scholarly journals Real World Experience of Etanercept in Steroid Refractory Acute Graft Versus Host Disease from a Tertiary Cancer Centre in India

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-3
Author(s):  
Akanksha Chichra ◽  
Sachin Punatar ◽  
Anant Gokarn ◽  
Sumeet Prakash Mirgh ◽  
Vijay Shirure ◽  
...  
Keyword(s):  
Response Assessment ◽  
Response Rates ◽  
Median Number ◽  
Systemic Steroid ◽  
First Line ◽  
Graft Versus Host ◽  
Steroid Dose ◽  
Initial Agent ◽  
First Line Treatment ◽  
Steroid Refractory

Introduction Acute graft versus host disease (aGVHD) is an important complication of allogeneic hematopoietic stem cell transplant (AHSCT). Steroid refractory (SR) aGVHD is seen in about 40- 50% of patients with no recommended standard of care. We report our experience with etanercept (ETA) as the initial agent in SR aGVHD. Materials and Methods We retrospectively analysed 43 AHSCT patients from 2010 to 2019 who received ETA as initial agent for SR aGVHD amongst 311 patients who underwent AHSCT in the same period. Patients received myeloablative (MAC) or reduced intensity conditioning (RIC). The transplants were from matched sibling donor (MSD), matched unrelated donor (MUD) and haploidentical donor (Haplo). GVHD prophylaxis was calcineurin inhibitor (CNI) plus methotrexate (MTX)/ mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide (PTCy) with CNI and MMF. aGVHD was graded as per the modified Glucksberg criteria. Additionally, all aGVHD episodes were also classified as per the Minnesota Scoring into High Risk (HR) and Standard Risk (sr) GVHD. First line treatment of aGVHD Grade II-IV was systemic steroids with methylprednisolone 1-2 mg/kg/day. SR aGVHD was defined as per standard criteria. ETA was started as 25 mg (0.4 mg/kg in children) subcutaneously every 72 hours initially and was tapered gradually depending on response. Response of SR aGVHD to ETA was defined as follows:Complete response (CR) was the complete resolution of aGVHD manifestations in all organs. Partial response (PR) was improvement in GVHD stage in at least 1 of the initially involved organs without CR and worsening in any other organs. Very good partial response (VGPR) was improvement in GVHD in all initial organs, with maximum stage I involvement in 1 or more organs (except upper gut). No response (NR)/Progression/Failure of therapy was defined as same grade or progression of GVHD in any organ or the addition of further GVHD therapy beyond ETA. Death prior to 1st response assessment was taken as NR. Response assessment was done at 3 time points - Day 14, Day 28 and Day 56 after initiation of ETA. Reduction of initial systemic steroid dose by ≥30% from baseline on day 28 after start of ETA was analysed as a subgroup to assess outcomes of patients. Results The characteristics of all 43 patients are shown in Table 1. ETA was required in a total of 45 episodes in 43 patients. The overall grade of GVHD and organs involved at the start of first line treatment are as in Table 2. The median day of onset of acute GVHD was 58 days (range 8-738 days). The median day of start of ETA was 86 days (range 16-74 days). The median number of days steroid was given prior to start of ETA was 7 days. The median number of ETA doses given were 11 (range 2-25). Response assessment on the predetermined time points are as in Table 2. The response rates (CR+VGPR+PR) at Day 14, Day 28 and Day 56 were 62%, 69% and 64% respectively. The organ specific response rates (CR+VGPR+PR) were 70% for lower gut, 67% for skin and 50% for liver. A third line agent for aGVHD was added in 10 patients, which included ruxolitinib, cyclosporine, mycophenolate mofetil, basiliximab or low dose weekly cyclophosphamide. The median OS of the whole cohort of SR aGVHD was 5.2 months. The median OS of the responders (CR+PR+VGPR) at Day 28 from ETA start was 6.8 months versus 2.8 months (p=0.0003) in non-responders (Fig 1). The median OS of sr group of Minnesota Grading was 24 months versus 10 months in HR group (p=0.085) (Fig 2). Patients, in whom reduction in the systemic steroid dose ≥ 30% at Day 28 from start of ETA was possible, had a significantly better median OS (9.5 months versus 3.5 months; p=0.000021) (Fig 3). In multivariate analysis, steroid dose reduction on day 28 of start of ETA was the most significant factor (p=0.008; hazard ratio 3.33; CI 1.3-8.1) CMV reactivation was seen in 64% of the patients. Fungal infections in 51% and bacterial infections in 78% patients after start of ETA. The causes of death were infection in 25 (58%) patients, refractory GVHD in 8 (18%), combination of GVHD and infection in 2 (5%) and relapse in 4 (9%) patients. Conclusion ETA used as initial agent has shown acceptable response rates for SR aGVHD in our cohort, especially for lower gut and skin. However, infections were the major cause for mortality for this cohort and early tapering of systemic steroids may be the key to improving outcomes. 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.

Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): Safety and activity in RTKI refractory RCC patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5039-5039 ◽  
Author(s):  
J. R. Merchan ◽  
H. C. Pitot ◽  
R. Qin ◽  
G. Liu ◽  
T. R. Fitch ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Stage Iv ◽  
Response Assessment ◽  
Response Rates ◽  
Median Number ◽  
Primary Objective ◽  
Phase 2 ◽  
Open Label

5039 Background: Combined mTOR and VEGF blockade is a potentially promising and rational strategy for the treatment of advanced RCC. We previously reported the phase I safety and efficacy results of CCI 779 (C) +bevacizumab (B) n RTKI naïve stage IV RCC patients (pts) (J Clin Oncol. 2007;25[18S Suppl]:5034). We now report the interim results of the phase 2 study of C+B in RTKI refractory RCC patients. Methods: Design: Open label, phase I/II study of C+B in advanced RCC pts. Patients with measurable stage IV RCC with a component of clear/conventional cell type, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed (at least one prior RTKI). Phase II dose was C = 25 mg IV weekly and B = 10 mg/kg every 2 weeks repeated in 4 week cycles. The primary objective of the phase II portion was to assess the proportion of patients who were progression-free 6 months after study entry. Secondary objectives were assessment of response rates and toxicity. Accrual goal = 40 pts. Results: Thirty-five pts have been enrolled into the phase 2 portion to date with 4 pts ineligible. Twenty-five pts are evaluable for response assessment and 29 pts are evaluable for toxicity. Baseline characteristics (N: 35): M/F: 28/7; Number of met. sites: 1/2/3+: 15/9/11; prior nephrectomy: 31; Number of prior therapies: 1 = 29; 2 = 2. Most common (>5%) Gr 3–4 AEs (N = 29) included fatigue (6), hypercholesterolemia (2), hypertriglyceridemia (2), anorexia (2), rash (2), and anemia (2). Responses were: PR/SD/PD = 4 (16%)/18 (72%)/3 (12%). Median number of cycles administered was 4. Six month progression free rates will mature by may 2009. Conclusions: C+B combination at the recommended phase 2 doses is feasible and well tolerated. Clinical benefit rates (PR/SD) in RTKI refractory RCC patients (88%) are encouraging. Data on 6 month progression-free rates are expected to mature in 4/09. Updated data on safety, response rates, and 6-month progression free rates will be presented on all evaluable patients. Correlative studies on available plasma, serum and tumor samples for angiogenic and molecular biomarkers are underway. Supported by N01-CM62205, R21 CA 119545–02, and Commonwealth Foundation. [Table: see text]

FOLFIRI + bevacizumab as first-line treatment in advanced colorectal cancer (ACC): Final results (prot. GOIM 2601)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15007-e15007
Author(s):  
F. Giuliani ◽  
F. De Vita ◽  
V. Lorusso ◽  
S. Cinieri ◽  
I. Nugnes ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Data ◽  
Advanced Colorectal Cancer ◽  
Median Number ◽  
Line Treatment ◽  
First Line ◽  
Bleeding Events ◽  
History Of ◽  
Optimal Regimen ◽  
First Line Treatment

e15007 Background: The addition of Bev to IFL obtained better OS and RR than chemotherapy alone. However IFL is not considered an optimal regimen and is certainly more toxic than FOLFIRI. To investigate the activity and efficacy of the addition of Bev to FOLFIRI, the GOIM started the following phase II study. Methods: seventy-two untreated pts with histologically/citologically confirmed diagnosis of colorectal cancer, with at least one measurable disease, age > 18 yrs, PS < 2 (ECOG), adequate bone marrow reserve and hepatic and renal function, with no history of cardiovascular disease, thromboembolic events or coagulative disorders and who signed informed written consent, were enrolled and received the following treatment: CPT-11 at 180 mg/m/mq on day 1, FA at 100 mg/mq as 2h infusion on days 1–2, FU at 400 mg/mq bolus on days 1–2 and FU at 600 mg/mq as 22h infusion on days 1–2 (FOLFIRI) plus Bev at 5 mg/Kg on day 1, every two weeks. A maximum of 12 cycles of chemotherapy was planned and a maintenance with Bev for 6 months was permitted. The evaluation of activity (Recist criteria) was performed every 4 cycles Results: all the enrolled pts were evaluable for activity and safety. Their main characteristics were M/F: 38/34; median PS: 0; median age 60 (range 33–73); primary site colon/rectum: 50/22 (69.4%/30.6%); main sites of disease liver: 50 (69.4%), lung: 18 (25%), lymph nodes: 19 (26.4%); synchronous/metacronous disease: 55/17 (77.7%/22.3%); multiple/single lesions: 40/32 (55.5%/44.5%).Seven (9.6%) CR, 25 (34.8%) PR, 33 (45.8%) SD and 7 PRO were observed for an ORR of 44.4% and a disease control of 90.3%. The response rate according to the main sites of disease were: liver 25/50 (50%), lung 6/18 (33.3%). The median number of administered cycle were 9 and the median TTP was 10.0 months. The main haematologic side-effects (% G3–4 NCI criteria) were: neutropenia 11%, thrombocytopenia 2.7% and anemia 4.7%, while diarrhea affected only 2.7% of pts; hypertension, thromboembolic and bleeding events were observed in 2.7%, 1.3% and 1.3% respectively. Conclusions: the addition of Bev to FOLFIRI is an active and effective first-line treatment in ACC with a good safety profile. Survival data will be presented during the meeting. No significant financial relationships to disclose.

Amrubicin monotherapy for patients with platinum-refractory gastroenteropancreatic neuroendocrine carcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 328-328
Author(s):  
Takayuki Ando ◽  
Ayumu Hosokawa ◽  
Hiroki Yoshita ◽  
Akira Ueda ◽  
Shinya Kajiura ◽  
...  
Keyword(s):  
Partial Response ◽  
Neuroendocrine Carcinoma ◽  
Progression Free Survival ◽  
Median Number ◽  
Line Treatment ◽  
First Line ◽  
Ki 67 ◽  
Platinum Based Chemotherapy ◽  
Platinum Refractory ◽  
First Line Treatment

328 Background: Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, because studies on salvage chemotherapy are limited, its role remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC. Methods: Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2006 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively. Results: Eight males and two females ((median age, 67 years (range, 52–78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n = 7, 70%), cisplatin plus etoposide (n = 2, 20%), and carboplatin plus etoposide (n = 1, 10%) before amrubicin therapy. A total of 30 cycles of amrubicin was administered in 10 patients, with a median number of cycles per patients was 2.5 (range, 1-7). Median progression-free survival (PFS) and overall survival after amrubicin therapy were 2.6 and 5.0 months, respectively. Two patients had partial response (20% response rate), and their PFS were 6.2 months and 6.3 months, respectively. Two patients with partial response had characteristics of NEC with a high Ki-67 index (99% and 89%, respectively) and had received cisplatin and irinotecan as first-line treatment. Grade 3–4 neutropenia and anemia were observed in four (40%) and five (50%) patients, and they were manageable in all cases by careful monitoring of myelosuppression and appropriate dose reduction of amrubicin. Conclusions: Amrubicin monotherapy appears to be potentially active and well-tolerated for platinum-refractory gastroenteropancreatic NEC.

Fludarabine, Mitoxantrone and Dexamethasone for the First Line Treatment of Patients with Indolent Non-Hodgkin Lymphoma (NHL): GATLA First Interim Report (Grupo Argentino de Tratamiento de la Leucemia Aguda).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4680-4680
Author(s):  
Gustavo Milone ◽  
A. Rodriguez ◽  
Jorge Milone ◽  
R.F. Bezares ◽  
S. Rudoy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Response Rate ◽  
Response Rates ◽  
Low Grade ◽  
Line Treatment ◽  
First Line ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
First Line Treatment

Abstract Background: fludarabine (F) is licensed for the management of indolent non-Hodgkin lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (N) and Dexamethasone (D) in indolent NHL patients (pts). The GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda) started a prospective multicenter national study to evaluate the use FND as a first line treatment for low grade NHL. Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FND as first line treatment for indolent NHL during (2002–2006). Methods: Ninety-six patients in the period of January 2002 to April 2006 were recruited. Sixty-nine patients were valuable at the time of analysis. Median age 54 years old (range: 21–79). Gender: male 51% and female 49%. Inclusion criteria for low grade NHL-LG was: non-previous, age &gt; 18 years old with symptomatic disease, ECOG performance status 0–2 and written informed consent. Ann Arbor staging: 5,8%, 14,5%, 24,6% and 55%. FND treatment consisted of F 25 mg/m2 i.v. (days 1–3), N 10 mg/m m2 i.v. (day 1) and D 20 mg (days 1–5) each 28 days for 6 cycles. All patients received oral antibiotics for intestinal decontamination, antifungal prophylaxis and Trimethoprim-Sulfamethoxazole as P. carinii prophylaxis for one year. Results: on this low grade NHL cohort the overall response rate (ORR) was 93% (ORR) with 70% (48 pts) with complete response (CR) and 23% (16 pts) with partial response; progressive disease and non-response 7% (5 pts). The probability of event free survival (EFS) and overall survival (OS) at 24 months was 60% and 90% respectively. Two patients developed secondary malignancies after treatment and one died. Only one patient died in CR. Conclusions: in this population FND treatment demonstrate a high CR rate with low toxicity and high probability of EFS and OS as previous experience published in the literature.

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.

Intra-Arterial Catheter Guided Steroid Administration For The Treatment Of Steroid-Refractory Intestinal GvHD

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4604-4604
Author(s):  
Michael Medinger ◽  
David Buergler ◽  
Jakob Passweg ◽  
Arne Fischmann ◽  
Christoph Bucher
Keyword(s):  
Median Time ◽  
Adult Patients ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Steroid Administration ◽  
The Mean ◽  
Grade Iii ◽  
First Line Treatment ◽  
Steroid Refractory

Background Acute gastrointestinal GvHD (GI-aGvHD) refractory to first line treatment with systemic corticosteroids is resulting in death in the majority of patients. Intra-arterial local dose intensification in the gut has been reported in pediatric but not in adult patients. We prospectively assessed the feasibility and efficacy of regional intra-arterial steroid treatment in adult patients with severe (>= grade III) GI-aGvHD not responding to first line treatment. Patients and Methods Patients with more than +++ GI-aGvHD not responding to intravenous methylprednisolone at a dose of 2 mg/kg/day within 14 days were eligible for inclusion. Catheter guided intra-arterial steroid administration (IASA) was performed by accessing the right or left common femoral artery; a 4 Fr angiography catheter was used to locate and select the superior and inferior mesenteric artery and, in patients with upper gastrointestinal symptoms into the celiac trunk (9 patients) and the left gastric artery (2 patients). The mean total dose of methylprednisolone administered over 1 minute was 180 mg (120-240 mg). In 7 patients with persistent or recurring symptoms, IASA was repeated within 14 days. Response assessment was at 28 days after IASA. CR was defined as complete resolution of GI symptoms; partial response was defined as reduction of GI score from +++ to ++. Non-response was defined as the same grade of aGvHD, progression of symptoms or death within 28 days after IASA. Results Between January 2010 and June 2012, 12 consecutive patients with steroid-refractory GI-aGvHD received IASA as second line treatment. The patient's baseline characteristics are summarized in Table 1. The mean patient's age was 53 years (range 30 - 69), 9 were male and 3 female. All patients received peripheral blood stem cells as stem cell source. All 12 patients had grade III GI-aGvHD. At time of initial IASA, 4 patients had skin (grade + - +++) and 2 patients had liver (grade +) involvement. In all patients the overall grade of aGvHD was III. The median time from HSCT to onset of GI-aGvHD was 20 days (range 6 - 278). The median time from onset of GI-aGvHD to initial IASA was 19 days (range 9 - 41). 7 patients not responding to the first IASA received a second IASA (median period of time between IASA was 13 days, range 6 - 14). 83% of patients had gastrointestinal response including four patients (33%) with complete response at 28 days after IASA (Table 2). 6/12 patients were alive at a median time of 531 days (389 – 1362) after IASA. During IASA no technical complications occurred. There was one duodenal ulcer in one patient two days after second IASA that resolved after treatment. Conclusion Regional treatment of severe GVHD with IASA treatment seems to be a safe and effective second line treatment for steroid-refractory GI-aGvHD in adult patients. Our results compare favorably with reported results of steroid-refractory GI-aGvHD. Disclosures: No relevant conflicts of interest to declare.

First LINE Treatment of Aplastic Anemia with Thymoglobuline in Europe and ASIA: Outcome of 976 Patients Treated 2001-2012.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2422-2422 ◽  
Author(s):  
Andrea Bacigalupo ◽  
Rosi Oneto ◽  
Schrezenmeier Hubert ◽  
Dufour Carlo ◽  
Seiji Kojima ◽  
...  
Keyword(s):  
Response Rate ◽  
Univariate Analysis ◽  
Response Rates ◽  
Early Mortality ◽  
Line Treatment ◽  
First Line ◽  
Number Of Patients ◽  
Time Periods ◽  
Severity Of The Disease ◽  
First Line Treatment

Abstract Background. Recent studies have suggested inferior outcome of patients treated with rabbit ATG (Thymoglobulin) as compared to horse ATG (ATGAM , Pfizer or Lymphoglobulin, Genzyme- the latter no longer available); other studies have shown comparable responses and survival. However these studies are based on a relatively small number of patients and a short follow up. Aim of the study. The aim of this study was to assess real life outcome of a large number of AA patients , treated in Europe and Asia with rabbit ATG (Thymoglobulin, SANOFI) and cyclosporin, as first line treatment . Methods and patients Eligible for this study were patients with AA treated with Thymoglobulin between 2001 and 2008 (n=501) and 2009-2012 (n=473) in Europe (n=519) or Asia (n=457). Median year of treatment was 2008 : median age (20 and 21 years), interval diagnosis treatment (23 and 25 days) and severity of the disease (46% and 48% with vSAA) were comparable in the 2 time periods. Early mortality. Mortality <90 days was 5,5% and 2.1% in the time period 2001-2008 and 2009-2012 (p=0.007). In patients aged 0-60 early mortality was reduced from 3.5% to 1.4% and in patients over 60 , from 22% to 9%. Response. Overall response was recorded in 799 patients. At 6 months , responses were comparable in the 2 time periods: 56% vs 57%, and at 1 year, 75% vs 73%. Response rates at 6 months were age dependent: 60%, 58%, 52%, 40% respectively in patients aged 0-20, 21-40, 41-60, >60. When non responders at 3 months were re-evaluated at 1 year, 59% had responded , 26% were non responders , 5% had died, and 10% had received other treatment. Survival: The actuarial 10 year survival for the entire population was 73%, and 72%, when patients were censored as surviving at transplant. The actuarial survival has significantly improved after year 2008, from 71% to 81% , not because of more transplants, which have remained stable (29% vs 30% before or after 2008). Other predictors of 10 year survival in univariate analysis were the following : 89%, 86%, 59% for complete, partial responders and non responders (p<0.01), 68% vs 80% for males versus females (p=0.07); 69%, 77%, 78% in patients with neutrophils <0.2x10^9/L, 02-05x10^9/L and >0.5x10^9/L (p<0.001); 77%, 75%, 68% for patients with an interval diagnosis-treatment of <30 days, 31-60 days or > 60 days (p=0.002); 82%, 72%, 66%, 27% in patients aged 0-20, 21-40, 41-60, > 60 years (p<0.001). Survival at 5 years for patients aged 1-60 in the recent period (2009-2012) was 83% and 62% for patients over 60 years; for patients treated within 60 days from diagnosis these figures are 86% and 83%. In multivariate Cox analysis the following variables remained independent predictors of survival : patient age, year of treatment , severity of the disease, interval diagnosis treatment, gender. Conclusions. With a current overall early mortality (<day 90) of 1.4% , a response rate at 6 months of 58% and 5 year survival of 81%, the combination of CsA and Thymoglobulin appears to be safe and effective as first line treatment in patients aged 1-60. In patients over 60 years of age, early mortality is higher , response rate and 5 year survival is lower, but results have improved after year 2008 , and current 5 year survival is 69%, for older patients treated within 2 months from diagnosis. Finally, response rates and survival, in this large retrospective analysis are quite favourable , compared to other recent publications, although a comparison with horse ATG was not the aim of the present study. Disclosures Bacigalupo: PIERRE FABRE: Speakers Bureau; SANOFI: Speakers Bureau. Carlo:Pfizer, Novartis: Consultancy. Kojima:SANOFI: Honoraria, Research Funding.

scholarly journals Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 429-440
Author(s):  
Tomomi Toubai ◽  
John Magenau
Keyword(s):  
Graft Versus Host Disease ◽  
Molecular Mechanisms ◽  
Phase 1 ◽  
T Cell Signaling ◽  
First Line ◽  
Major Life ◽  
Host Disease ◽  
Graft Versus Host ◽  
Novel Treatments ◽  
Steroid Refractory

Abstract Acute graft-versus-host disease (GVHD) is 1 of the major life-threating complications after allogeneic cell transplantation. Although steroids remain first-line treatment, roughly one-half of patients will develop steroid-refractory GVHD (SR-GVHD), which portends an extremely poor prognosis. Many agents that have shown encouraging response rates in early phase 1/2 trials for prevention and treatment have been unsuccessful in demonstrating a survival advantage when applied in the setting of SR-GVHD. The discovery of novel treatments has been further complicated by the absence of clinically informative animal models that address what may reflect a distinct pathophysiology. Nonetheless, the combined knowledge of established bone marrow transplantation models and recent human trials in SR-GVHD patients are beginning to illuminate novel mechanisms for inhibiting T-cell signaling and promoting tissue tolerance that provide an increased understanding of the underlying biology of SR-GVHD. Here, we discuss recent findings of newly appreciated cellular and molecular mechanisms and provide novel translational opportunities for advancing the effectiveness of treatment in SR-GVHD.

Prophylaxis and Treatment of Graft Versus Host Disease After Allogeneic Stem Cell Transplantation: A Survey on Center Strategies by the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1261-1261
Author(s):  
Tapani Ruutu ◽  
Anja van Biezen ◽  
Bernd Hertenstein ◽  
Anja Henseler ◽  
Laurent Garderet ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Ex Vivo ◽  
Chronic Gvhd ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Graft Versus Host ◽  
Corticosteroid Resistance ◽  
First Line Treatment

Abstract Abstract 1261 Allogeneic stem cell transplantation is a poorly standardized treatment. Reported outcomes vary markedly, partly due to differences in treatment procedures. The EBMT performed a survey among its member centers about their present strategies in preventing and treating graft versus host disease (GvHD). Seventy-three centers from 23 countries participated in this survey. The main prophylactic regimens used in transplantations with myeloablative conditioning were cyclosporine (CsA) + methotrexate (MTX) in 83%, CsA + mycophenolate mofetil (MMF) in 14 %, tacrolimus (tacro) + MTX in 6%, CsA alone in 8%, and tacro alone, tacro + MMF and ex vivo T-cell depletion (TCD) in 1% of the centers. The administration of CsA was initiated on day -6 (1%), day -3 (13%), day -2 (7%), day -1 (78%) or day 0 (1%). CsA was initially given as short i.v. infusions in 56% (twice daily 91%), continuous infusion in 39% and orally in 5% of the centers. The initial CsA dose was most commonly 3 mg/kg/day (49%); 1–2,5 mg/kg/day was given in 16%, 4–6 mg/kg/day in 31%, and 10–12,5 mg/kg/day in 4% of the centers. Further doses were then usually adjusted according to CsA concentrations (88%), measured from whole blood (81%) or serum (19%). When measured from whole blood, the target CsA concentrations at 1 wk post-Tx ranged from 80 to 400 (mean 230) ng/ml, and at 2–4 wks and 2 mths the ranges (means) were 95–400 (210) and 60–350 (200) ng/ml, respectively. The typical duration of CsA prophylaxis was 60–100 (32%), 120–150 (10%), 180 (54%), or 210–365 (14%) days. In 56% of the centers the estimated risk of relapse affected the length of prophylaxis. MTX was given in the dose of 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11 in 63% and without the last dose in 28% of the centers. There were 6 other variants. Leucovorin rescue was given in 43% of the centers with variable dose and timing. ATG was included in the prophylaxis for one or more subgroups (one center all patients) in 79%, alemtuzumab in 25%, corticosteroids in 10%, and TCD in 24% (one center all patients) of the centers. The main prophylactic regimens in reduced intensity transplantations (RIC) were CsA + MMF (67%), CsA + MTX (33%), CsA (23%), in vivo TCD (19%), tacro + MMF (10%), ex vivo TCD (3%), and tacro alone and tacro + MTX (1% each). ATG was used in some groups of patients in 73% of the centers. The development of chimerism affected the intensity of prophylaxis in 82% of the centers. All centers used corticosteroids as first line treatment of acute GvHD. The treatment was started at first signs likely to be caused by GvHD (17%) or for grade II or higher (83%). The decision to treat was based on clinical signs only in 70% of the centers while in 30% histological documentation was needed. The corticosteroid of choice was methylprednisolone (83%) or prednisolone (17%). The initial daily dose/kg was 1-1, 5 mg (19%), 2 mg (76%), 3 mg (6%), 5–10mg (3%), or 20 mg (1%), given in 1 (16%), 2 (69%), 3 (9%) or 4 (6%) doses, i.v. (79%) or orally (21%). The severity of aGvHD affected the initial dose in 53% and the organ manifestation in 27% of the centers. The dose per kg/day indicating corticosteroid resistance and need for second line treatment was 1mg (3%), 2 mg (72%), 4–5 mg (13%), or 10 mg or more (12%). The minimum time to confirm corticosteroid resistance was 2 (2%), 3 (11%), 4–5 (27%), 6–7 (44%), 10–14 (13%) or 21 (3%) days. The most widely used second line treatments were MMF (33%), anti-TNF antibodies (31%), other monoclonal antibodies (16%), ATG (27%), extracorporeal photopheresis (ECP, 14%), mesenchymal stem cells (7%), alemtuzumab (7%), pentostatin (5%) and “keep going with corticosteroids” (12%). The initial treatment for newly diagnosed chronic GvHD in patients with no ongoing immunosuppressive treatment was corticosteroid (57%), calcineurin inhibitor (CNI) + corticosteroid (38%), or CNI alone (10%). The minimum duration of first line treatment of chronic GvHD to allow the evaluation of efficacy was 2 wks or less (21%), 2–4 wks (12%), 1 mth (42%), 1,5-4 mths (21%), or 9–12 mths (4%). The most commonly used second line treatments were ECP (53%), MMF (36%), rituximab (12%), CNI (12%), mTOR inhibitors (9%), corticosteroids (8%), and tyrosine kinase inhibitors (6%). In conclusion, the present results show marked differences between centers in the prophylaxis and management of GvHD. These findings underline the need for standardization and prospective controlled studies in GvHD prevention and treatment. Disclosures: No relevant conflicts of interest to declare.

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