scholarly journals Extensive Chronic Graft-Versus-Host-Disease Significantly Increases the Risk of Severe and Multifocal Genital Tract HPV Disease in Long-Term Survivors of Allogeneic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1956-1956
Author(s):  
Dana L Shanis ◽  
Prathima Anandi ◽  
Caitlin Grant ◽  
Priyanka A Pophali ◽  
Eleftheria Koklanaris ◽  
...  

Abstract Background: High rates of cervical HPV disease in women after allogeneic stem cell transplantation (SCT) have been reported, but risk factors related to severe, multifocal, including vaginal and vulvar, HPV disease are not defined. Objective: To determine rates and risk factors for multifocal and severe HPV disease in post-transplant women. Methods: In a prospective long-term study after SCT, gynecologic history and assessment, cervical cytology and HPV testing were obtained with follow-up colposcopy and surgery as indicated for abnormal results. Prior HPV disease, genital graft-versus-host-disease (gGVHD), chronic GVHD (cGVHD) and immunosuppression treatment (IST) >3years were assessed for their association with extent and severity of genital HPV disease. Logistic regressions were used for multivariate analysis. Results: Sixty five long term (>3 year) SCT survivors were studied prospectively on protocol. Patients received allogeneic transplantation from HLA-identical sibling donors with most undergoing myeloablative total body irradiation (94%) and T lymphocyte-depleted peripheral blood stem cells in 91% Of 65 women, 62 had gynecologic assessment with 8 (13%) having prior history of HPV disease; 16 (26%) had gGVHD. 20 women (32%) had acute GVHD, 46 (74%) had cGVHD; extent was limited in 23(37%) and extensive in 23(37%). 26(42%) had cGVHD requiring IST >3years. Of 21(34%) women with HPV disease after transplant, 12 required surgery and 7 had multifocal disease. Extensive chronic GVHD (but not acute GVHD) was found to significantly impact occurrence (OR=3.5, p=0.038), high-grade severity (OR=7.1, p=0.024) or multifocal HPV disease (OR=14.6, p=0.017). Conclusion: Women who have undergone SCT have an increased risk of genital HPV disease, with highest rates in women with extensive cGVHD. Likely as a result of chronic immune dysregulation and the temporal nature of HPV, these women are at high risk of severe, multifocal disease, which if untreated may progress to genital cancer. Thus, gynecologic assessment as well as possible post-transplant HPV vaccination are critical aspects of care for women with significant GVHD post-transplant. Support: Intramural programs of NHLBI, Clinical Center and NICHD, NCT00106925 Disclosures Stratton: Allergan: Research Funding.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3051-3051
Author(s):  
Victor Noriega ◽  
Carolina Martinez-Laperche ◽  
Leyre Bento ◽  
Noemi Sanchez-Hernandez ◽  
Milagros Gonzalez-Rivera ◽  
...  

Abstract Abstract 3051 INTRODUCTION The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+, Tregs) which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation (allo-SCT), Tregs are known to mitigate graft versus host disease (GVHD) while maintaining a graft versus leukemia effect (GVL). Allele (GT)15 for the functional (GT)n polymorphism in the promoter/enhancer of the FOXP3 gene is associated with a higher expression of FOXP3 and production of a greater amount of Tregs. However, its impact in the allo-SCT setting has not been analyzed. OBJECTIVE To analyze the impact of the (GT)n polymorphism in the promoter/enhancer of the FOXP3 gene on the development of complications and ultimately on the success of conventional HLA-identical allo-SCT. MATERIALS AND METHODS The study includes 33 patients with hematological malignancies, treated with myeloablative HLA-identical peripheral blood allo-SCT (Table 1). Diagnosis, classification and grading of GVHD were made by clinical criteria and confirmed when necessary by pathological examination of histological samples from gut, skin, liver or lung, according to international consensus criteria. Donor and recipient genomic DNA was purified from EDTA anticoagulated peripheral blood before allo-SCT and using QIAamp Blood DNA extraction kit (Qiagen). Genotyping of the (GT)n microsatellite polymorphism in the FOXP3 gene was performed by a fluorescence-based short tandem repeat-polymerase chain reaction (STR-PCR) method (GeneAmp 7900; Applied Biosystems) and sized by capillary electrophoresis (POP7 - ABI PRISM 3130 xL Genetic Analyzer; Applied Biosystems) followed by fragment analysis (GeneMapper 4.0 Software; Applied Biosystems) as previously described [Bassuny WM, et al. Immunogenetics. 2003;55 :149–56]. RESULTS The median follow-up time for the cohort was 34 months (range 9.5–110). Allelic frequencies observed were similar to those previously reported (50.5% (GT)15, 41% (GT)16 and 7% (GT)17; no (GT)14 or (GT)18 alleles were found). Patients transplanted from donors harboring allele (GT)15 showed a lower incidence of grades II-IV acute GVHD (29% vs 67%; p =0.049). These patients also showed a trend to a lower incidence of severe (grades III-IV) GVHD (12% vs 33%; p =0.167) as well as chronic GVHD (75% vs 100%; p =0.143; Table 1, Figure 1). No statistically differences were found between patients transplanted from (GT)15 and non-(GT)15 donors in terms of relapse rate (38% vs 33%; p =0.825; Table 1) or cumulative incidence of relapse (CIR at 2 years 35.3% vs 37.5%, Figure 2). Finally, survival analysis did not show statistically significant differences between the two groups of patients in terms of median event (relapse) free survival (EFS, 15.6 months vs 4.5 months, p =0.686) or overall survival (OS, 29 months vs not reached, p =0.610). CONCLUSIONS Tregs are known to modulate the allotolerance-alloreactivity balance between donor and recipient in the allo-SCT setting, mitigating GVHD while preserving the anti-tumor effect (GVL) of the donor graft. In the present study, the presence of allele (GT)15 in the donor, which promotes a higher expression of FOXP3 and greater amount of Tregs, affected allo-SCT outcome by decreasing grades II-IV acute GVHD and chronic GVHD, without affecting GVL (no differences in CIR and OS). Analysis of this polymorphism can help in appropriate donor selection and, more importantly, drive a tailored management of patients submitted to allo-SCT. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4122-4122
Author(s):  
Eshrak Al-Shaibani ◽  
Shiyi Chen ◽  
Wilson Lam ◽  
Arjun Law ◽  
Ivan Pasic ◽  
...  

Abstract Background: Recent advances and improvement of supportive care allowed allogeneic stem cell transplantation (HCT) to be offered to selected older patients. However, data regarding outcome and factors affecting the outcomes are limited. Method: We retrospective analyzed the outcome in 332 patients, median age 65 years (60-76), who underwent HLA-matched related (n=85), matched unrelated (n=205) and haploidentical donor (n=42) HCT, between January 2014 to December 2019. Of these 60% were male. Diagnosis was leukemia: 193, MDS: 76, MF: 46 and others: 17. Graft source was PBSC in 98%. Reduce-intensity conditioning regimen was used in 95%, and in vivo T-cell depleted in 89% of patients. We categorized them to 3 age-groups (G): G1 60-65y, (n=175), G2 >65-70y (n=127), and G3 >70y (n=30).Cox models were used to compare the rates of overall survival (OS), non-relapse mortality( NRM), event free-survival (EFS), length of hospitalization for HCT, GVHD and reasons of re-hospitalization during the first year post HCT. Results: The median follow up was 14 months (range: 1-123 months). Median days of hospitalization during HCT period were 30-days (range: 20-132 days), with trend towards significance when stratified by age group (p=0.049). HCT-CI scores were 0-1 (n=143), 2-3 (n=107) and >3 (n=70). The cumulative incidences of grade II-IV acute-GVHD was 38.3% and 16.3% for grades III-IV. Moderate-severe chronic-GVHD was 23.7%. Increasing age was not associated with increases in acute GVHD (p=0.86) or chronic-GVHD (p= 0.6). Overall, 188 (56%) patients were re-hospitalized within the first 6-month of HCT, and 61 (18%) in the second 6-month period. The 2-year OS rate (Fig 1) were 56% in G1, 53% in G2 and 34% in G3 (p=0.05). The 2-year EFS rate (Fig 2) were 54% for G1, 49% for G2, and 31% for G3 (P=0.04). Cumulative incidence of NRM at 2-year (Fig 3) were 25% in G1, 36% in G2 and 52% in G3 (p=0.008). Further results are illustrated in Table 1. Risk factors such as age, KPS, HCT-CI, donor-type, readmission and GVHD were analyzed for their associations with outcomes using univariate analyses, those with significant results entered in multivariate-analysis Table 2. Patients aged 60-≤65 had significantly better EFS (p=0.04) and associated with a border line significant trend for lower NRM (p=0.05) than those aged >70. Re-admission in the first 6-month post HCT had a significant impact on the OS, EFS and NRM. HCT-CI >3 had significant impact on NRM. Conclusion: Age had a significant impact on hospitalization period during HCT. Age >70 had significant impact on EFS and trend toward higher NRM. HCT-CI, acute and chronic-GVHD and readmission in first 6-month post-HCT were significant risk factors. Readmission in the first 6 months correlated with lower OS, EFS and higher NRM. Acute GVHD III-IV or moderate-severe chronic GVHD associated with poor outcomes. Selecting patients based on HCT-CI, and good management of GVHD and post-HCT complication may improve the clinical outcome. Figure 1 Figure 1. Disclosures Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Paladin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding.


Author(s):  
Steffen T. Simon ◽  
Anne Pralong ◽  
Michael Hallek ◽  
Christoph Scheid ◽  
Udo Holtick ◽  
...  

AbstractPatients undergoing allogeneic stem cell transplantation (allo-SCT) are given a real chance of cure, but at the same time are confronted with a considerable risk of mortality and of severe long-term impediments. This narrative, non-systematic literature review aims to describe the supportive and palliative care needs of allo-SCT recipients, including long-term survivors or those relapsing or dying after transplantation. It also evaluates the feasibility and effectivity of integrating palliative care early in transplant procedures. In this appraisal of available literature, the main findings relate to symptoms like fatigue and psychological distress, which appear to be very common in the whole allo-SCT trajectory and might even persist many years post-transplantation. Chronic GvHD has a major negative impact on quality of life. Overall, there is a paucity of research on further issues in the context of allo-SCT, like the distress related to the frequently unpredictable post-transplant trajectory and prognosis, as well as the end-of-life phase. First randomized controlled results support the effectiveness of early integration of specialized palliative care expertise into transplant algorithms. Barriers to this implementation are discussed.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 299-299
Author(s):  
Michael Schleuning ◽  
Christoph Schmid ◽  
Georg Ledderose ◽  
Johanna Tischer ◽  
Meike Humann ◽  
...  

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4980-4980
Author(s):  
Issa F. Khouri ◽  
Rima M. Saliba ◽  
Daniel R. Couriel ◽  
Grace-Julia Okoroji ◽  
Sandra Acholonu ◽  
...  

Abstract It has been postulated that B cells functioning as antigen-presenting cells may have an important role in the pathogenesis of GVHD. Depletion of donor cells from B-cells resulted in a low incidence of GVHD in mouse model (Schultz et al. BMT1995:16:289–289). More recently, we observed a lower incidence of chronic (and to a lesser extent acute GVHD) in patients with CLL who received an allogeneic stem cell transplantation after a non-myeloablative conditioning regimen containing rituximab (Exp Hematol32:28–35, 2004). The purpose of this study is to investigate the effect of rituximab on GVHD in the setting of a more intense chemotherapy with BEAM, in patients who received an allogeneic peripheral blood stem cell from HLA-identical siblings. To test this hypothesis, we retrospectively studied 11 consecutive patients with non-Hodgkin’s lymphoma who received BEAM/Rituximab at the M. D. Anderson Cancer Center. We attempted to match these patients by age, donor-recipient gender, and donor-recipient CMV reactivity to a historical control of 44 patients with lymphoma, who received BEAM alone as a conditioning regimen, without the Rituximab. Tacrolimus and methotrexate were used for GVHD prophylaxis in both groups. A total of 10 patients in the study group, could be matched with 19 patients in the control group and were included in the final analysis. The outcome of the 2 groups is shown below: Rituximab-Study Group Control Group -value P No. of patients 10 19 Median age 41 44 0.4     (range) (19–55) (19–60) Patient-Donor sex-matched 9(82%) 18(95%) 0.6 Median # CD34 + cells infused (106/kg) 5.1 4.73 0.1 Patient or Donor CMV+ 9(82%) 18(95%) 0.6 Patient and Donor CMV − 1(10%) 1(5%) Median # prior chemoregimens 3 3 0.9     range (1–8) (1–9) Median follow-up 17 38     range (8–48) (27–77) Acute GVHD 2–4 (n,%) 5(50%) 7(37%) 0.5 Acute GVHD 3–4 (n,%) 3(30%) 5(26%) 0.6 Chronic GVHD (n, % cumulative incidence) 8 (90% + 15) 10 (53% + 12 0.01 Our data suggest that the described protective effect of Rituximab against GVHD in mouse models or in the setting of non-myeloablative allogeneic transplantation, may be overcome by the BEAM. This more intense conditioning regimen may induce more GVHD by enhancing T-cell cytokines release and by causing more gastrointestinal toxicity, thus allowing for a greater antigen presentation.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1800-1800
Author(s):  
Tom Fong ◽  
Kim Trinkaus ◽  
Douglas R. Adkins ◽  
Ravi Vij ◽  
Steven Devine ◽  
...  

Abstract Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). We previously reported low incidences of acute GVHD in unrelated donor transplant recipients who received prophylactic HCQ in addition to standard GVHD prophylaxis (BBMT2003; 9: 714–721). We herein report results of a single-institution phase III trial, in which 95 recipients of matched sibling allogeneic peripheral blood stem cell transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ or placebo starting 21 days pre-transplant and continued until d+365. HCQ was very well tolerated and not associated with side effects. The addition of HCQ had no effects on lymphocyte subsets both pre- and post-transplant. Overall, the incidence of acute GVHD was 59% in both arms, and severe acute GVHD occurred in 11% (HCQ) and 14% (placebo) (p=0.76). Sixty-one and 46% of patients developed chronic GVHD in the placebo and the HCQ arms, respectively (p = 0.15). With a median follow-up of 18 months, relapse-free and overall survivals were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single agent CSA was not associated with a reduction of either acute or chronic GVHD; additionally, no significant effects on relapses or survival were observed.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5337-5337
Author(s):  
Sang Kyun Sohn ◽  
Dong Hwan Kim ◽  
Jin Ho Baek ◽  
Jong Gwang Kim ◽  
Kyu Bo Lee ◽  
...  

Abstract Background: As a series of our previous investigation (Haematologica, 2005. 90: 939–48) identifying poor prognostic factors (lymphocytopenia and visceral involvement) at the onset of acute GVHD (aGVHD) in patients with a history of aGVHD after allogeneic stem cell transplantation (SCT), we tried to identify variables that could predict the development of chronic GVHD of progressive or quiescent type (pq cGVHD) and patients’ outcome after the diagnosis of cGVHD in cohort of 99 patients who experienced aGVHD after allogeneic SCT. Patients and Methods: We evaluated the risk factors for cGVHD of pq cGVHD with various clinical parameters in patient group with a history of aGVHD and also the prognostic significance of various clinical parameters at diagnosis of cGVHD to determine the prognostic factor for GVHD-specific survival (GSS) in patients with pq cGVHD. Results: From 118 patient experienced aGVHD of any degree, 99 patients were evaluated for cGVHD. The cumulative incidence of overall and extensive pq cGVHD at 2 years was estimated as 84.4% and 63.1%, respectively. In univariate analyses for risk factors of pq cGVHD, severe grade 3,4 aGVHD, primary treatment failure (PTF), lymphocytopenia (≤100/μl), elevated ALP (>160IU/l), visceral involvement, hepatic or gut involvement were identified. Especially, severe aGVHD (p=0.022 and <0.001), PTF (p=0.009 and 0.010) for overall and extensive pq cGVHD, lymphocytopenia (p=0.031) for extensive pq cGVHD, and elevated ALP (p=0.001) for overall pq cGVHD were independent risk factors. The prediction model of subsequent pq cGVHD validated these risk factors with respect to the incidences of overall pq cGVHD (48.6% versus 91.9% for no risk factor versus 1~3 risk factor(s)) and of extensive pq cGVHD (34.2% versus 59.6% versus 92.2% for no / 1 / 2~3 risk factors). HLA-disparity and stem cell source did not influence on the development of pq cGVHD in this cohort. The GSS and probability of systemic immunosuppressive treatment at 2 year after diagnosis of cGVHD was estimated as 55.9% and 51.9%. The GSS was significantly associated with the performance status (p=0.004) and lymphocytopenia (≤ 1,000/μl, p=0.022) at diagnosis of cGVHD by Cox’s proportional hazard model. Conclusion: Severe aGVHD, PTF, lymphocytopenia and elevated ALP may be useful predictive factors for the development of pq cGVHD in a cohort of patients who experienced a GVHD after allogeneic SCT. Figure. The significance of the predictive model for the development of overall (A) or extensive chronic graft-versus-host disease (GVHD; B) after occurence of acute GVHD Figure. The significance of the predictive model for the development of overall (A) or extensive chronic graft-versus-host disease (GVHD; B) after occurence of acute GVHD


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