«Graft-Versus-Host» Disease after Haploidentical Hematopoietic Stem Cell Transplantation from Relative Donors in Children with Cancer, Prophylaxis Regimens and Correlation with «Graft-Versus-Tumor» Effect: a Retrospective Cohort Study

2019 ◽  
Vol 6 (2) ◽  
pp. 113-122
Author(s):  
Natalia N. Subbotina ◽  
Igor S. Dolgopolov ◽  
Vidmante V. Daylidite ◽  
Vasiliy K. Boyarshinov ◽  
George L. Mentkevich
Keyword(s):  
Cohort Study ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Solid Tumors ◽  
Retrospective Cohort ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Background. «Graft-versus-host» disease (GVHD) is a major complication of allogeneic Hematopoietic Stem Cell Transplantation (HSCT), the main cause of non-relapse mortality. The actual problems of alternative donors HSCTs are GVHD prophylaxis and its distinction from «graft-versus-tumor» (GVT) effect. Objective. Assessment of incidence and severity of GVHD in children with very high-risk cancer after non-T-depleted haplo-HSCT; searching some correlation between controlled chronic GVHD (chGVHD) and GVT effect after HSCT, compare cyclosporine (CSA) and tacrolimus based GVHD prophylaxis. Methods. We provided the GVHD assessment in 74 recipients of haplo-HSCs from relatives since 2001 till 2018 in retrospective cohort study. Effect of chGVHD on the HSCT results was assessed in 23 patients with acute myeloid leukemia (AML) and 15 patients with solid tumors. We analyzed the incidence of severe acute and chronic GVHD in patients who received CSA or tacrolimus-based prophylaxis. Results. The incidence of severe aGHVD in our study was 15%, chGVHD — 12%. Switch CSA to tacrolimus resulted in reduction of severe aGVHD from 21% to 9% and full elimination of severe extensive chGVHD. Controlled chGVHD after haplo-HSCT was associated with relapse reduction from 48.7% to 30% and improvement of overall survival (OS) from 46.5% to 80.8% in patients with AML. We haven’t seen any clinically significant antitumor effect of graft in patients with solid tumors. Conclusion. In our study the incidence of severe GVHD corresponds to world data after HSCTs from alternative donors, it went down after switch from CSA to tacrolimus. We found some correlation between controlled chGVHD development and HSCT results improvement in patients with AML. The GVT effect of haplo-graft in solid tumors is almost absent.

Low Incidence of Pulmonary Graft-Versus-Host Disease in Older Patients After Reduced Toxicity Conditioning with FBM Prior to Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4660-4660
Author(s):  
Jesus Duque-Afonso ◽  
Antje Prasse ◽  
Ralph M. Waesch ◽  
Hartmut Bertz ◽  
Jürgen Finke ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Pulmonary Function ◽  
Older Patients ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Reduced Toxicity

Abstract Abstract 4660 Allogeneic hematopoietic stem cell transplantation (HSCT) of older or comorbid patients has become feasible due to new protocols for reduced toxicity/intensity conditioning. Particularly using fludarabine, BCNU and melphalan (FBM) as preparative regimen confers reduced toxicity with substantial anti-leukemic activity, therefore allowing allogeneic HSCT in patients up to ages well above 70. Nevertheless, chronic Graft-versus-Host disease (cGvHD) of the lung remains a serious non infectious, late onset pulmonary complication, contributing to treatment related morbidity and mortality of the older patients. Since the clinical entity of pulmonary cGvHD in an older population after reduced toxicity/intensity conditioning has not yet been well characterized, we performed a retrospective analysis of patients, who were transplanted after FBM conditioning at the University Hospital Freiburg between 2003 and 2005 and were alive at least 100 days after HSCT. 92 patients were enrolled in this study (median age of 60 years (range 29-71)). All patients received conditioning with fludarabin (4-5 × 30 mg/m2), BCNU (or carmustin, patients> 55 years: 2×150 mg/m2, <55 years: 2×200 mg/m2) and melphalan (patients >55 years 1×110mg/m2, <55 years: 1×140 mg/m2, fo). Peripheral stem cell grafts were used in most of the cases together with cyclosporin based GvHD prophylaxis. Seven patients (8.2%) developed a pulmonary cGvHD as defined by NIH criteria with a median time after HCT of 13.3 months (range 7-19m). In those patients, pulmonary function tests prior to HCT and on day +100 (prior to pulmonary GvHD) revealed a significant reduction in mean % of predicted value in FEV1 (88 v. 71 %), and of absolute values in MEF50 (3.33 v. 1.91) and MEF25 (0.96 v. 0.42) as characteristic changes. The patients with pulmonary GvHD showed at the time of diagnosis in comparison to values before HSCT a mixed pattern of obstruction (% of predicted FEV1 71 v. 50 %), restriction (mean % of predicted VCmax 78 v. 64 %) and changes in diffusions capacity (% of predicted TLCOc SB 79 v. 62%). In univariate analysis, risk factors for developing pulmonary cGvHD were: unrelated donor, chronic GvHD, smoking and lung disease (e.g. infections) after HCT. The latter emphasizes the importance of infections due to immunosuppression for the development of pulmonary GvHD in this patients. Interestingly, uncontrolled disease status or pre-existing lung disease per se did not increase the risk for the development of pulmonary GvHD. In conclusion, we found several risk factors and changes in pulmonary function test associated with developing pulmonary GvHD in HCT after reduced toxicity conditionig. These findings might help to identify a risk population in older patients and therefore result in personalized measures for GvHD prophylaxis. Disclosures: Marks: Novartis: Research Funding.

Incidence and Outcome of Auto/Alloimmune Hepatitis with Hepatic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4534-4534
Author(s):  
Michael Koldehoff ◽  
Ahmet H Elmaagacli ◽  
Reinhild Klein ◽  
Dietrich Beelen
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Abstract 4534 Auto/alloimmune hepatitis (AIH) is an inflammatory liver disease characterized histological by a dense mononuclear cell infiltrate in the portal tract and serological by the presence of non-organ and liver-specific antibodies, high transaminases and increased levels of IgG. The relation between allogeneic hematopoietic stem cell transplantation (HSCT) and auto/alloimmune disease is complex. To examine this association, we retrospectively studied 1,636 allogeneic patients (median age 43, range 18–73 years) between May 1996 and December 2008. Among these patients, 311 (19%) developed hepatic graft-versus-host disease (GvHD) (162 pts had a hepatic GvHD of grade > II). We followed 25 patients (11 male, 14 female) in whom GvHD of the liver presented with marked elevation of serum aminotransferases, clinically resembling acute hepatitis and auto/antibodies characteristics for AIH. The median age at transplant was 35 (range, 18–54) years. Onset of liver dysfunction was at 286 days (range, 55–2766) after HSCT. Median peak serum was 312 (range 105–1750) U/L for alanine aminotransferase, 629 (133-2410) U/L for gamma-glutamyl transferase and 1.74 (0.5-23.4) mg/dl for bilirubin. The autoantibody profiles of AIH were 60% for anti-nuclear antibody, 44% for antibodies to liver-kidney microsomes, 24% for antibodies to smooth-muscle antigens, 28% for anti-mitochondrial antibody, 16% for antibodies to actin, 8% for antibodies to nucleoli, and 4% for other autoantibodies. AIH had a higher prevalence in younger and in female patients. AIH occurred in 92% in patients, who were transplanted with G-CSF mobilized and peripherally collected stem cells (PSC), but in only 8% in patients with bone marrow (BM) source (p<0.02), comparing all transplanted patients (1326 PSC, 310 BM). Stem cell grafts from matched sibling donor or matched unrelated donor were similar in the two groups. Acute GvHD of grade> II occurred more frequently in the groups with AIH (15/25 vs. 649/1636, p<0.002), and chronic GvHD (11 limited, 14 extensive) was ascertained in all AIH patients vs. 49.8% in all transplanted patients (p<0.0001). Three patients with AIH died from pulmonary bleeding, chronic GvHD, and relapse, whereas 22 patients with AIH are still alive (88%) at a median survival time of 2570 days. In conclusion, our evaluation confirms a strong association between G-CSF mobilized PSC, chronic GvHD and the development of AIH. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 490-500 ◽  
Author(s):  
Francisco M. Marty ◽  
Julie Bryar ◽  
Sarah K. Browne ◽  
Talya Schwarzberg ◽  
Vincent T. Ho ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Cmv Reactivation

AbstractSirolimus-based immunosuppressive regimens in organ transplantation have been associated with a lower than expected incidence of cytomegalovirus (CMV) disease. Whether sirolimus has a similar effect on CMV reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We evaluated 606 patients who underwent HSCT between April 2000 and June 2004 to identify risk factors for CMV reactivation 100 days after transplantation. The cohort included 252 patients who received sirolimus-tacrolimus for graft-versus-host disease (GVHD) prophylaxis; the rest received non–sirolimus-based regimens. An initial positive CMV DNA hybrid capture assay was observed in 225 patients (37.1%) at a median 39 days after HSCT for an incidence rate of 0.50 cases/100 patient-days (95% confidence interval [CI], 0.44-0.57). Multivariable Cox modeling adjusting for CMV donor-recipient serostatus pairs, incident acute GVHD, as well as other important covariates, confirmed a significant reduction in CMV reactivation associated with sirolimus-tacrolimus–based GVHD prophylaxis, with an adjusted HR of 0.46 (95% CI, 0.27-0.78; P = .004). The adjusted HR was 0.22 (95% CI, 0.09-0.55; P = .001) when persistent CMV viremia was modeled. Tacrolimus use without sirolimus was not significantly protective in either model (adjusted HR, 0.66; P = .14 and P = .35, respectively). The protective effect of sirolimus-containing GVHD prophylaxis regimens on CMV reactivation should be confirmed in randomized trials.

scholarly journals Impact of graft-versus-host disease prophylaxis on immune reconstitution in patients after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 23 (5) ◽  
pp. 1125-1136
Author(s):  
E. D. Mikhaltsova ◽  
N. N. Popova ◽  
M. Yu. Drokov ◽  
N. M. Kapranov ◽  
Yu. O. Davydova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Mycophenolate Mofetil ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cyclosporine A ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

The graft-versus-host disease (GVHD) is among the most common complications after hematopoietic stem cell transplantation (allo-HSCT). The main tools for GVHD prevention remain calcineurin inhibitors (cyclosporin A, tacrolimus), methotrexate, mycophenolate mofetil. Upon implementation of reduced-intensity conditioning regimens, antithymocyte globulin was widely introduced. However, negative effects upon reconstitution of T-cell immunity have been noted, thus increasing risk of severe infectious complications and disease relapse. With extended practice of HSCT from alternative (partially matched or haploidentical) donors, cyclophosphamide was increasingly used. Our aim was to study reconstitution of immune cell subpopulations in the patients undergoing bone marrow transplantation (BMT), when using different GVHD prophylaxis regimens, including the schedules with post-transplant CP usage. The study concerned 44 cases classified into 2 groups. The first one included patients with standard immunosuppressive therapy, antithymocyte therapy, cyclosporine A, methotrexate, mycophenolate mofetil. The second group included the patients who received CP as immunosuppressive drug combined with other treatments (cyclosporine A, methotrexate, mycophenolate mofetil). At specified control terms, (D+14, +30, +60, +90) the blood leukocyte subpopulations were assayed by means of multicolor flow cytometry. Absolute counts of CD4+ cells in HSCT recipients treated with CP post-BMT proved to be sufficiently lower at D+14 and +30, than in those treated with classical immunosuppressive therapy. However, at later terms, (D+60, +90), these differences were not observed. Moreover, in CP-treated bone marrow recipients, absolute numbers of CD8+ cells was significantly higher, compared to the patients who received conventional GVHD prophylaxis. Reconstitution of the studied lymphocyte populations in hematopoietic cell recipients did not depend on the GVHD prophylaxis regimen. Usage of CP combined with bone marrow as a source of stem cells, brings about sufficient decrease of some cell populations (CD4+; CD8+; NK cells) at early terms post-transplant. Administration of CP combined with hematopoietic stem cells as the source of hematopoietic graft seems to be more reasonable.

Graft Versus Host Disease (GVHD) Prophylaxis with Everolimus and Tacrolimus Is Associated with a High Incidence of Sinusoidal Obstruction Syndrome and Microangiopathy – Results of the EVTAC Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1172-1172
Author(s):  
Uwe Platzbecker ◽  
Malte Bonin ◽  
Eray Goekkurt ◽  
Joergen Radke ◽  
Alexander Kiani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Prophylactic Regimen ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract Beyond disease biology, the success of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies is mainly determined by the occurrence and extent of graft versus host disease (GVHD). Therefore, prevention of GVHD is the major goal and challenge in clinical HSCT. A calcineurin-inhibitor combined with methotrexate is the standard graft versus host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus is a derivative of sirolimus, which also seems to mediate anti-leukemia effects. Given the potential synergism and favourable toxicity profile of everolimus and tacrolimus (EVTAC) after allogeneic HSCT we sought to investigate the efficacy of this combination in patients with either myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). We report a combination of everolimus (days 0–56) and Tacrolimus (from day −1 on) in 24 patients (pts, median age 62 years) with either MDS (n=17) or AML (n=7) undergoing intensive busulfan-based conditioning followed by HSCT from related (n=4) or unrelated matched (n=12) or 1-allele mismatched (n=8) donors. All pts engrafted and only one experienced grade IV mucositis. However, although everolimus was scheduled to be administered up to day 56, patients received the drug a median of 44 days (range 10–56) only. The reason for premature discontinuation (50%) were either occurrence of early-onset (day 6) GVHD associated hyperbilirubinemia CTC grade 4 (n=1), transplantation-associated microangiopathy (TMA, n=3), sinusoidal obstructive syndrome (SOS) of the liver (n=6) or a drop of platelets after engraftment by at least 50% (n=2). Nine pts (37%) developed grade II–IV acute GVHD, however, chronic extensive GVHD was observed in 11 of 17 (64%) evaluable pts. TMA occurred in 7 pts (29%) with two cases of acute renal failure. In five out of seven patients with TMA either tacrolimus (n=4) or everolimus (n=1) blood through levels were slightly above the upper target level at the time of TMA appearance. The study was terminated prematurely because additional 6 pts (25%) developed SOS, which was fatal in two cases. With a median follow-up of 26 months, the 2-year overall survival rate is 47%. In conclusion, although this new combination appears to be effective as prophylactic regimen for acute GVHD, the incidence of TMA and SOS seems to be higher compared to other regimens. As a result this combination cannot be recommended as prophylactic regimen after busulfan-based intensive conditioning. However, studies in the context of TBI-based or reduced-intensity conditioning regimens might come to a different conclusion.

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