Extracorporeal Photopheresis versus Anticytokine Therapy as a Second-Line Treatment for Steroid-Refractory Acute GVHD: A Multicenter Comparative Analysis

Abstract Introduction: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and non-relapse mortality in allogeneic haematopoietic stem cell transplant patients (Allo-HSCT). Extracorporeal Photopheresis (ECP) is now an established second-line treatment for steroid-refractory cGVHD. Here we report a large, multi-centre case series of 115 patients treated with ECP for cGVHD. To the best of our knowledge, this is the largest reported series of patients receiving fortnightly ECP for cGVHD. Method:A retrospective case note audit identified 115 consecutive Allo-HSCT patients who commenced fortnightly ECP for cGVHD between 2007 and 2016 at The Christie and Central Manchester NHS Foundation Trusts. cGVHD was classified and graded using the National Institutes of Health (NIH) consensus response criteria. Results: Median age when starting ECP was 49 years (range 18-75). 61% patients were male (n=70) and 39% Female (n=45). Underlying disease groups undergoing Allo-HSCT included Acute Leukaemia/Myelodysplastic Syndrome (n=69; 60%), Lymphoma (10%; n=12), Chronic leukaemia (13%; n=15) Myeloma (14%; n=16) and Aplastic Anaemia (3%; n=3). 24% of patients had myeloablative conditioning (n=27) and 76% had reduced-intensity conditioning (n=88). 61% (n=70) received stem cells from Voluntary Unrelated Donors (VUD) and 39% (n=45) Siblings (Sib). Patients received post Allo-HSCT GvHD prophylaxis with Calcineurin inhibitors, either alone, or in combination with Methotrexate and/or Mycophenolate Mofetil. Median time to stopping Calcineurin inhibitor post Allo-HSCT was 12 months (range 0-88). 14 patients received Donor Lymphocyte Infusions (DLI). Median time to development of GvHD post Allo-HSCT was 5 months (range 0-33). 94% developed cutaneous cGVHD (n=108), 32% oral cGVHD (n=37), 23% gut cGVHD(n=27), 24% liver cGVHD (n=28), 11% lung cGVHD (n=13) and 26% ocular cGVHD (n=30). 49% (n=57) patients had sclerodermoid disease. 37% (n=43) had one, 31% (n=36) two, 21% (n=24) three, 9% (n=10) four and 2% (n=2) five organ involvement. All 115 patients had been previously treated with immunosuppressive drugs - 109 Prednisolone; 73 Calcineurin Inhibitors; 60 Mycophenolate mofetil and other (ATG, n=1; Basiliximab, n=1; Methotrexate, n=6; Rituximab, n=10; and Thalidomide, n=18). Median duration of ECP treatment was 12 months (range 1-27 months). Response to ECP was assessed using NIH Criteria - 29% (n=33) Complete Response (CR), 19% (n=22) Partial Response (PR), 16% (n=18) Stable Disease (SD), 11% (n=13) Progressive Disease (PD), 17% (n=19) Death and 9% (n=10) Other. As a result of ECP treatment 26% (n=30) were able to stop steroid treatment while the remaining 74% were able to reduce their steroid dose. There was no overall difference in response between the two centres. Patients with cutaneous and oral cGVHD were more likely to achieve a PR or better (cutaneous p=0.03; oral p=0.05) but there was no difference with other organ involvement. The chance of response was not influenced by the number of organs involved. Median Overall Survival (OS) from the date of Allo-HSCT was 110 months (range 8-221). OS was not influenced by age, donor type, diagnostic group (Acute Leukaemia/Myelodysplastic Syndrome, Lymphoma, Chronic Leukaemia, Myeloma and Aplastic Anaemia), gender or the number and type of organs involved. The only exception was oral cGVHD which was associated with a lower OS (p=0.03). Patients with cGVHD achieving a CR/PR with ECP treatment, had a significantly better OS (40 months vs. median not reached, p<0.0001). Conclusion: ECP is an effective second line treatment for steroid-refractory and steroid-dependent cGVHD with a 50% response rate. This is not affected by the underlying diagnostic group or pattern of organ involvement, however patients with cutaneous and oral cGVHD seem to respond better. As response to ECP translates into better OS, this most likely reflects the reduction in immunosuppressive related complications. Therefore it is worth considering the use ECP treatment early in the management of cGVHD. Disclosures Routledge: Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria. Dignan:Jazz: Honoraria; Adienne: Speakers Bureau; Therakos/Mallinckrodt: Honoraria, Research Funding, Speakers Bureau; Gilead: Other: Cl for GvHD Study. Bloor:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria; GSK: Consultancy, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. Tholouli:Johnson and Johnson: Speakers Bureau; MSD: Speakers Bureau; Celgene: Honoraria; Giles: Speakers Bureau; Amgen: Honoraria, Speakers Bureau.

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Second-Line Treatment In Steroid Refractory Acute Graft Versus Host Disease During a 10-Year Period: A Single Centre Experience Comparing 4 Strategies

Blood ◽

10.1182/blood.v116.21.1255.1255 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1255-1255 ◽

Cited By ~ 1

Author(s):

Alienor Xhaard ◽

Raphael Porcher ◽

Vanderson Rocha ◽

Regis Peffault de Latour ◽

Benjamin Bueno ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Disease Status ◽

Liver Involvement ◽

Line Treatment ◽

Second Line ◽

Graft Versus Host ◽

Grade 3 ◽

Steroid Refractory ◽

Acute Graft

Abstract Abstract 1255 Background: Steroid-refractory acute graft versus host disease (SR-aGVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). Long-term mortality rate remains around 80% (Robin et al. Transplantation 2009: 88:1131) whatever the treatment is and there is no consensus concerning the optimal second-line treatment for SR-aGVHD. In our centre, the policy to treat SR-aGVHD has changed over time: tacrolimus (FK) or cyclosporine (CsA) plus mycophenolate mofetil (MMF) from 2000 to 2004, etanercept or inolimomab after this period with a preference for etanercept in patients with gut or liver involvement. Aim: An observational study was conducted to compare survival of patients who received the 4 different strategies. Method: All consecutive patients with SR-aGVHD were included. Ninety-four patients met the criteria and were included in this study. The main end-point was overall survival. Survival curves were estimated by Kaplan-Meier estimator and compared using log-rank test. The proportional hazards assumption was checked by examination of Schoenfeld residuals and Grambsch and Therneau's lack-of-fit test. SR-aGVHD was defined as progressive disease after 3 days, stable disease at 7 days or partial response at 14 days. Results: Median age was 37 years (range: 5 to 64). Sixty-two (66%) patients had received a myelo-ablative conditioning regimen and 64 (68%) were transplanted from an unrelated donor. Stem cell source was peripheral blood stem cell (PBSC) in 41 patients (44%), bone marrow in 40 (43%) and cord blood in 13 (14%). Most patients received CsA as part of the GVHD prophylaxis regimen, either with methotrexate or MMF (except for MMF second-line treatment patients). GVHD occurred at a median of 15 days after transplant (range: 4 to 105). All patients received steroids as first-line treatment of acute GVHD. Second-line treatment was CsA/MMF in 15 patients (16%), FK/MMF in 38 (40%), inolimomab in 20 (21%) and etanercept in 21 (22%), and was initiated a median of 12 days (range: 1 to 218) after GVHD diagnosis. Grade III-IV acute GVHD was more frequent in patients treated by etanercept (72%) compared to inolimomab (35%), FK/MMF (40%) or CsA/MMF (40%). Overall, 36 (39%) patients responded to the second-line treatment (complete response (CR): 27%, partial response (PR): 12%). Overall response (CR+PR) was 30%, 15%, 53% and 47% with inolimomab, etanercept, FK/MMF and CsA/MMF, respectively. With 74 (range: 3 to 103) months median follow-up from the date of initiation of second-line treatment, 2-year survival was 29% (95%CI: 21–41). Risk factors for overall survival in univariate analysis were age (HR: 1.17, 95%CI: 1.01–1.36), disease status at transplant (HR: 3.09, 95%CI: 1.84–5.2), PBSC as graft source (HR: 1.86, 95%CI: 1.08–3.19), recipient CMV positive status (HR: 1.78, 95%CI: 1.07–2.96), grade 3–4 GVHD (HR: 2.92, 95%CI: 1.77–4.82), liver involvement (HR: 4, 95%CI: 2.39–6.69) and etanercept as second-line treatment (HR: 2.04, 95%CI: 1.09–3.82). In multivariate analysis, only disease status at transplant, grade 3–4 GVHD and liver involvement were significantly associated with survival. Conclusion: Four strategies of treatment including 2 anti-cytokines treatment over a 10-year period give similar survival in patients with steroid refractory acute GVHD. Disclosures: No relevant conflicts of interest to declare.

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Fecal Microbiota Transplant: Is It an Effective Option for Treating Steroid Refractory Acute Graft Versus Host Disease of Gut?

Blood ◽

10.1182/blood-2020-140143 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Joydeep Chakrabartty ◽

Manthan Kathrotiya ◽

Kasturi Sengupta ◽

Pronati Gupta

Keyword(s):

Partial Response ◽

Complete Resolution ◽

Acute Gvhd ◽

Line Treatment ◽

Second Line ◽

Graft Versus Host ◽

Upper Gi ◽

Number Of Patients ◽

Gi Symptoms ◽

Steroid Refractory

Introduction: One is left with very few options in patients with steroid refractory Gut Graft versus Host Disease (GVHD) which occurs post allogenic stem cell transplant (AlloSCT) with most of them increasing the financial burden, especially in resource poor countries like India and many others. Many studies looking in to the pathogenesis of Gut GVHD have confirmed the hypothesis that patients with less diverse faecal microbiome have a greater chance of developing intestinal GVHD and are more prone to succumb to transplant-related complications. Looking at the mechanism of cure in various diseases of the gut, led us to the thinking that reversal of intestinal dysbiosis could improve Gut GvHD. We used FMT as a second line treatment in few of our patients and got encouraging results. Our findings indicate the safety and effectiveness of FMT in acute Gut GVHD. Patient details: Please see image Materials and methods: Fecal material for FMT was taken from healthy donors who passed screening for transmissible disease. 100 gm of stool was prepared into a 200 ml solution and given once daily, serially for 4 days through naso-jejunal tube over 8 to 10 minutes. All patients received FMT as second line treatment after they were found non-responding or partially responding to steroids. All adverse events (AEs) that were first noted within 1 week of infusion of FMT were evaluated in terms of the safety. Response to FMT was evaluated at 14 days starting from the 1st FMT dose or at the time of maximum response whichever was first. Complete resolution of loose motions and gastrointestinal (GI) symptoms was considered as complete response (CR). Decrease in severity of GVHD by at least one stage was considered as partial response (PR). Results: All four patients include were treated between 2018 to 2020. All of them were diagnosed with GI acute GVHD (Gut ± upper GI) on the basis of clinical, scopy (colonoscopy ± endoscopy) findings and histopathology. Case 2 and Case 4 had liver GVHD simultaneously with Gut GVHD. The median time for initiation of FMT was at 52.5(14-90) days from the day of AlloSCT. Three patients (Case 2,3,4) had GVHD immediately post AlloSCT, while Case 1 had GVHD at day 90. All patients had stool microscopy, culture and a stool BIOFIRE test sent to rule out viral, bacterial and parasitic infections. Clostridium difficile infection was not observed in any of the patients. Three patients (Case 1,2,3) received single course (4 days serially) while case 4 required 2 courses 14 days apart. Case one had sigmoid colon involvement and we also gave him per rectal FMT via a flatus tube which was placed in his sigmoid colon. The procedure was well tolerated by all patients. No side effects related to FMT were suspected or confirmed in any patients. Three patients (Case 1,2,3) achieved CR with complete resolution of loose stools and GI symptoms. The median time to response was 4 days (3-5 days). We were able to reduce the dose and taper off steroids in all four patients. Case 4 showed partial response but again had aggravation of GVHD after each course of FMT. At last follow up, two (case 2 and 3) out of four patients were alive. Case 1 expired 2 months after resolution of GVHD due to anginal attack. Case 3 had a secondary graft failure but is still transfusion independent. Case 4 expired due to sever uncontrolled acute GI GVHD (colonic + upper GI). Conclusion: In summary, FMT can be considered as a potential, relatively safe and well tolerated option for treatment of acute Gut GVHD in AlloSCT patients. Further clinical trials with large number of patients are required to explore FMT as one of the effective options for treatment of acute GVHD. Despite the small number of patients, previous findings and our data corroborate that interventions to maintain intestinal diversity can improve outcomes of AlloSCT. Table Disclosures No relevant conflicts of interest to declare.

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Steroid-Refractory Acute Gvhd in Children: Retrospective Analysis of the AIEOP HSCT Registry

Blood ◽

10.1182/blood-2018-99-114862 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4578-4578

Author(s):

Marco Zecca ◽

Daria Pagliara ◽

Franca Fagioli ◽

Attilio Rovelli ◽

Edoardo Lanino ◽

...

Keyword(s):

Board Of Directors ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

Grade Ii ◽

Grade Iii ◽

Steroid Refractory

Abstract Introduction. Severe acute graft-versus-host disease (GVHD) remains the most relevant complication after allogeneic HSCT. Although its incidence in the pediatric population is lower than in adults, children with severe acute GVHD and who do not respond to first-line treatment with systemic steroids still have a poor prognosis. The exact incidence of steroid-refractory acute GVHD in children is still not precisely defined, as well as the risk of non-relapse mortality (NRM) due to steroid-refractory acute GVHD. Aim of our study was to analyze the frequency of acute GVHD unresponsive to first-line steroid treatment in children and adolescents given allogenic HSCT, to describe the second line treatment employed, and the outcome of patient with this complication. Patients and methods. This retrospective study included patients younger than 18 years at the time of transplantation and given a first allogeneic HSCT between 2010 and 2015 in one of the HSCT Centers of the Italian Association for Pediatric Hematology / Oncology (AIEOP). Overall, 1608 patients (59% M and 41% F) were analyzed. Median age at HSCT was 8 years (range 0.2 - 18) 1084 (67%) were affected by malignant diseases and 524 (33%) by non-malignant disorders. The donor was an HLA-matched family donor (MFD) in 28% of cases, an unrelated donor (UD) in 52% and an HLA-haploidentical family donor in 20%. In MFD transplants Cyclosporine (CSA) was used as GVHD prophylaxis in 30% of cases and the combination of CSA + short-term methotrexate (MTX) in 48%. 75% of UD transplant recipients received CSA + MTX + anti-thymocyte globulin (ATG) as GVHD prophylaxis, and 25% other drug combinations. Ex vivo T-cell depletion of the graft was employed in most patients given a HLA-haploidentical HSCT (79% of transplants), and high-dose post-transplant cyclophosphamide in 11% of cases. Results. The cumulative incidence (CI) of grade II-IV acute GVHD was 31%, while that of grade III-IV acute GVHD was 10%. The overall incidence of chronic GVHD was 13% and that of extensive chronic GVHD was 6%. The CI of NRM was 14% for grade 0 acute GVHD patients, 9% for grade I, 11% for grade II, 26% for grade III and 68% for grade IV (P < 0.001). Of the 491 patients with grade II-IV acute GVHD, 250 (51%) required a second-line treatment after first-line steroid therapy (30% of grade II, of 75% grade III and 83% of grade IV patients). Acute GVHD requiring second-line treatment was more frequent in UD transplant recipients (21% of patients) than in matched sibling or haploidentical donor recipients (7% and 13% respectively, P < 0.01), while age at HSCT and diagnosis (malignant vs. non-malignant disease) were not associated with this complication. Second-line treatment was extracorporeal photochemotherapy in 60% of patients, mofetil mycophenolate (MMF) in 46%, mesenchymal stromal cells (MSC) in 12%, monoclonal antibodies (MoAbs) in 5% and other treatments in 28%; 32% of patients received more than one second line treatment. Overall NRM was 13% for patients with grade 0-I acute GVHD, 15% for grade II-IV responding to steroids, and 25% for grade II-IV patients requiring second-line therapy (P < 0.001). The addition of a second-line treatment partially decreased NRM only in patients with grade IV acute GVHD, but the difference was not statistically significant (66% vs. 78%; P = 0.313). In multivariable analysis, grade III (HR = 1.84; P = 0.044) and grade IV acute GVHD (HR = 7.07; P < 0.001), and the use of an UD (HR = 1.63; P = 0.007) were associated with an increased NRM, while the use of a second-line treatment did not decrease this risk (HR = 0.80; P = 0.368). Conclusions. Despite being less frequent than in adults, severe steroid-refractory acute GVHD is still associated with a very high NRM also in pediatric patients. Second or third-line treatments adopted so far have not been effective in improving control of the complication and in decreasing NRM. The prospective evaluation of acute GVHD biomarkers (such as ST2 and REG3α) could help in identifying patients at higher risk of NRM. Prospective studies are warranted to define new treatment modalities that could decrease the mortality rate associated with the most severe form of disease. Disclosures Zecca: Chimerix: Honoraria. Locatelli:bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

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Excellent Therapeutic Results Achieved in Salvage Therapy for Steroid-Refractory Grades III-IV Acute Gvhd with Basiliximab and Etanercept: A Multicenter Prospective Study

Blood ◽

10.1182/blood.v126.23.3130.3130 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3130-3130

Author(s):

Yamin Tan ◽

Haowen Xiao ◽

Jianping Lan ◽

Yi Luo ◽

Jimin Shi ◽

...

Keyword(s):

Combination Therapy ◽

Acute Gvhd ◽

Median Number ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Post Transplantation ◽

Line Therapy ◽

Multicenter Prospective Study ◽

Steroid Refractory

Abstract Introduction: Standard first-line therapy for the treatment of acute graft-versus-host disease (aGVHD) involves corticosteroids. However, fewer than half of patients have durable complete response. Steroid refractory aGVHD (SR-aGVHD) is associated with increased mortality, and long-term mortality rate remains around 70%. Second-line treatments included antithymoglobulin (ATG), mycophenolate mofetil (MMF), tacrolimus (FK), IL-2R antibodies, alemtuzumab, etanercept, infliximab, sirolimus and others. The overall complete remission (CR) rate from the 28 published retrospective studies that evaluating agents for second-line therapy of SR-aGVHD was 32%, the median survival was only about 6 months and no agent was clearly superior. To date, no consensus has been reached regarding the optimal secondary treatment of SR-aGVHD. Based on the pivotal roles of T cells and inflammatory cascade in aGVHD induction, since 2009 we performed a multicenter prospective study to assess the efficacy and safety of an approach to treat severe (grades III-IV) SR-aGVHD by the combination of basiliximab (anti-IL2-R) and etanercept (anti-TNFα). Methods: We conducted an open-label, non-randomized, phase II study at three centers, Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou), Department of Hematology, Zhejiang Provincial People's Hospital (Hangzhou), and Department of Hematology, Guangzhou General Hospital of Guangzhou Military Command (Guangzhou), between January 2009 and October 2013. Patients fulfilled one of the following criteria were included: (1)when newly diagnosed with grades III-IV aGVHD or overlap syndrome and showed progression after 3 days, or no improvement after at least 7 days of treatment or partial response at 14 days with 2 mg/kg per day prednisolone; or (2) de novo grades I-II aGVHD but eventually evolved into grades III-IV during treatment with prednisolone. Basiliximab was given intravenously at 20mg/d on days 1, 4, 8, 15, 22, 29, 36 (if necessary). Etanercept was given subcutaneously at 25mg per dose twice a week for 4 weeks and then pursued at 25mg once a week for another 4 weeks. During combined therapy all patients received cyclosporine and maintained on therapeutic level. Prednisolone was tapered by 10% of the total dose twice weekly. Results: (1) Forty-one patients with steroid-refractory grades III-IV aGVHD were included. Acute GVHD occurred at a median time of 13 days post-transplantation (range: 5-85). First-line treatment with 2 mg/kg/day steroids was initiated at GVHD diagnosis. Thirty patients (73.2%) were diagnosed as grade II aGVHD but evolved into severe aGVHD during treatment with prednisolone, and 11 patients (26.8%) were severe aGVHD at onset. Median time from diagnosis of aGVHD to study enrollment was 12 days (range 3-49). Fifteen patients (36.6%) presented with overall grade III aGVHD and 63.4% with grade IV. (2) Median number of infusions of basiliximab was 4 (range 2-7) and median number of etanercept was 8 (range 1-11). At day 28 after treatment by the combination therapy of basiliximab and etanercept was initiated, overall response (CR+PR) to second-line treatment was 92.7% with 78% of CR. The incidences of CR per organ was 100%, 80.5% and 85.4% for skin, gut and liver involvement, respectively. Nine of 24 evaluable patients developed chronic GVHD (cGVHD), in which 4 cases were with mild cGVHD and 5 with extensive cGVHD. (3)The cumulative incidence of a invasive pulmonary fungal infection at 12 months post-transplantation was 42.4%. Although twenty-eight patients (69.3%) experienced at least 1 cytomegalovirus (CMV) reactivation, all patients developed CMV-positive antigenemia without CMV disease. One patient developed viral encephalitis by human herpesvirus 6 (HHV6). No case of Epstein-Barr virus (EBV) reactivation was reported. Five-year overall survival (OS) rate after the combination therapy was 55.2% . A total of 17 patients died and causes of death ordered by the number of patients were invasive pulmonary fungal infection, (n=8, 47.1%), relapse (n=4, 23.5%), aGVHD (n=4, 23.5%), and arrhythmia (n=1, 5.9%). Conclusions: Here we developed a novel salvage treatment approach for grades III-IV SR-aGVHD by using the combination of basiliximab and etanercept, which achieved a clinically meaningful response in approximately more than 90% of patients and 55.2% of 5-year OS. Disclosures No relevant conflicts of interest to declare.

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Second-Line Treatment for Steroid-Refractory Graft-Versus-Host Disease with Mesenchymal Stromal Cells. A Conceptual Disease Model

Value in Health ◽

10.1016/j.jval.2017.08.835 ◽

2017 ◽

Vol 20 (9) ◽

pp. A545-A546

Author(s):

F Thielen ◽

HM Blommestein ◽

L Oosten ◽

W Fibbe ◽

K Le Blanc ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Graft Versus Host Disease ◽

Stromal Cells ◽

Disease Model ◽

Line Treatment ◽

Second Line ◽

Host Disease ◽

Graft Versus Host ◽

Steroid Refractory

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The role of capecitabine and eribulin in the treatment of metastatic HER2-negative metastatic breast cancer

Modern Oncology ◽

10.26442/1815-1434_2018.3.26-29 ◽

2018 ◽

Vol 20 (3) ◽

pp. 26-29

Author(s):

I V Kolyadina ◽

I V Poddubnaya

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Comparative Analysis ◽

Metastatic Breast ◽

Antitumor Action ◽

Line Treatment ◽

Second Line ◽

Efficacy And Safety

The review analyzed the role of capecitabine and eribulin in the treatment of HER2-negative metastatic breast cancer in patients pretreated with anthracyclines and taxanes. The mechanism of the antitumor action of capecitabine and eribulin, the efficacy in various biological subtypes of breast cancer and safety of treatment is described. The results of a comparative analysis of the efficacy and safety of eribulin monotherapy compared with capecitabine therapy as a second-line treatment for advanced HER2-negative breast cancer are presented.

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Mycophenolate Mofetil (MMF) with or without Tracolimus (FK506) as a Second Line Treatment for Steroid-Resistant Acute Graft-Versus-Host Disease. The Experience of Saint Louis Hospital.

Blood ◽

10.1182/blood.v108.11.2892.2892 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2892-2892

Author(s):

Gustavo Fisher ◽

Vanderson Rocha ◽

Moema dos Santos ◽

Agnes Devergie ◽

Marie Robin ◽

...

Keyword(s):

Median Time ◽

Phase Ii ◽

Acute Gvhd ◽

Phase Ii Trial ◽

Conditioning Regimen ◽

High Dose ◽

Line Treatment ◽

Second Line ◽

Steroid Resistant ◽

Gvhd Prophylaxis

Abstract Acute GVHD remains a major problem following allogeneic HSCT. Use of steroids is the first line to treat aGVHD, with an overall improvement of 55%, but durable responses of 35%. Recently, results of a randomized trial testing ATG in patients non-responding to steroids have been disappointing. Drugs such as MMF or FK506 have been used as GVHD prophylaxis, but few data is available as a second line treatment of steroid-resistant aGVHD. We conducted a prospective phase II trial in our unit to test the role of MMF associated or not to FK506 in steroid-resistant aGVHD in 53 patients. Four criteria of steroid-resistant aGVHD were defined: A) no improvement of signs of skin GVHD after 1 week of treatment with prednisolone 2mg/kg; B) signs of skin progression or no response of visceral (gut or liver) GVHD 3 days after treatment; C) visceral signs of progression 2 days after treatment; D) progression to organ stage 4 (Gluksberg classification) 1 day after treatment. Response of signs of aGVHD to MMF (30 mg/kg day) or FK506 (0.05mg/kg/day) was defined as complete remission (CR) (all organs); partial remission (PR) or failure (progression even in one organ). HSCT were performed from 1999 to 2004 for patients with hematological malignancies (73%) or aplastic syndromes (27%). The median age was 29 y (5–58) (34% of children) and the median follow-up time was 24 mo (1–54). The donor was HLA identical in 23 (43%) and unrelated in 30 (57%) (including 18 cases of HLA mismatched). Myeloablative conditioning regimen was used in 77%. As GVHD prophylaxis CsA+MTX was used in 26 patients (68%), CsA alone in 14 (26%) and in 3 patients CsA+ steroids. Bone Marrow cells were used in 62% of the cases, PB in 25% and CB in 13%. Treatment of aGVHD consisted in prednisolone 2mg/kg IV in all patients associated to CsA. Once criteria of resistance were established, CsA was stopped and replaced by MMF and/or FK506. FK was not added if renal insufficiency was observed. Criteria of steroid-resistant aGVHD were A in 7 patients; B in 26; C in 19, and D in 1 patient. Steroid resistant acute GVHD grade I was observed in 9 patients (17%); II in 26 (49%); III in 19 (36%) and IV in 3 (6%). MMF was used in 15 patients (28%) and associated to FK506 in 38 (72%). Median time to start second line treatment was 16 days (7 to 100). Complete response in skin was observed in 74% of the patients, 66% in gut and 75% in liver. However, overall CR was observed in 21 patients (40%), partial response in 5 (9%) and failure in 27 (51%). Median time to obtain CR or PR was 8 days (2–20) after starting second line treatment. Cumulative incidence of CR at one year was 39%. Recipient’s age, CMV serology, source of stem cells, conditioning regimen, HLA incompatibility were not associated with CR; there was not statistical difference of CR if MMF was used alone or associated to FK. For those patients with aGVHD in progression, third line treatment consisted most frequently in the use of high dose steroids or ATG/ALG. Overall survival at 1y was 35±7%; it was 74±10% for patients achieving CR (n=21), 5±4% for non-responders (n=27) and 4 out of 5 patients with PR died. Cause of death was commonly associated to infections. In conclusion, in this phase II trial, use of MMF and/or FK506 is an option to treat steroid resistant GVHD but did not result in 1-y survival rate that would justify to set-up a larger randomized study.

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

Blood ◽

10.1182/blood.v122.21.4604.4604 ◽

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.

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