Re-Evaluation of Chronic Graft-Versus-Host Disease Using National Institute of Health Consensus Criteria.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2239-2239
Author(s):  
Dae-Young Kim ◽  
Je-Hwan Lee ◽  
Jung-Hee Lee ◽  
Se Hyung Kim ◽  
Sung-nam Lim ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Scoring System ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Prognostic Significance ◽  
P Value ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background: The National Institutes of Health (NIH) proposed new consensus criteria for the diagnosis and scoring of chronic graft-versus-host disease (cGVHD). Using the new system, we re-evaluated the patients with cGVHD that was diagnosed by classic criteria. Methods: Of 618 patients who underwent allogeneic hematopoietic cell transplantation (HCT) from December 1994 to April 2008 at the Asan Medical Center, Seoul, Korea, we retrieved 236 patients who had cGVHD by classic criteria from the AMC BMT Registry. Among 236 patients, 20 patients with liver-only involvement could not be diagnosed as cGVHD by the NIH criteria, thus we reclassified and graded 216 patients according to the NIH criteria. We also evaluated the ability of the NIH criteria to stratify and predict the risk of cGVHD patients, as assessed by GVHD-specific survival (GSS). Results: Twenty patients (9.3%) were reclassified as acute GVHD by NIH criteria (‘classic acute’ in 7 and ‘persistent, recurrent, or late-onset acute’ in 13) and 196 patients (90.7%) remained as chronic GVHD (‘classic chronic’ [Cl-Ch] in 170 and ‘overlap syndrome’ [Ov-Sy] in 26). Median age of 196 patients with cGVHD by NIH criteria, 119 males and 77 females, was 35.5 years (range, 15 to 57). Acute GVHD preceded cGVHD in 70 patients (35.7%). The probability of GSS at 5 years was 86.2% with 22 cGVHD-related deaths. The GSS was significantly different between two subtypes of cGVHD by NIH criteria: 88.6% for Cl-Ch vs 70.2% for Ov-Sy (p=0.002). NIH global scoring system stratified risk of cGVHD patients better than stage by classic criteria at both onset and peak of cGVHD (Table 1). We evaluated 12 variables at onset of cGVHD to determine their prognostic significance for GSS. Multivariate analysis demonstrated that NIH global score at onset (mild vs moderate, HR 6.1, p=0.027; mild vs. severe, HR 7.0, p=0.015), preceding aGVHD (no vs. yes, HR 6.2, p=0.001), and number of HLA ABDR mismatch (0 vs. 1, HR 2.0, p=0.555; 0 vs 2, HR 200.4, p=0.009) were independent predictors for GSS. Conclusion: Our results indicate that a new NIH system can provide a proper risk-stratification of patients with cGVHD and global scoring system at onset of cGVHD can predict the prognosis of patients. Table 1. GVHD-specific survival according to NIH global scoring system or stage by classic criteria Onset of cGVHD Peak of cGVHD Pt. No. GSS (5-y) P-value Pt. No. GSS (5-y) P-value NIH criteria mild 70 95.2% 0.022 36 100% 0.004 moderate 64 82.8% 42 92.2% severe 62 79.7% 118 79.6 Classic criteria limited 86 90.1% 0.305 45 97.8% 0.039 extensive 110 83.7% 151 83.0%

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

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

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

scholarly journals Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3214-3219 ◽  
Author(s):  
Mary E. D. Flowers ◽  
Yoshihiro Inamoto ◽  
Paul A. Carpenter ◽  
Stephanie J. Lee ◽  
Hans-Peter Kiem ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
National Institutes Of Health ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

Association of IL-10 and IL-10 Receptor Gene Polymorphisms and Graft-Versus-Host Disease Following Hematopoietic Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 421-421 ◽  
Author(s):  
Li-Hui Tseng ◽  
Ming-Tseh Lin ◽  
Barry Storer ◽  
Paul J. Martin ◽  
Bryan Grogan ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Lower Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
P Value ◽  
Host Disease ◽  
Graft Versus Host

Abstract Polymorphisms in cytokine genes can influence immune responses and may affect the outcome of hematopoietic cell transplantation (HCT). We have shown that the IL-10/-592*A allele of the recipient is a marker for less severe acute graft-versus-host disease (GVHD) and a lower risk of non-relapse mortality (NRM) after HCT from an HLA-identical sibling (N Engl J Med, 2003). To further test the hypothesis that IL-10 pathway is important in the intensity of acute GVHD, we undertook a study of variation in the IL-10 receptor β gene. A single nucleotide polymorphism (A/G) at cDNA position 238 of the IL-10 receptor β gene (IL-10RB/1304) was genotyped in 953 HCT recipients and their HLA-identical sibling donors. IL-10/-592 and IL-10RB alleles and genotypes were tested for association with GVHD by multivariable analysis. The IL-10/-592*A allele of the recipient and IL-10RB/238*G allele of the donor were significantly associated with a lower risk of acute grades III-IV GVHD (trend p value 0.0008 and 0.02, respectively). None of the 16 cases with a patient IL-10 A/A genotype and donor IL-10RB G/G genotype developed grades III-IV acute GVHD (HR = 0.0 and p value = 0.007), compared to pairs with a patient IL-10 C/C genotype and donor IL-10RB A/A genotype. The hazard ratios were 0.4–0.6 among pairs with a patient IL-10 A/A genotype and donor IL-10RB A/G or A/A genotype and among pairs with a patient IL-10 A/C genotype and donor IL-10RB G/G or A/G genotype. The effect of donor IL-10RB genotype on GVHD was observed only among pairs with a patient IL-10 A/C or A/A genotype (trend p value = 0.005 and 0.06 respectively), but not among pairs with a patient IL-10 C/C genotype (trend p value = 0.82). These data suggest an interaction in the effect of the patient IL-10/-592 and donor IL-10RB/1304 genotypes on GVHD, further supporting the hypothesis that the IL-10 pathway plays an important role in controlling the severity of acute GVHD.

Early Onset of Acute Graft-Versus-Host Disease Indicating a Worse Prognosis in Terms of Chronic Graft-Versus-Host Disease and Survival Compared to Late Onset.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4979-4979
Author(s):  
Sang Kyun Sohn ◽  
Joon Ho Moon ◽  
Jong Gwang Kim ◽  
Yee Soo Chae ◽  
Yoon Young Cho ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Early Onset ◽  
Acute Gvhd ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Onset Time ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Abstract Background: Acute graft-versus-host disease (GVHD) is an important risk factor for predicting chronic GVHD. The transplant outcome can be influenced by the onset time of acute GVHD in patients who received allogeneic stem cell transplantation (SCT) Methods: The medical records of one hundred six patients with hematological malignancies who received allogeneic transplantation were retrospectively reviewed. Results: Fifty four (39.7%) patients developed grade II to IV acute GVHD within D+30 after allogeneic SCT (<D+30 group) and 13 (9.6%) patients manifested acute GVHD after D+30 (≥D+30 group). The cumulative incidence of chronic GVHD was 81.5% and 53.8% in <D+30 group and ≥D+30 group, respectively.(p<0.001) On multivariate analysis, grade II to IV acute GVHD developed before D+30 and primary diagnosis of chronic myeloid leukemia were identified as independent variables predicting chronic GVHD. The overall survival rate was significantly lower in the <D+30 group than grade 0 or I group (p<0.001). But there was no statistical difference between the group with grade 0 or I and ≥D+30 group in terms of the incidence of chronic GVHD (p=0.295). Among the 54 patients with grade II to IV acute GVHD developed at before D+30, 26 (48.1%) patients developed into quiescent chronic GVHD and 20 (37%) patients progressive chronic GVHD. The quiescent chronic GVHD showed a better survival than progressive chronic GVHD (p=0.063). Conclusion: Acute GVHD of early onset (within D+30) was regarded as a worse prognostic indicator in terms of chronic GVHD and survival.

T Regulatory Cells in Graft-Versus-Host Disease of the Skin

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4354-4354
Author(s):  
Jose Azar ◽  
Steven Billings ◽  
Jennifer E. Schwartz ◽  
Yunlong Liu ◽  
Menggang Yu ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Outcomes ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Treg Cells ◽  
P Value ◽  
Host Disease ◽  
Graft Versus Host

Abstract FoxP3+ CD25+ T regulatory (Treg) cells are known to be present in normal skin. Treg cell functional deficiency resulting in loss of suppression of activation, differentiation or expansion of effector T cells could conceivably contribute to the pathophysiology of graft-versus- host disease (GVHD). Rezvani et al. suggest that levels of peripheral blood Treg cells in donors and recipients may predict the risk of acute GVHD. Rieger et al. found a significantly lower number of Treg cells in human colonic biopsies with GVHD versus CMV colitis or normal samples. There are no reports that evaluate tissue Treg cells in human skin affected by GVHD. This study was conducted to evaluate the distribution of Treg cells in skin affected by acute GVHD versus chronic GVHD. Archived samples from patients previously reported by routine histopathological methods as acute or chronic GVHD were collected, coded and entered into a database. For immunostaining, 4-μm thick serial sections were cut and deparaffinized. Immunohistochemical stains for CD4 (Neomarkers, 1:20), CD8 (Dako, prediluted), CD25 (Dako, 1:100), and Foxp3 (Serotec, 1:250) were performed using standard techniques. The dermatopathologist evaluating the samples was blinded to the clinical outcomes. Results were scored as 0 (&lt;10% of lymphocytes positive), 1+ (10–25% positive), 2+ (26–50% positive), and 3+ (≥50% positive). Fourteen patients with acute skin GVHD and seventeen with chronic GVHD were identified from a database of patients who had undergone nonmyeloablative allogeneic peripheral blood transplantation in the recent past. The average scores for each immunostain were calculated and are summarized in table 1. The average FoxP3 score in acute GVHD specimens was significantly lower than that in chronic GVHD specimens (average, 0.57 versus 1.41; p-value = 0.011). The average scores of CD3, CD4, CD8 and CD25 immunostains were not significantly different between acute and chronic GVHD biopsies. These findings represent the initial observation of a distinction between the distribution of regulatory T cells in acute and chronic GVHD of the skin. These observations should be confirmed in a larger sample, supported by functional assays of Treg cells, and correlated with clinical outcomes. Such studies may help to elucidate the role of Treg cells in acute and chronic skin GVHD. Table 1. Average score CD 3 CD 4 CD 8 CD 25 Fox P3 Acute GVHD 2.93 2.21 2.14 0.29 0.57 Chronic GVHD 2.82 2.44 2.24 0.71 1.41 p-value 1.00 0.42 0.43 0.34 0.011

Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease

2018 ◽  
Vol 141 (1) ◽  
pp. 19-22
Author(s):  
Liat Shargian-Alon ◽  
Pia Raanani ◽  
Uri Rozovski ◽  
Tali Siegal ◽  
Shlomit Yust-Katz ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cerebellar Atrophy ◽  
Acid Decarboxylase ◽  
High Dose ◽  
Host Disease ◽  
Graft Versus Host ◽  
Aged Woman

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient’s condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

scholarly journals Acute and chronic graft versus host disease after hematopoietic stem cell transplant

JBMTCT ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 53-66
Author(s):  
Vaneuza A. M. Funke ◽  
Maria Claudia Rodrigues Moreira ◽  
Afonso Celso Vigorito
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Primary Therapy ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Graft versus host disease is one of the main complications of Hematopoietic stem cell, in­volving about 50% to 80% of the patients. Acute GVHD clinical manifestations and therapy is discussed, as well as new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both refractory chronic and acute GVHD is an important field of discussion once there is no superiority for the majority of the agents after primary therapy has failed. Hence, this review is meant to be a useful tool of consultation for clinicians who are dealing with this complex complication.

scholarly journals The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Ronjon Chakraverty ◽  
Megan Sykes
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Tissue Injury ◽  
Chronic Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells ◽  
Antigen Presenting

After allogeneic blood or bone marrow transplantation, donor T cells interact with a distorted antigen-presenting cell (APC) environment in which some, but not all, host APCs are replaced by APCs from the donor. Significantly, host APCs are required for the priming of acute graft-versus-host disease (GVHD). Donor APCs play a lesser role in the induction of acute GVHD despite their predicted capacity to cross-present host antigens. In contrast, donor APCs may play a role in perpetuating the tissue injury observed in chronic GVHD. Host APCs are also required for maximal graft-versus-leukemia responses. Recent studies have suggested potential strategies by which the continued presence of host APCs can be exploited to prime strong donor immunity to tumors without the induction of GVHD.

scholarly journals Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia [published erratum appears in Blood 1989 Aug 15;74(3):1180]

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1720-1728 ◽  
Author(s):  
KM Sullivan ◽  
PL Weiden ◽  
R Storb ◽  
RP Witherspoon ◽  
A Fefer ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Host Disease ◽  
Graft Versus Host

Abstract To assess the influence of graft-versus-host disease (GVHD) on recurrent leukemia and survival after allogeneic marrow transplantation, we studied 1,202 patients with acute nonlymphocytic leukemia (ANL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML) given unmodified marrow grafts from HLA- identical siblings. Proportional hazards regression models using acute GVHD and chronic GVHD as time-dependent covariates demonstrated a significant association of GVHD with a decreased relative risk (RR, 0.33 to 0.42) of relapse in patients with ANL, ALL, and CML transplanted in advanced disease. Among patients developing either acute or chronic GVHD, treatment failure (that is, mortality or relapse) was decreased in patients with ALL transplanted in relapse (RR = 0.70, P less than .033) and CML in blast crisis (RR = 0.37, P less than .009). This effect was independent of age, sex, preparative regimen, GVHD prophylaxis, or length of follow-up. Five-year actuarial estimates were derived for the subset of 657 patients who survived in remission 150 days after transplant and were at risk for development of chronic GVHD. Among patients with ANL in first remission or CML in chronic phase, GVHD had an adverse effect on survival and no apparent influence on relapse. Among patients with ANL and ALL transplanted in relapse, the probability of relapse after day 150 was 74% without [corrected] GVHD, 45% with acute and chronic GVHD, 35% with [corrected] only acute GVHD, and 34% with only chronic GVHD (P less than .001). Actuarial survival in these four GVHD groups was 25%, 34%, 59%, and 62%, respectively (P less than .009). Among patients with CML in acceleration or blast crisis, the probability of relapse after day 150 was 65% without GVHD and 36% with acute and/or chronic GVHD (P less than .017). We conclude that acute and chronic GVHD were associated with a durable antileukemic effect and improved survival in patients transplanted in advanced stages of ALL and CML.

Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2886-2886 ◽  
Author(s):  
Uwe Platzbecker ◽  
Caroline Pabst ◽  
Alexander Kiani ◽  
Johannes Schetelig ◽  
Martin Wermke ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Clinical Signs ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: The use of a calcineurin-inhibitor in combination with methotrexate is the current standard in the prophylaxis of graft versus host disease (GVHD). Everolimus is a newly developed m-TOR inhibitor, which, besides a potent immunosuppressive action including the stimulation of regulatory CD4+foxp3+ T-cells (Tregs), seems to mediate anti-neoplastic effects in MDS and AML. Methods: We report results of a prospective study investigating for the first time a combination of everolimus (days 0–56) with tacrolimus (starting day 0) in 16 patients with MDS (RCMD n=3, RAEB-1 n=3, RAEB-2 n=3, CMMOL-1 n=1, CMMOL-2 n=1, MDS/AML n=1) or de novo AML (n=4) undergoing allogeneic myeloablative conditioning (busulfan 16 mg/kg over 4 days, fludarabine 120 mg/m² over 4 days) followed by a median of 7.0 x 106/kg CD34+ peripheral blood stem cells (PBSC) from related (n=2) or unrelated donors (n=14). It is of note that 5 unrelated donor/recipient pairs displayed one allel-mismatch whereas all others were matched in 10 out 10 HLA characters. The median age of the patients was 61 years (range 47–69) and the majority (n=7) of MDS patients were classified INT-2 or HIGH according to IPSS. Results: All patients engrafted a median of 14 days (platelets) and 17 days (neutrophils) after transplant. On day 21 and 56 after PBSCT the median number of CD4+foxp3+ cells in the blood was not significantly different from normal donors (patients, n=5: 3.2 and 2.3 x 104/ul, controls n=4: 3.7 x 104/ul) Nevertheless, the rate of acute GVHD was moderate with five patients (31 %) developing acute GVHD grade II and only one patient experiencing grade IV GVHD after cessation of immunosuppression due to thrombotic-thrombocytopenic purpura (TTP). Decrease of thrombocytes together clinical signs of TTP were seen in two additional patients while four patients developed VOD of the liver, which was fatal in one case. Extensive chronic GVHD was seen in 50 % of evaluable patients. Mucositis CTC grade III was observed in 5 patients only. The total day 100 mortality rate was 19 % and currently eleven out of sixteen patients (69%) are alive and in remission. Conclusion: Everolimus and tacrolimus are highly efficient in preventing GVHD after unrelated PBSCT in older patients with MDS and AML, which seems not to be mediated by an increase in Tregs. Nevertheless, side effects associated with thrombotic microangiopathy might be more prevalent compared to other regimens.

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