Acute GVHD: think before you treat

Abstract The treatment of acute graft-versus-host disease (aGVHD) has become more nuanced in recent years with the development of improved risk classification systems and a better understanding of its complex, multisystem pathophysiology. We review contemporary approaches to the risk stratification and initial treatment of aGVHD, including ongoing clinical trials. We summarize the findings that led to the first US Food and Drug Administration approval for steroid-refractory aGVHD (SR-aGVHD), ruxolitinib, as well as some of the challenges clinicians still face in treating SR-aGVHD. Finally, we discuss the evaluation and management of steroid-dependent aGVHD, which affects approximately one-third of patients who have long-term, waxing and waning symptoms distinct from chronic GVHD. Future clinical trials for aGVHD treatment may identify steroid-sparing approaches for patients who have a high likelihood of response and approaches to improve tissue repair and dysbiosis for those unlikely to respond to immunosuppression alone.

Download Full-text

Extracorporeal Photopheresis (ECP) for Acute Graft-Versus Host Disease (GvHD) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

Blood ◽

10.1182/blood.v126.23.5466.5466 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5466-5466

Author(s):

Sandra Eder ◽

Marie-Thérèse Rubio ◽

Ramdane Belhocine ◽

Myriam Labopin ◽

Eolia Brissot ◽

...

Keyword(s):

Immunosuppressive Therapy ◽

Calcineurin Inhibitor ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Median Number ◽

Low Grade ◽

Graft Versus Host ◽

Steroid Dependent ◽

Grade Iii ◽

Steroid Refractory

Abstract Background Graft-versus-host disease (GvHD) is a major limitation after allo-HSCT and remains a frequent cause of death. The 5-years survival is 25% and 5% for grade III and IV, respectively. Acute GvHD occurs in up to 45% of HLA-matched and up to 75% in case of unrelated donors. The standard-treatment consists of methylprednisolone (usually 2 mg/kg/day) and a calcineurin-inhibitor. No standardized second-line treatment for acute GvHD exists. Here, we report a pilot single-centre experience with extracorporeal photopheresis (ECP) for acute GvHD: the objective was to investigate the efficacy of ECP for patients with steroid-refractory/-dependent acute GvHD as well as an early intervention in patients with low-grade acute GvHD to avoid/taper steroids. Furthermore, we evaluated the reduction of immunosuppressive therapy. Patients' characteristics Between 2013 and 2014, 17 patients with acute GvHD (of whom two patients developed GvHD after donor lymphocyte infusion) were treated. Eight patients had a maximum grade of GvHD I/II (2/6 patients) and nine patients were graded as III/IV (6/3 patients). Organ involvement was as follows: skin only in 10, skin and liver in one, skin and gastrointestinal tract in two and all three organs were involved in four patients. Treatment before ECP consisted of topical steroids in one and 0.5 mg/kg methylprednisolone (due to side-effects of calcineurin-inhibitor) in the other patients with grade I. Six patients received 1 mg/kg and eight patients received 2 mg/kg methylprednisolone. One patient was treated with 2 mg/kg methylprednisolone and weekly methotrexate. Before start of ECP, one patient was steroid-free, six patients were steroid-refractory and nine patients were steroid-dependent. Thus, we treated patients with acute GvHD not only for steroid-refractory disease but also steroid-dependent disease and grade I GvHD to avoid a treatment with steroids. Results The median number of ECP sessions per patient was 12 (range, 5 - 36), seven patients received ECP twice a week. Best response to ECP was complete remission in 71%, partial response in 12% and no response in 17%, after a median number of 6 treatments (range, 2 - 9). Response was better for grade I/II: 87.5% received complete remission compared to 56% with grade III/IV, partial response was observed in 12.5% in patients with grade I/II versus 11% with grade III/IV. No responders comprised 33% with grade III/IV and 0% with grade I/II. Immunosuppressive therapy could be tapered successfully: mean reduction of steroids was 95% (range, 60 - 100) and mean reduction of calcineurin-inhibitor was 83% (range, 40 - 100). Six patients developed a rebound of GvHD during tapering (two patients) or after discontinuation (four patients) of ECP. Eleven patients (78%) developed chronic GvHD (two patients with severe grade), whereas it appeared in four patients during tapering of ECP and in seven patients after discontinuation of ECP after a median time of 116 days (range, 30 - 287). We could observe seven bacterial, 14 viral and one fungal infection in 14 patients, which are expected rates after allo-HSCT in patients with acute GvHD. After a median follow up of one year, two patients relapsed from their underlying disease and five patients died (one due to relapse and four due to infections). Conclusion In this single-centre pilot experience, we could show that ECP is an efficient and safe treatment in patients with steroid-refractory or steroid-dependent acute GvHD as well as an upfront-treatment in patients with low-grade GvHD. We were able to taper immunosuppressive therapy with a mean reduction of steroids of 95% and mean reduction of calcineurin-inhibitor of 83%. Best responses were seen in patients with I/II grade GvHD which concludes that ECP should be started as early as possible. Further studies are warranted to investigate a schedule to reduce the risk of rebound of acute GvHD (42% in our cohort) and development of chronic GvHD (78%). Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria.

Download Full-text

Updates in chronic graft-versus-host disease

Hematology ◽

10.1182/hematology.2021000301 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 648-654

Author(s):

Betty K. Hamilton

Keyword(s):

Clinical Trials ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Host Disease ◽

Graft Versus Host ◽

Late Morbidity ◽

Prevention And Treatment

Abstract Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Symptoms and manifestations of chronic GVHD are heterogeneous and pleomorphic, and there are no standard treatments beyond corticosteroids. Therapy is typically prolonged, and chronic GVHD and its treatment are associated with adverse effects that have a significant impact on long-term quality of life and functional status. Several advances have been made over the last 2 decades to define the diagnosis of chronic GVHD as well as its severity and response criteria for clinical trials. Further understanding into the biologic mechanisms of the development of chronic GVHD has led to the investigation of several novel immunomodulatory and targeted therapies. Multi-institutional collaboration and pharmaceutical support in the development of therapies based on sound biologic mechanisms and clinical trials with defined end points and responses have led to several promising agents on the horizon of approval for treatment of chronic GVHD. This article reviews advances in our knowledge of chronic GVHD and its biologic framework to improve approaches to prevention and treatment.

Download Full-text

Excellent Long-Term Survival of Patients with Steroid-Refractory and Steroid-Dependent Acute Graft-Versus-Host Disease after Extracorporeal Photochemotherapy.

Blood ◽

10.1182/blood.v104.11.1244.1244 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1244-1244

Author(s):

Hildegard T. Greinix ◽

Robert M. Knobler ◽

Nina Worel ◽

Margit Mitterbauer ◽

Axel Schulenburg ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Acute Gvhd ◽

Complete Response ◽

Graft Versus Host ◽

Steroid Dependent ◽

Grade Ii ◽

Grade Iii ◽

Steroid Refractory ◽

Acute Graft

Abstract Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Second-line therapies for steroid-refractory acute GVHD have been used with limited success. Extracorporeal exposure of peripheral blood mononuclear cells to the photosensitizing agent 8-methoxypsoralen and UV-A radiation (ECP) has been shown to be effective in the treatment of selected diseases mediated by T cells. We have reviewed the responses and long-term outcome of 59 hematopoietic stem cell transplant (HSCT) patients treated from 1996 to 2003 with ECP for steroid-refractory acute GVHD, defined as progression or no improvement of acute GVHD after a minimum of 4 (range, 4–49, median 17) days of treatment with prednisone (n=37) or steroid-dependent acute GVHD, defined as flare-up of GVHD during prednisone taper (n=22). Patients received HSCT from 17 related and 42 unrelated donors. In 28 cases an HLA-mismatch between recipient and donor was present. Prior to ECP, grade III–IV GVHD was observed in 23 patients (39%) and grade II GVHD in 36 (61%). Organs involved included skin in 97% of patients, liver in 39%, and GI tract in 17%. Treatment consisted of ECP on two consecutive days per week (=1 cycle) for a median of 7 (range, 1–45) cycles administered within a median of 3 (range, 0.5–31) months in addition to cyclosporine A and prednisone. Three months after initiation of ECP complete resolution of GVHD was achieved in 82% of patients with cutaneous, 61% with liver, and 61% with gut involvement. Complete responses were obtained in 86% of patients with grade II, 55% of patients with grade III, and 30% of patients with grade IV acute GVHD. Probability of transplant-related mortality (TRM) at 4 years after HSCT is 15% in patients with complete response to ECP compared to 88% in patients not responding completely. After a median follow-up of 46 (range, 9–45) months since discontinuation of ECP, 28 (47%) patients are alive including 22 without chronic GVHD. Probability of survival (OS) at 4 years after HSCT is 59% in patients with complete response to ECP compared to 11% in patients not responding completely. Besides response to ECP only organ involvement and grade of GVHD at start of ECP, and ability to timely taper steroids during ECP had a significant impact on both TRM and OS. Thus, ECP is an effective adjunct therapy for acute steroid-refractory and steroid-dependent GVHD. Our long-term results demonstrate durability of responses without adverse events.

Download Full-text

Evaluation of Graft Versus Host Disease and Relapse Free Survival As Novel Endpoint in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Joint Naples-Paris Study

Blood ◽

10.1182/blood.v128.22.2285.2285 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2285-2285

Author(s):

Simona Pagliuca ◽

Antonio M Risitano ◽

Sylvie Chevret ◽

Flore Sicre de Fontbrune ◽

Alienor Xhaard ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Graft Versus Host

Abstract The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes of our transplanted cohort, we retrospectively analysed GRFS of 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital (n=840) in Paris between 2007 and 2014, identifying prognostic factors associated with a better outcome and estimating the incidences of all components of this endpoint: rates of acute and chronic GVHD, disease relapse and death. Patient, disease and transplant characteristics are listed in table 1. Median duration of follow-up after HSCT was 22.1 months (IQR: 5.6-51 months). Cumulative incidence at day 100 of grade II-IV acute GVHD and grade III-IV were 42% and 16%, respectively. Cumulative incidence of chronic GVHD requiring systemic treatment at 1 and 5 years was 23% and 33%, respectively, diagnosed according to NIH criteria [14% of patients had score 1 (mild), 58% score 2 (moderate) and 27% score 3 (severe)cGVHD]. Cumulative incidence of relapse (considering all malignant and non-malignant diseases) was 26.7% (N=219) at 5 years. Overall survival for the whole population was 57% (95%CI, 53.3-60.8) at 5 years and Disease free survival (DFS) and non-relapse mortality (NRM) were respectively 50% (95%CI, 46.6-53.8) and 23% at 5 years. GRFS was 25% (95%CI, 21.8-28.5) at 5 years. Factors identified as influencing GRFS based on univariate analyses were age higher than 45 years (HR=1.64, 95%CI, 1.40-1.92), bone marrow (BM) as stem cell source (HR=0.40, 95%CI, 0.32-0.50); reduced intensity conditioning (RIC) (HR=0.63, 95%CI, 0.53-0.74); disease type [non-malignant disorders: HR=0.24, 95%CI, 0.17-0.33; myelodysplastic and myeloproliferative syndromes (MPN/CML/MDS): HR=1.34, 95%CI, 1.10-1.63; whereas other diagnosis did not influence GRFS] and than unrelated donor (matched: HR=1.71, 95%CI, 1.41-2.07;mismatch:HR=1.81, 95%CI, 1.48-2.23). Based on a multivariable Cox model, only diagnoses (non-malignancies, HR=0.27, 95%CI, 0.19-0.38 and MPN/CML/MDS, HR= 1.35, 95%CI, 1.11-1.65), and HLA unrelated graft (matched, HR=1.42, 95%CI, 1.17-1.73 and mismatched, HR=1.55, 95%CI, 1.26-1.92) remained associated with the outcome (Figure 1 and 2). GRFS could represent the ideal endpoint following HSCT. It differs significantly based upon type of disease and donor type, essentially. This composite indicator yields more information regarding complications of HSCT than the simpler measurement of OS or DFS. Its use willbetter compare these clinically important outcomes that accompany disparate HSCT techniques. All examined prognostic factors could enhance our ability to optimally judge the risk and the probability of true recovery after allogeneic HSCT. Our data support the use of this composite endpoint to describe HSCT outcome, and also pave the way for the investigation of novel endpoints, which may also track the dynamic changes of post-transplant events in the long-term. These retrospective data represent the background to investigate the impact of novel strategies of HSCT aiming to improve the outcome of HSCT, as detectable, by using more sensitive endpoints, tracking clinical events associated with detrimental long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Download Full-text

The Use of Placenta-Derived Decidua Stromal Cells for Treatment of Severe Acute Gastrointestinal Graft-Versus-Host-Disease in Adults and Children

Blood ◽

10.1182/blood-2019-122674 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4456-4456

Author(s):

Sadeghi Behnam ◽

Remberger Mats ◽

Per Frisk ◽

Britt-Marie Frost ◽

Olle Ringden ◽

...

Keyword(s):

Stromal Cells ◽

Acute Gvhd ◽

Pediatric Population ◽

Chronic Gvhd ◽

Gi Tract ◽

Graft Versus Host ◽

Grade Ii ◽

Steroid Refractory ◽

Long Term Mortality

Introduction:Acute graft-versus-host disease (aGVHD) can develop into a life-threatening complication after allogeneic hematopoietic cell transplantation (HSCT). The gastrointestinal (GI) tract is considered to play a key role in the pathophysiology of aGVHD, where the disease-process can start and be one of the target organs.The clinical presentation of acute aGVHD in the lower GI tract includes secretory diarrheas, sometimes bloody stools, abdominal pain with or without paralytic ileus. In the upper GI, symptoms such as nausea, anorexia, vomiting and weight loss are common. First-line therapy for aGVHD includes steroids at doses of 1-2 mg/kg /day. Approximately 50-60 % of the patients with aGI-GVHD fail to respond to steroids and their outcomes are very poor with a long-term mortality between 70-90 %. Bone marrow derived mesenchymal stromal cells (BM-MSCs) were introduced as a novel cell-based therapy by us for aGVHD a few decades ago, but not all patients responded, and many patients died due to invasive fungal infection. Decidua stromal cells (DSCs), isolated from the fetal membrane, express a stronger immunosuppression activity compared to other sources of MSCs and have been used to treat patients with severe steroid-refractory GVHD (SR-GVHD). The placenta protects the haploidentical fetus from the mother's immune system during pregnancy. So far, no severe side effects have been seen using DSCs. Material and Methods;DSCs were isolated from full-term placentas following elective Caesarian-sections using a GMP facility. The study included 18 adult patients, median age was 50 (21-72) years and 4 pediatric patients, median age of 5.4 (0.3-14). The diagnosis was verified by GI biopsy. Histology confirmed GVHD, grade II-IV (Table 1). The study period took place between 2012 and 2016. Four adults presented with GVHD grade II and fourteen had GVHD grade III. In the pediatric population two patients were diagnosed with GVHD grade II, one child with GVHD grade III and one with GVHD grade IV.Twelve patients were steroid refractory after > 7 days and ten patients after>3 days. Subsequently DSCs were given at a median dose of 1.2 (0.9-2.9) x 106cells/kg and the frequency of 2 (1-6) doses/patient, given one week apart. Viability of thawed DSCs was 95% (89-100) and median passage number of infused cells was 4 (2-4). The study was approved by the regional ethical committee. Results:In summary all patients responded to the DSCs. Complete resolution of GVHD was seen in16 patients from the adult population and 2 showed partial response at day 28. All children presented a partial response at day 28 (Table II). The cumulative incidence of chronic GVHD was observed in 50% including both the adult and pediatric population, in accordance to the NIH GVHD severity scoring (Fig 1 and 2). Nine patients died, 3 from relapse, 1 acute GVHD in combination with septicemia, 1 zygomycetes infection, 1 liver insufficiency, 1 multiorgan failure, 1 chronic GVHD with obstructive bronchiolitis and one child died from cerebral hemorrhage (Table II). Four years transplant related mortality was 28.6% and overall four years survival was 57% and 75 % in the adult and pediatric group respectively (Fig 3). Conclusion:There is a necessity for an effective therapy, with fewer side effects, when the patient develop SR-GVHD. Overall long time-survival in patients with steroid-refractory GVHD is poor, with a long-term mortality up to 70-90 %. In our study, decidua stromal cells showed a strong immunosuppression with a high efficacy in SR-GVHD patients to achieve long-term survival. To conclude, DSCs seem to be a useful cell therapy for severe acute GVHD. Randomized trials are under way. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Stärken der Graft-versus-Leukämie-Effekte durch richtig terminierte Photochemotherapie

Karger Kompass Dermatologie ◽

10.1159/000489283 ◽

2018 ◽

Vol 6 (3) ◽

pp. 149-150

Author(s):

Percy Lehmann

Keyword(s):

Acute Leukemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Free Survival ◽

Graft Versus Host ◽

Treatment Start ◽

Graft Versus Leukemia ◽

Primary Predictor ◽

Graft Versus Leukemia Effect

Background: Cure of acute leukemia after transplantation is mediated by the grafted cells. We investigated the graft-versus-leukemia effect (GVL) in patients with cutaneous acute graft-versus-host disease (GVHD) treated with photochemotherapy (psoralen and ultraviolet light type A). Method: Forty-seven patients with acute leukemia were followed 5,000 days after transplantation to assess survival and GVL by multivariate analysis. The primary predictor was time to treatment of cutaneous acute GVHD by photochemotherapy separated into treatment start during the first week of acute GVHD versus after the first week of acute GVHD. Results: Photochemotherapy started after the first week of acute GVHD predicted GVL with a hazard ratio (HR) of 3.94 (95% confidence interval, CI, 1.67-9.33, p = 0.0018) and survival with preserved GVL with an HR of 2.63 (95% CI 1.30-5.32, p = 0.007). The effects on GVL and survival with preserved GVL were present regardless of whether the patients were transplanted in remission or relapse (p < 0.05). Chronic GVHD came earlier in the group that started photochemotherapy after 1 week of acute GHVD, but chronic GVHD did not increase the GVL. Conclusion: The timing of photochemotherapy after cutaneous acute GVHD may direct the GVL and predict long-term leukemia-free survival.

Download Full-text

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 ◽

10.1182/blood.v126.23.1956.1956 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1956-1956

Author(s):

Dana L Shanis ◽

Prathima Anandi ◽

Caitlin Grant ◽

Priyanka A Pophali ◽

Eleftheria Koklanaris ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Graft Versus Host ◽

Post Transplant ◽

Multifocal Disease

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.

Download Full-text

Incompatibilities of HA-1 and 3 Polymorphic Adhesion Molecules Including CD62L, CD31 codon563 and CD31 codon125 Induce Graft-Versus-Leukemia Effect Rather Than GVHD Resulting in Long-Term Survival in HLA Identical SCT.

Blood ◽

10.1182/blood.v106.11.3095.3095 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3095-3095

Author(s):

Nahoko Kuba ◽

Shintaro Shiobara ◽

Tatsuo Hurukawa ◽

Jyunichi Tsukada ◽

Sinji Nakao ◽

...

Keyword(s):

Stem Cell ◽

Adhesion Molecules ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Survival Rates ◽

Term Survival ◽

Graft Versus Host ◽

Standard Risk ◽

Relapse Rates

Abstract Mismatches of minor histocompatibility antigen (mHag) between HLA identical stem cell donor and host are known as a major risk factor for graft-versus-host disease (GVHD). We determined the alleles of 4 polymorphic molecules including HA-1 and 3 adhesion molecules; CD62L, CD31 codon563 and CD31 codon125 in 114 patients transplanted HLA identical stem cell grafts and investigated the association of mismatches as rates of relapse and GVHD. All 114 recipients underwent stem cell transplantation after myeloablative conditioning between 1985 and 2004. Risk ststus of the disease at SCT was standard (n=71) and high (n=43). After SCT, 36, 57 and 35 developed acute GVHD (≥2), chronic GVHD and relapsed, respectively. Our patients relapsed at rates of 14.3% and 38.0% with one or more and without incompatibilities (P=0.011). In standard risk group, the relapse rates of 20 and 51 patients with and without mHag incompatibilities were 5.0% and 39.2%, respectively (P=0.011). The relapse rates of patients with CD62L, CD31 codon563, HA-1, CD31 codon125 incompatibilities were 5.3%, 11.8%, 16.7%, 23.1% respectively. The frequency of acute GVHD (≥2) did not differ regardless of incompatibilities. The probability of 10 year survival rates were 84.0% with incompatibility and 54.3% without incompatibility patients (P=0.009). Our data suggests that incompatibilities of at least one of 4 polymorphic molecules contribute to GVL effect rather than to GVHD, resulting in prolonged survival after HLA identical SCT. Figure Figure

Download Full-text

Ruxolitinib for Therapy of Graft-versus-Host Disease

BioMed Research International ◽

10.1155/2019/8163780 ◽

2019 ◽

Vol 2019 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Thomas Neumann ◽

Laila Schneidewind ◽

Martin Weigel ◽

Andrzej Plis ◽

Rem Vaizian ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Calcineurin Inhibitors ◽

High Dose ◽

Steroid Resistant ◽

Host Disease ◽

Graft Versus Host ◽

Severe Diarrhea ◽

Steroid Sparing

Objective. Steroid-resistant graft-versus-host disease (GvHD) is a major challenge after allogeneic stem cell transplantation and associated with significant morbidity and mortality. There is no therapeutic standard defined beyond calcineurin inhibitors (CNI) and steroids. Furthermore, some patients may have contraindications against CNI or high-dose steroids. Efficacy of ruxolitinib against GvHD has been described recently. Methods. Ruxolitinib was used for treatment of acute or chronic GvHD in eight patients. The patients either needed intensification of therapy or had contraindications against use of CNI or high-dose steroids. Results. Supplementation of therapy in acute GvHD with severe diarrhea with ruxolitinib was unsuccessful. All these patients died from acute GvHD. Introduction of ruxolitinib into therapy and relapse prophylaxis in other patients was successful in 4/4 cases (CR=3, PR=1). Indications for ruxolitinib were contraindications against CNI due to aHUS in two cases and the need for steroid sparing in two other cases. None of these patients suffered from diarrhea at the initiation of ruxolitinib. Conclusion. Ruxolitinib was effective for therapy of acute and chronic GvHD in higher lines in patients without severe diarrhea. Ruxolitinib could replace successfully CNI and high-dose steroids. Further investigations are necessary to define the position of ruxolitinib in GvHD-therapy.

Download Full-text

Depletion of donor lymphocytes by counterflow centrifugation successfully prevents acute graft-versus-host disease in matched allogeneic marrow transplantation

Blood ◽

10.1182/blood.v67.5.1302.bloodjournal6751302 ◽

1986 ◽

Vol 67 (5) ◽

pp. 1302-1308

Author(s):

T de Witte ◽

J Hoogenhout ◽

B de Pauw ◽

R Holdrinet ◽

J Janssen ◽

...

Keyword(s):

Bone Marrow ◽

Marrow Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Host Disease ◽

Allogeneic Marrow Transplantation ◽

Primary Graft Failure ◽

Acute Graft

Bone marrow from 22 histocompatible siblings was depleted of 98% of the lymphocytes using a combination of density flotation centrifugation followed by counterflow elutriation. Even with the marrow suppressive influence of methotrexate (MTX), the viability of the hematopoietic stem cells was not affected, as indicated by the normal repopulation after grafting in the evaluable patients. One patient (UPN 9) showed a primary graft failure, possibly resulting from persisting septicemia and long-term antibiotic therapy. Two patients have persistent host lymphocytes, one of whom was examined during relapse; the other remains in remission. Two patients did not receive immunosuppression after bone marrow transplantation (BMT), and acute graft-v-host disease (GVHD) developed in both. Nine patients received MTX as immunosuppression following BMT. GVHD did not develop in any of them, but fatal infections in the immediate posttransplant period developed in five patients. Eleven patients received cyclosporine (CsA) after transplantation. Beginning in week 5 after BMT, CsA was gradually replaced by MTX. Acute GVHD, substantial chronic GVHD, or fatal infections did not develop in any of these patients. Removal of 98% of the lymphocytes by counterflow centrifugation prevents development of acute GVHD, provided that immunosuppression is administered after BMT. Graft rejection was not observed, but the number of evaluable patients is limited at present.

Download Full-text