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

Blood ◽  
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.

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

Blood ◽  
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.

Subcutaneous Alemtuzumab May Be Useful in the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2983-2983
Author(s):  
David Gomez-Almaguer ◽  
Guillermo J. Ruiz-Arguelles ◽  
Oscar Gonzalez-Llano ◽  
Homero C. Gutierrez-Aguire ◽  
Olga G. Cantu-Rodriguez ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Background: Acute graft-versus-host disease (GvHD) is mediated by activated T lymphocytes. Alemtuzumab is an unconjugated, humanized IgG1 kappa monoclonal antibody which targets the CD52 antigen on T lymphocytes and other cells and has been used successfully in conditioning regimens for allogeneic transplantation to remove donor T cells so as to prevent GvHD. Patients and methods: Eighteen patients with steroid-refractory acute GvHD ≥ grade II were analyzed to evaluate the safety and efficacy of alemtuzumab. The patients received subcutaneous alemtuzumab 10 mg daily on days 1–5. The proportion of patients with grade II, III and IV were eight, eight and two, respectively. The main organ involved was the liver in four, gut in five, skin and liver in three, and skin and gut in three patients. Results: Fifteen out of 18 patients (83%) responded to alemtuzumab with 6 (33%) complete and 9 (50%) partial responses. All three unresponsive patients died of GvHD. Ten of 15 responders are alive at a median follow-up of 9 months (range 2–23) after alemtuzumab, with limited, extensive and no signs of chronic GvHD in 1, 4, and 5 patients, respectively. Fourteen patients (78%) developed some kind of infection; eleven of them developed cytomegalovirus reactivation. All patients tolerated alemtuzumab with minimal side effects; grade 3 neutropenia and thrombocytopenia were seen in six and four patients, respectively. Conclusions: Alemtuzumab is a well tolerated agent and has a beneficial effect in the treatment of steroid-refractory acute GvHD. Infections are common and anti-infective prophylaxis is mandatory.

Steroid Refractory Acute and Chronic Graft Versus Host Disease (GVHD) - Response to Photophoresis+/− Rituximab.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5358-5358 ◽  
Author(s):  
Ramakrishnan Parameswaran ◽  
Maggie Sekeramayi ◽  
Kelly McCaul ◽  
Bill Bradfeldt
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Bk Virus ◽  
High Dose ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Gi Tract ◽  
Steroid Refractory

Abstract Acute GVHD is an important complication following hematopoeitic stem cell transplantation (HSCT), with significant attendant morbidity and mortality. High dose steroids remain the cornerstone of therapy. Steroid refractory GVHD carries a very poor prognosis. Various therapies are available for steroid refractory acute GVHD, but response is not uniform. Among the less intensive regimens, extracorporeal photopheresis (ECP) and rituximab, a chimeric humanized anti CD 20 monoclonal antibody have been shown to be useful in treating refractory acute and chronic GVHD. We describe 8 patients who developed GVHD following transplantation of HLA-identical stem cells, from siblings in 7 and from an unrelated donor in one. 2 patients had steroid refractory chronic GVHD of the liver, 3 patients had a refractory chronic GVHD of the skin and one had a steroid responsive restrictive pulmonary syndrome. Of the patients with skin GVHD, 2 had chronic scelrodermatous GVHD, which was of 20 years duration in one patient and 8 in the other. 2 patients had acute GVHD of the GI tract. The age range was 21– 53 years. All patients were in complete remission from their primary disease at the time of therapy for GVHD. 3 patients had a diagnosis of acute lymphoblasitc leukemia and 5 acute myeloid leukemia All had failed treatment with high dose steroids and/or tacrolimus and/or cellcept, and, one had also failed ATG therapy. Then therapy for refractory GVHD was initiated with rituximab in 3 patients and with photopheresis in 5. 7 patients received ECP. One patient with refractory chronic GVHD of the liver received rituximab alone in addition of steroids and tacrolimus. The patients with acute GVHD were treated with daily ECP for 10 days and then were weaned down to two procedures every 2 weeks. Patients with chronic GVHD received ECP 2 to 3 times a week for 6 weeks and were subsequently similarly weaned down. In the patients with acute GVHD of the GI tract complete responses occurred at 10 days in one patient and 45 days in the second as determined by complete cessation of diarrhea, cramps and nausea. Both patients with chronic GVHD of the liver achieved normalization of the serum bilirubin by 26 and 38 days after initiation of therapy. All patients tolerated successful taper of steroid therapy. The two patients with sclerodermatous GVHD have shown marked improvement in skin texture and range of motion at the involved joints. The patient with the pulmonary symptoms has shown complete normalization of pulmonary function. 5 patients were at risk of CMV reactivation, but failed to do so. One patient developed BK virus associated hemorrhagic cystitis that required therapy with cidofovir. There were 3 admissions for neutropenic fever, three for pneumonia and one each for gastroenteritis, HSV gingivostomatitis and line related sepsis. Two patients had line related thrombosis. None of the patients had relapse of their disease. 2 of the responders had an ECOG performance status 2, two of 3, one of 4 and four of </= 1 while being treated. All patients demonstrated improvement in functional status. ECP and rituximab is a well tolerated and effective modality for therapy of steroid refractory chronic and acute GVHD in both related and unrelated marrow stem cell transplant recipients.

Response and Long-Term Outcome After Treatment With Third-Party Mesenchymal Stromal Cells - Updated Results In 58 Patients With Steroid-Refractory Acute Graft-Versus Host Disease -

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4612-4612
Author(s):  
Felix von Dalowski ◽  
Michael Kramer ◽  
Martin Wermke ◽  
Christoph Röllig ◽  
Nael Alakel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Partial Response ◽  
Stromal Cells ◽  
Acute Gvhd ◽  
Third Party ◽  
Graft Versus Host ◽  
Historic Cohort ◽  
Steroid Refractory ◽  
Acute Graft

Introduction Acute Graft-versus-Host Disease (aGvHD) remains the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). So far, corticosteroids are the only first-line treatment proven to be effective. Steroid-resistance is associated with poor outcome and no commonly accepted second-line salvage therapy is available until now. Mesenchymal stromal cells (MSC) have shown promising immunomodulatory effects and have been suggested as cell-based treatment option in patients with steroid-refractory acute GvHD. Here, we report our experience from a large cohort of patients treated with MSC. Patients, Materials and Methods Fifty-eight patients with steroid-refractory acute GvHD after HSCT were treated with MSC at our centre between 2007 and 2012. MSC were obtained from volunteer third-party donors and expanded in platelet-lysate containing medium. Median age at transplantation was 55 years (range 19-71). In 25 patients AML was diagnosed initially. Further diagnoses were CLL (n=9), ALL (n=5), MDS (n=5) and others (n=14). For transplantation, patients received peripheral blood stem cells (n=56) or bone marrow (n=2) from HLA-identical (n=43) or HLA mismatched donors (n=15) after varying reduced-intensity conditioning regimens (n=50) or myeloablative conditioning (n=8). Eight-teen patients received anti-thymocyte globulin as part of their conditioning. GvHD prophylaxis consisted mostly of cyclosporine A (CsA) plus methotrexate, CsA alone or CsA plus mycophenolate mofetile. The majority of patients suffered from aGvHD grade IV (79%), median interval from HSCT to onset of GvHD was 36 days. Involvement of gastrointestinal tract, liver and skin was observed in 91%, 43% and 41% of patients, respectively. Most patients (64%) had involvement of 2 or 3 organs at the same time. Besides corticosteroids, 48 patients (83%) received at least one additional immunosuppressive agent before the first MSC infusion. Response was assessed 28 days after initiation of MSC treatment and overall survival of the MSC treated cohort was compared to a historic patient cohort (n=36) with steroid-refractory aGvHD not receiving MSC. Results Median time between onset of aGvHD and first application of MSC was 12 days (range 6-62). Altogether 139 doses of MSC were transfused at a median dosage of 0.99x106cells/kg bodyweight (range 0.448 -2.077). A median number of 2 MSC infusions were given per patient (range 1-6). During MSC treatment, 39 patients needed further escalation of immunosuppression due to persistence or progression of GvHD. No side-effects directly related to MSC infusions were observed. Four weeks after first MSC application, 9% (n=5) of patients showed a complete response (CR), 9% (n=5) exhibited a very good partial response (VGPR), 29% (n=17) experienced partial response (PR) whereas 53% (n=31) were classified as non-responders. There were no significant differences in organ specific response. One-year and 2-year-survival after onset of aGvHD was 19% [95% CI: 9-29%] and 17% [95% CI: 7-26%], respectively. Median survival was 69 days [95% CI: 38-100 days]. Causes of death were aGvHD (54%), infectious complications (29%), relapse of the underlying disease (4%) and others (13%). Median follow up was 1689 days and at the end of follow-up, 8 patients were still alive (median survival after HSCT 58 months). Of those eight, 6 were initially classified as responders (CR n=4, VGPR n=1, PR n=1). Responders showed higher survival compared to non-responders (hazard ratio 0.38; p=0.004). Overall survival in the MSC treated cohort did not differ significantly to that of the historic cohort not receiving MSC. Conclusions MSC in combination with further immunosuppressive strategies resulted in a response rate of 47% in patients with steroid-refractory aGvHD and should therefore be considered as a valuable treatment option in a difficult clinical situation. However, compared to our historic cohort, treatment with MSC did not lead to an improvement of survival. Future studies need to define which patient subsets are likely to benefit from MSC therapy and whether certain MSC preparations from specific donors may have a more pronounced and long-lasting immunosuppressive effect. Therefore, further insights into MSC biology are urgently needed to optimize the translation into clinical practice. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
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.

scholarly journals Acute GVHD: think before you treat

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 642-647
Author(s):  
Laura F. Newell ◽  
Shernan G. Holtan
Keyword(s):  
Clinical Trials ◽  
Tissue Repair ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Classification Systems ◽  
High Likelihood ◽  
Graft Versus Host ◽  
Steroid Dependent ◽  
Steroid Sparing

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.

scholarly journals Butyrogenic bacteria after acute graft-versus-host disease (GVHD) are associated with the development of steroid-refractory GVHD

2019 ◽  
Vol 3 (19) ◽  
pp. 2866-2869 ◽  
Author(s):  
Jonathan L. Golob ◽  
Martha M. DeMeules ◽  
Tillie Loeffelholz ◽  
Z. Z. Quinn ◽  
Michael K. Dame ◽  
...  
Keyword(s):  
Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Epithelial Monolayer ◽  
Graft Versus Host ◽  
Key Points ◽  
Colonic Stem Cells ◽  
Steroid Refractory ◽  
Acute Graft

Key Points The presence of butyrogenic bacteria after the onset of acute GVHD associates with subsequent steroid-refractory GVHD or chronic GVHD. Butyrate inhibits human colonic stem cells from forming an intact epithelial monolayer.

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.

A Multicenter Retrospective Analysis on Pentostatin As Salvage Therapy of Severe Steroid Refractory Intestinal Acute Graft Versus Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3048-3048
Author(s):  
Stefan A. Klein ◽  
Thomas Schmitt ◽  
Gesine Bug ◽  
Johannes Schetelig ◽  
Rainer Schwerdtfeger ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Gi Tract ◽  
First Line ◽  
Term Survival ◽  
Long Term Survival ◽  
Graft Versus Host ◽  
Probability Of Survival ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Abstract 3048 Acute graft-versus-host disease (aGvHD) of the gastrointestinal (GI) tract is still a major clinical challenge after allogeneic stem cell transplantation. Patients with steroid-refractory disease have a poor prognosis. Pentostatin, an inhibitor of adenosine deaminase, has shown efficacy as salvage therapy in steroid-refractory aGvHD of the GI tract in small single center studies. Here we report on the experience with pentostatin in severe steroid-refractory aGvHD of the GI tract at seven German transplant centers. PATIENTS: A total number of 123 patients who had been treated with pentostatin due to intestinal steroid-refractory aGvHD between 2000 and 2011 were retrospectively analyzed. Steroid-refractory aGvHD was defined as progression or no improvement of diarrhea despite treatment with prednisolone (≥ 2mg/kg/d) for ≥ 3 days. Pentostatin was infused at a dose of 1mg/m2 for 3 consecutive days. In patients with impaired renal function the dose of pentostatin was reduced. Patients received 1–4 cycles. Steroids and calcineurin inhibitors (CNI) were continued. Response after therapy with pentostatin was classified as complete (CR, no ongoing symptoms of GvHD), very good partial (VGPR, residual symptoms only) or no response (NR). 50 females and 73 males with a median age of 50 (range: 19–70) years were included. The underlying diseases were AML (n=71), ALL (n=15), CML/MPS (n=6), lymphoma (n=12), MDS (n=10), and multiple myeloma (n=9). 85 patients received reduced intensity and 38 myeloablative conditioning. Patients had been transplanted from matched related (n=38), matched unrelated (n=53) or mismatched donors (n=32). All patients suffered from severe steroid-refractory intestinal aGvHD overall grade III (n=59) or IV (n=64). Patients received pentostatin as first line salvage (n=109) or beyond first line salvage therapy (n=14). Results: 52 patients (43%) responded after salvage therapy with pentostatin. 39 patients (32%) achieved CR, 13 patients (11%) VGPR. Median survival was 104 days; 2-year and long term survival rates were 26 and 19% with a median follow up of 45 months. Among 109 patients who received pentostatin as first line salvage therapy 49 (45%) responded (37 × CR [34%] and 12 × VGPR [11%]). Median survival, 2-year and long term survival were essentially the same as in the total cohort of patients. After the first infusion of pentostatin clinical improvement occurred within a median of 14 (range: 1–58) days. 71 patients (57%) did not respond. Responding patients had a significantly (p<0.0001) higher probability of survival in comparison with non-responders (2 year survival 44 vs. 14%, long term survival 41 vs. 0%). 94 patients (76%) died (66% therapy related, 10% due to relapse of the malignant disease). Patients who had been transplanted from a matched related donor had a significantly (p=0.04) higher probability of survival in comparison with patients with other donors (2-year survival: 38 vs. 21%, long term survival 35 vs. 8%). 53% (n=20) of these patients responded. Out of the 109 patients who were treated with pentostatin as first line salvage therapy 15 received simultaneously additional immunsuppressive salvage therapies (infliximab, mesenchymal stem cells [MSC] or extracorporeal photopheresis [ECP]). None of these patients survived. 46 patients without CR after one cycle of pentostatin received further immunosuppressive salvage treatment: 28 of these patients were treated with 1–3 further cycles of pentostatin. 18 of the 46 patients received pentostatin plus simultaneous or subsequent additional immunsuppressive therapies (infliximab, alemtuzumab, basiliximab, MSC or ECP). In both groups the probability of survival was identical (2-year survival: 17%). Conclusions: The outcome after salvage therapy of III/IV° steroid-refractory intestinal aGvHD with pentostatin is at least within the range as reported for other salvage approaches. In this critical clinical situation pentostatin has some superior characteristics: a sustainable effect, moderate toxicity, easy application and cost-effectiveness. Moreover, this analysis suggests that the outcome of steroid-refractory aGvHD cannot be improved by the application of more than one immunosuppressive salvage drug in addition to steroids and CNI or by second line salvage approaches. Disclosures: Klein: Hospira: Honoraria, Research Funding. Off Label Use: pentostatin is not licensed for use in acute GvHD.

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