L mismatch in recipients of a RIC UCB transplant was associated with a significant increased risk of death (RR 1.8, 95%CI, 1.0–3.1, p=.05). This data identify divergent effects of NK cell alloreactivity which are unmasked when comparing myeloablative versus RIC transplant platforms. We conclude that KIR-L mismatch should be avoided in recipients of a reduced intensity UCB transplant.

Polyoma (BK) Viruria Prior to Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) from Donors Other Than Matched Siblings: A Prospective Evaluation of Hemorrhagic Cystitis (HC) Incidence

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 50-50
Author(s):  
Leandro de Padua silva ◽  
Poliana Patah ◽  
Rima M. Saliba ◽  
Nicholas A. Szewczyk ◽  
Lisa Gilman ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Univariate Analysis ◽  
Bk Virus ◽  
Time Dependent ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Donor Type

Abstract Background: BK virus infection has been associated with development of HC after HSCT, but most studies detected the virus at the time of bleeding, therefore not allowing estimation of the risk imposed by asymptomatic infection. We hypothesized that viruria prior to HSCT increased the risk of HC, and sought to investigate this hypothesis in a cohort of consecutive patients receiving HSCT from donors other than HLA-identical siblings in our institution from 09/2005 and 08/2007. Patients and Methods: We prospectively performed a quantitative PCR on urine samples collected before admission to transplant and on day 30 after transplant. The quantitative BK virus assay was performed at Focus Diagnostics, Inc., Cyprus, CA with a commercially available kit. A set of quantitative standards are run in parallel and assay is linear through 39 million copies/mL. Risk factors for the development of HC were evaluated on univariate and multivariate analysis using Cox’s regression model. The cumulative incidence (CI) of HC was estimated considering death without HC as a competing event. Results: 209 pts were studied (132 males). Median age was 49 years (range, 19–71). Diagnoses included leukemias (n=161, 77%), lymphoma and myeloma (n=46, 22%) and others (n=2, 1%). Donors were unrelated (n=178), haploidentical (n=8) and unrelated cord blood (CB) (n=23). Stem cell source was bone marrow (BM, n=78), peripheral blood (PB; n=108), and CB (n=23). . Conditioning regimen was myeloablative in 110 pts and reduced intensity (RIC) in 99 pts; 38 pts (18%) received cyclophosphamide-containing regimens. GVHD prophylaxis was tacrolimus and mini-methotrexate. Median time to platelet engraftment was 20 days (range, 0–164). Pre transplant BK viruria was detected in 96 patients (46%). The number of viral copies ranged from 300 to &gt; 200 million copies. Twenty five patients (11%) developed HC within one year after HSCT at a median of 59 days (range, 8–225). In 6 pts, HC was diagnosed before platelet engraftment. The severity of HC was grade 1 in 3 pts, grade 2 in 11, grade 3 in 8, an grade 4 in 3. On univariate analysis, donor type was the most significant predictor of the incidence of HC within a year of HSCT, with recipients of haploidentical or CB transplant having the highest incidence rate (HR=3.1, p=0.009). There was also a trend for higher HC incidence in patients who received a myeloablative conditioning (HR=2.3, p=0.06), and in those who had a positive PCR before transplant (HR=2, p =0.095). Because of the small number of HC cases in pts who received a RIC (n=7/99, CI of HC 7%) we could not perform a multivariate analysis adjusting for the type of conditioning. In patients who received a myeloablative conditioning multivariate analysis showed a significantly higher incidence of HC in pts who received a haploidentical or CB transplant (HR=3.8, p=0.006); and in pts with a positive PCR before transplant (HR=2.9, p=0.03). The cumulative incidence of HC in pts who had both adverse factors was 58%, compared with 11% and 13% in those who had either one or none of these factors, respectively. There was no significant association between the incidence of HC and grade II-IV acute GVHD, considered as a time dependent variable, patient age, stem cell type (BM vs. PB), use of cyclophosphamide in conditioning, BK viral load, or PCR positivity on day 30 post HSCT. With a median follow-up among survivors of 11 months (range 4–32), HC, considered as time dependent variable, did not have a significant impact on survival. Conclusion: BK viruria pre-HSCT may be a predict factor for development of HC, especially for those receiving haploidentical or CB transplants using a myeloablative regimen. Cumulative incidence of HC as a function of preparative regimen intensity and BK virus PCR status pre transplant Figure Figure Incidence of HC Variable (n) No patients with HC (%) Total (209) 25 (12%) Age ≤ 50 years (99) 12 (12%) &gt; 50 years (110) 13 (12%) Sex M/F 132/77 16(12%)/9(12%) Diagnosis Leukemia (161) 18 (11%) Lymphoma (40) 7 (17.5%) Conditioning Ablative (110) 18 (16%) Non-ablative (99) 7 (7%) Donor Type MUD(169) 17 (10%) Haplo/cords (31) 8 (25%) acute GVHD I – II (88) 10 (12%) III – IV (26) 4 (15%) Pre SCT PCR Positive (96) 16 (17%) Negative (111) 9 (8%)

Impact of HLA Haplotype Matching On Engraftment in Reduced Intensity Cord Blood Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3043-3043
Author(s):  
Kazuya Ishiwata ◽  
Hikari Ota ◽  
Aya Nishida ◽  
Masanori Tsuji ◽  
Hisashi Yamamoto ◽  
...  
Keyword(s):  
High Resolution ◽  
Cord Blood ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Post Transplant ◽  
Matched Group ◽  
Blood Transplantation ◽  
The Impact ◽  
Reduced Intensity

Abstract Abstract 3043 Introduction HLA-mismatched unrelated cord blood transplantation (UCBT) is feasible and, in retrospective comparative analyses, allows survival rates similar to conventional unrelated HLA-matched adult-derived grafts. Although it is clear that the degree of UCB HLA mismatch in patients has a negative effect on outcomes, the biologic implications of HLA haplotype itself have not been explored for UCBT. In unrelated bone marrow transplantation, an effect of HLA haplotype matching on GVHD has been clarified. (S.Morishima. et al. Blood 2010). This study was conducted to determine the impact of HLA haplotype matching in reduced intensity UCBT. Patients and Methods To determine the impact of HLA haplotype matching with outcomes after UCBT, We retrospectively reviewed patients with hematologic malignancies who underwent reduced intensity CBT at Toranomon Hospital from August 2006 and December 2010 consecutively. Patients who had prior history of transplantation, were in poor performance status (ECOG PS >3), had active bacterial or fungal infections at the time of conditioning were excluded. Then, the remaining 164 consecutive patients were reviewed. The most frequently used conditioning regimens were fludarabine, alkylating agent (melphalan or busulfan) with total body irradination (TBI), tacrolimus plus mycophenolate mofetil for GVHD prophylaxis. DNAs of 164 pairs were analysed for HLA-A, -B, and -DRB1 based on High Resolution typing, and we have determined the HLA haplotype based on Japanese common HLA haplotypes referred from the previous reports. Results For A, B, DR based on high resolution typing the following mismatch occurred: no mismatch 3(2%), one mismatch 12(7%), two mismatch 58(35%), three mismatch 60(37%), four mismatch 28(17%), five mismatch 3(2%) in the GvH direction, and: no mismatch 2(1%), one mismatch 16(10%), two mismatch 55(34%), three mismatch 56(34%), four mismatch 32(20), five mismatch 3(2%) in the HvG direction. Then 37 among 164 pairs were defined as the HLA haplotype matched group. The number of total nucleated cells and CD34+ cells were not significantly different between HLA haplotype matched group and non-matched group. The cumulative incidence of neutrophil recovery was higher in HLA haplotype matched group than in non-matched group.( 94.6% vs. 80.3% up to day 60, p=0.0027). Lower incidence of pre-engraftment immune reaction(PIR) and acute GVHD were observed in haplotype matched group (37.8 % vs. 47.9 % up to day 60 post-transplant, P = 0.32), III to IV acute GVHD( 18.9% vs. 27.7% up to day 100 post-transplant, p=0.29). The cumulative incidences of relapse tended to be lower in haplotype matched group than in non-matched group (21.5% vs. 31.5%, P=0.28).Overall survival (OS) was estimated as 36.0 % at 3 years post-transplant. There were no significant differences between mathed and non-matched group in the cumulative incidence of OS (36.8 % vs. 34.3% at 3 years post-transplant, P = 0.84). Conclusion HLA haplotype matching in UCBT was found to have a significant impact on engraftment in this analysis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Delayed-onset cytomegalovirus infection is frequent after discontinuing letermovir in cord blood transplant recipients

2021 ◽  
Vol 5 (16) ◽  
pp. 3113-3119
Author(s):  
Joshua A. Hill ◽  
Danniel Zamora ◽  
Hu Xie ◽  
Laurel A. Thur ◽  
Colleen Delaney ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cumulative Incidence ◽  
Cord Blood Transplantation ◽  
High Dose ◽  
Close Monitoring ◽  
Historical Cohort ◽  
Delayed Onset ◽  
Blood Transplantation ◽  
The Impact ◽  
Cmv Reactivation

Abstract Cytomegalovirus (CMV)-seropositive umbilical cord blood transplantation (CBT) recipients have a high incidence of CMV-associated complications. There are limited data regarding the efficacy of letermovir for preventing clinically significant CMV infection (CS-CMVi), and the impact of letermovir prophylaxis on delayed-onset CMV reactivation after letermovir discontinuation, in CBT recipients. We compared the cumulative incidence of CS-CMVi and CMV detection in 21 CMV-seropositive CBT recipients receiving letermovir prophylaxis with a historical cohort of 40 CBT recipients receiving high-dose valacyclovir prophylaxis. Letermovir was administered on day +1 up to day +98. The cumulative incidence of CS-CMVi was significantly lower by day 98 in the letermovir cohort (19% vs 65%). This difference was lost by 1 year due to a higher incidence of delayed-onset CMV reactivation in the letermovir cohort. No patients developed CMV disease in the letermovir cohort within the first 98 days compared with 2 cases (2.4%) in the high-dose valacyclovir cohort; 2 patients developed CMV enteritis after discontinuing letermovir. Median viral loads were similar in both cohorts. Thus, letermovir is effective at preventing CS-CMVi after CBT, but frequent delayed-onset infections after letermovir discontinuation mandate close monitoring and consideration for extended prophylaxis.

scholarly journals Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jaime Sanz ◽  
Jacques-Emmanuel Galimard ◽  
Myriam Labopin ◽  
Boris Afanasyev ◽  
Moiseev Ivan Sergeevich ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Donor Type ◽  
Matched Sibling ◽  
The Impact

Abstract Background There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL). Methods We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years. Results Median age of patients was 38 years (range 18–76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II–IV and III–IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS. Conclusions Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

High-level ectopic HOXB4 expression confers a profound in vivo competitive growth advantage on human cord blood CD34+ cells, but impairs lymphomyeloid differentiation

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1759-1768 ◽  
Author(s):  
Bernhard Schiedlmeier ◽  
Hannes Klump ◽  
Elke Will ◽  
Gökhan Arman-Kalcek ◽  
Zhixiong Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cord Blood ◽  
Therapeutic Window ◽  
Hematopoietic Stem ◽  
Expression Levels ◽  
Cd34 Cells ◽  
Cord Blood Cd34 ◽  
The Impact

Ectopic retroviral expression of homeobox B4 (HOXB4) causes an accelerated and enhanced regeneration of murine hematopoietic stem cells (HSCs) and is not known to compromise any program of lineage differentiation. However, HOXB4 expression levels for expansion of human stem cells have still to be established. To test the proposed hypothesis that HOXB4 could become a prime tool for in vivo expansion of genetically modified human HSCs, we retrovirally overexpressed HOXB4 in purified cord blood (CB) CD34+ cells together with green fluorescent protein (GFP) as a reporter protein, and evaluated the impact of ectopic HOXB4 expression on proliferation and differentiation in vitro and in vivo. When injected separately into nonobese diabetic–severe combined immunodeficient (NOD/SCID) mice or in competition with control vector–transduced cells, HOXB4-overexpressing cord blood CD34+ cells had a selective growth advantage in vivo, which resulted in a marked enhancement of the primitive CD34+ subpopulation (P = .01). However, high HOXB4 expression substantially impaired the myeloerythroid differentiation program, and this was reflected in a severe reduction of erythroid and myeloid progenitors in vitro (P < .03) and in vivo (P = .01). Furthermore, HOXB4 overexpression also significantly reduced B-cell output (P < .01). These results show for the first time unwanted side effects of ectopic HOXB4 expression and therefore underscore the need to carefully determine the therapeutic window of HOXB4 expression levels before initializing clinical trials.

Hematopoietic Stem Cell Transplantation (HSCT) from Alternative Donors for Acute Leukemia at High-Risk of Relapse. The Haploidentical Option.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 441-441
Author(s):  
Franco Aversa ◽  
Antonio Tabilio ◽  
Adelmo Terenzi ◽  
Stelvio Ballanti ◽  
Alessandra Carotti ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Acute Leukemia ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Prognostic Features ◽  
Post Transplant ◽  
Leukemia Relapse

Abstract Despite advances in chemotherapy for acute leukemia, survival is poor when patients have unfavourable prognostic features at diagnosis, when they do not achieve CR after the first induction cycle and when they are in second or later remission. In these circumstances an allogeneic HSCT is preferred. The chance of finding a matched unrelated donor depends on the HLA diversity and although molecular analysis achieves closer matches it reduces the probability of finding a donor. Furthermore, many patients relapse while waiting for transplant. Transplantation of HSCs from a one-haplotype mismatched family member offers an immediate source of HSCs to almost all leukemia patients who urgently need an allogeneic transplantation because of the high-risk of leukemia relapse and who do not have a matched, either related or unrelated, avaible donor. Over the past decade, our group has shown the two major obstacles to mismatched transplants, that is severe acute GVHD in T-cell-replete transplants and graft rejection in T-cell-depleted transplants, can be overcome by infusing a megadose of extensively T-cell-depleted HSCs after an immuno-myelo-ablative conditioning regimen. Since our first reports (Aversa et al. Blood 1994 and NEJM 1998), the main modifications to our original approach were: a) in October 1995, fludarabine was substituted for cyclophosphamide in our TBI-based conditioning regimen; b) peripheral blood cells were positively selected by using initially the Ceprate device and then, since January 1999, the Clinimacs instrument which ensures a 4.5 log T-cell depletion in a one-step procedure with no E-rosetting; c) in the 138 patients transplanted since January 1999 post-transplant G-CSF administration was stopped so as to improve immune recovery. The patient population included 90 AML and 48 ALL, median age 28 years (range 9–62), 40 (29%) in bad-risk CR I, 43 (31%) in second or later CR and 55 (40%) in relapse at transplant. Primary full-donor engraftment was achieved in 125/134 evaluable patients (93%); 8 patients engrafted after second transplants. Overall engraftment was achieved in 133 patients (96%). Without any post-transplant immunosuppressive prophylaxis, grade II-IV acute GvHD occurred in 7/133 evaluable patients and 5/106 developed chronic GvHD. Cumulative incidence (C.I. 95%) of non-leukemia mortality was 36% (19%–53%) and 40% (19%–66%) for patients who were respectively in CR or in relapse at transplant. 38/51 deaths were infection-related. Disease status was the major risk factor for relapse and EFS. Cumulative incidence of leukemia relapse was 27% (12%–45%) and 60% (30%–80%), p=0.006, for ALL patients in CR and relapse respectively; 17% (8%–29%) and 46% (29%–61%), p=0.0001, for AML in CR and relapse respectively. ALL and AML patients transplanted in relapse have, respectively, a 6% and 13% probability of surviving event-free. For those transplanted in remission, EFS is respectively 38% and 50% for ALL and AML patients in any CR at transplant. These results indicate the mismatched transplant should be offered to high-risk acute leukemia patients without a HLA-identical donor not as a last resort, but as a viable option in the early stages of the disease.

Disseminated Adenovirus Infections after Allogeneic Hematopoietic Stem Cell Transplantation: High Rate of Associated Co-Morbidity and Mortality.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2925-2925
Author(s):  
Marie Robin ◽  
Stéphanie Marque-Juillet ◽  
Catherine Scieux ◽  
Régis Peffault de Latour ◽  
Christèle Ferry ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cord Blood ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Hematopoietic Stem ◽  
Grade Ii

Abstract Adenovirus (ADV) infection is associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to determine the cumulative incidence, the evolution and the risk factors of disseminated ADV infection defined as a real time ADV PCR positive in blood and 1 or more additional sites. Between January 2000 and April 2006, 38 patients with disseminated ADV were identified. Median age at diagnosis was 15 years (4 – 48). Primary diseases were leukemia (n=16), Fanconi anemia (n=10) or others (n=2). All but one patient received an unrelated HSCT. The graft consisted in peripheral blood (n=3), bone marrow (n=10) and cord blood (n=15). Plasma ADV PCR was positive at a median of 79 days after HSCT (range: 12 – 460). Involved organs were: liver (n=12), respiratory tract (n=15), gut (n=21), cystitis (n=12) and 19 patients had fever. Twenty-one patients had grade II-IV GVHD. The majority of the patients had other concomitant infections: invasive fungal infection (n=15), 1 to 4 other virus (CMV, EBV, RSV, parainfluenzae, BK virus) (n=21) and bacteremia (n=12). Risk factors for disseminated ADV were analyzed among patients who received an unrelated HSCT, and separately in adults and in children. 265 patients received an unrelated HSCT during the same period. Cumulative incidence (with death as a competing event) of disseminated ADV was 9% (95%CI: 4–3) in adults and 18% (95%CI: 10-27) in children. In adults, grade II–IV GVHD [time dependant covariate, Hazard Ratio (HR): 3.47, 95%CI: 1.14–10.6, p = 0.029] and cord blood as source of stem cell [HR: 7.10, 95%CI: 2.41-20.9, p = 0.0038] were associated with disseminated ADV infection. In children, grade II-IV GVHD [HR: 3.94, 95%CI: 1.15–13.5, p = 0.029] and Fanconi as primary disease [HR: 5.28, 95%CI: 1.69-16.6, p = 0.0043] were associated with disseminated ADV infection. Twenty-three patients were treated by cidofovir. Four patients had complete response (CR) [negative ADV PCR], 2 patients had primary CR followed by relapse and 2 patients had stable disease 90 and 67 days after treatment initiation. Fifteen patients were refractory to treatment. Main differences between responders and non-responders were ADV DNA load at onset of treatment (1343 versus 71 674 copies/ml), median time from HSCT to ADV diagnosis (98 versus 53 days), dosage of corticosteroids at time of treatment (0.75mg/kg/d versus 1.5 mg/kg/d), neutrophil (2× 109/L versus 1.5 × 109/L) and lymphocyte count (0.135 × 109/L and 0.070 × 109/L). An increase in the plasma viral load of ≥ 4 log10 in the 30 days after the first cidofovir dose was always followed by a fatal issue (n=9). Four-month infectious-related mortality and 1-year survival after diagnosis was 72% (95% confidence interval: 55–90) and 23% (95%CI:10–51). The only survivors were among the sustained responders in whom 1-year survival was 33% (95%CI: 7–100). In spite of earlier diagnosis and cidofovir treatment, disseminated ADV disease after HSCT leads to a high mortality rate, mainly related to multiple infections for all patients, reflecting a profound underlying immune defect.

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