Treatment of Steroid-Resistant Graft-Versus-Host Disease with Monoclonal Antibodies in Children.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5310-5310
Author(s):  
Tal Schechter ◽  
Samina Afzal ◽  
Yaron Finkelstein ◽  
Gideon Koren ◽  
John Doyle ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Partial Response ◽  
Graft Versus Host Disease ◽  
Complete Response ◽  
Antibody Treatment ◽  
Hematopoietic Stem ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

Abstract Acute graft-versus-host disease (aGVHD) carries a major risk of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). The prognosis is poor if aGVHD does not respond to corticosteroid treatment. Recently, monoclonal antibodies such as daclizumab, a humanized monoclonal IgG1, and infliximab, a chimeric monoclonal antibody that binds the precursor of tumor-necrosis factor-alfa, have shown promising results in the treatment of corticosteroid-resistant aGVHD. The reported response rate to monoclonal antibody therapy in adults with aGVHD reaches as high as 67%. Data describing the efficacy of monoclonal antibodies in children with corticosteroid-resistant aGVHD are limited. We conducted a retrospective analysis to evaluate the efficacy of daclizumab and/or infliximab in children diagnosed with steroid-resistant aGVHD in the Hospital for Sick Children, Toronto, from July 2002 to December 2005. Corticosteroid-resistant aGVHD was defined as aGVHD which did not respond or worsened after a minimum of 5 days of corticosteroid therapy. Complete response was defined as full recovery without any signs of aGVHD; partial response was defined as improvement of aGVHD symptoms in at least one organ without worsening in other organs. Sixteen children were treated for aGVHD, thirteen of them had aGVHD grade 3 or 4. The organs involved were gut (n=6), skin (n=4), liver (n=2) and multi-organ involvement (n=4). Thirteen children were given daclizumab; one was treated with infliximab and 2 children with their combination. Fourteen children received a full course of monoclonal antibodies for aGVHD. An additional child died after the first dose (from multi-organ failure) and one child developed reactive arthritis attributed to daclizumab. Seven of the 14 children (50%) who completed treatment responded: 5 had complete response and 2 had a partial response. Nine out of the 16 children died during the study period: 8 due to Transplant Related Mortality (TRM) and 1 due to relapse; three children developed fatal fungal infection and one had fatal adenovirus infection during or shortly after monoclonal antibody treatment. Median length of follow up in the remaining 7 patients was 18 months. We conclude that monoclonal antibodies were effective in the treatment of children with corticosteroid-resistant acute GVHD. The risk for infection, mainly fungal, was high.

scholarly journals Methotrexate for the Treatment of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Amr Nassar ◽  
Ghada Elgohary ◽  
Tusneem Elhassan ◽  
Zubeir Nurgat ◽  
Said Y. Mohamed ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Corticosteroid Treatment ◽  
Complete Response ◽  
Primary Treatment ◽  
Lower Grade ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Pooled Data

Glucocorticoids have been the primary treatment of graft-versus-host disease (GVHD) over the past decade. Complete responses to steroid therapy are usually expected in almost one-third of aGVHD cases and partial response is anticipated in another one-third of patients. However, for those patients not responding to corticosteroid treatment, there is no standard second-line therapy for acute or chronic GVHD. Methotrexate (MTX) for treatment of steroid refractory GVHD has been evaluated in a number of studies. Results from peer-reviewed original articles were identified and the pooled data analyzed. Despite several limitations in data collection and analysis, weekly administration of methotrexate at a median dose of 7.5 mg/m2seems to be safe with minimal toxicities in the context of both aGVHD and cGVHD treatments. The observed overall response (OR) in patients with aGVHD to MTX treatment in the published studies was 69.9%, with complete response (CR) in 59.2% and PR in 10.6%. In cGVHD the OR was 77.6%, with CR reported in 49.6% and PR in 28% of patients. Predictors of better responses were lower grade GVHD, cutaneous involvement, and isolated organ involvement. MTX as a steroid sparing agent might reduce long-term complications and improve the quality of life of GVHD affected individuals.

Response to JAK 1/2 Inhibition in Patients with Corticosteroid-Refractory Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3934-3934 ◽  
Author(s):  
Silvia Spoerl ◽  
Kristina Maas-Bauer ◽  
Mareike Verbeek ◽  
Petya Apostolova ◽  
Anna Lena Illert ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Serum Levels ◽  
Salvage Treatment ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Number Of Patients

Abstract Acute corticosteroid-refractory graft-versus-host-disease (GvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reported mortality rates of 40-60%. Our previous study (Spoerl S et al. Blood 2014) had shown the induction of tolerogenic regulatory T cells after ruxolitinib treatment in the mouse and clinical responses in six patients with corticosteroid-refractory GvHD. Here we report the outcome of 14 patients with GvHD refractory to steroids and at least two other lines of treatment who received ruxolitinib as a salvage treatment. Ten patients were classified as acute and four as chronic GvHD involving the skin, intestinal tract and liver as detailed in Table 1. Patients were treated with ruxolitinib at a starting dose of 5 mg orally twice daily with a dose increase to 10 mg orally twice daily. Clinical and histopathological grading of skin, intestinal and liver GvHD was performed according to established criteria. Of 14 patients, 13 responded with respect to clinical GvHD symptoms and serum levels of pro-inflammatory cytokines. Three patients with histologically proven acute skin or intestinal GvHD grade I, achieved a complete response. One non-responder discontinued ruxolitinib after one week because of lack of efficacy. In all other patients corticosteroids could be reduced after a median treatment of 1.5 weeks. Serum levels of IL-6 and soluble IL-2R were measured prior and after the start of ruxolitinib and declined in the majority of the analyzed patients (n=11). CMV reactivation was observed in four out of 14 patients and responded well to antiviral therapy. Two out of 14 patients developed cytopenia during ruxolitinib treatment that was mild and did not require dose reduction or transfusion. Our results indicate that treatment of corticosteroid-refractory GvHD with ruxolitinib is safe and well tolerated. Despite the low number of patients treated so far, our results demonstrate that ruxolitinib reduces the severity of corticosteroid-refractory GvHD and support further development of therapeutic JAK1/2 inhibition as a salvage treatment in GvHD. Table 1: GvHD and response to ruxolitinib Pt. no. 1 GvHD: organ/grade 2 Reduction of cortico-steroids after ruxolitinib Clinical response (PR / CR) 3 Time to response (weeks) Duration of response 4 / Current follow up (weeks) 5 01 Intestines / IV (acute) Yes CR 1 42 / 43 02 Skin / III (acute) Yes PR 1.5 46.5 / 48 03 Skin / IV liver / III (acute) Yes CR 1 57 / 58 04 Skin / III intestines / IV (acute) Yes PR 1.5 24.5 / 26 05 Skin / III (chronic) Yes PR 1 64 / 65 06 intestine/III-IV (acute) Yes PR 1 15 / 16 07 Skin/ III (chronic) Yes Response 1 46 / 47 08 Skin/ III (acute) Yes Response 1 2 / 3 09 Skin/ II intestine/II (chronic) Yes No response stopped after 1 week N/A N/A 10 Skin/ III liver/III (acute) Yes PR 1 1 / 2 11 intestines IV (acute) Yes PR 2 6 / 8 12 Skin/III (chronic) Yes Response 1 8 / 9 13 intestines/IV Skin/ II (late onset acute) Yes CR 1 17 / 18 14 intestines/IV Skin/ II (acute) Yes PR 1,5 3 / 4 1Pt.: patient, no: individual patient number, 2Acute and chronic GvHD were defined according to NIH criteria, 3PR: partial response, CR: complete response; 4Until last follow up, none of the patients experienced a relapse of GvHD. 5Follow up was calculated from the time of initiation of ruxolitinib treatment. In patient 01, ruxolitinib was discontinued at week 16 because of complete resolution of all GvHD signs. The patient did not develop any signs of GvHD after discontinuation of ruxolitinib until last follow up. Disclosures Off Label Use: Ruxolitinib in GvHD.

Complete Resolution of Extensive Chronic Graft-Versus-Host Disease with Ibrutinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5474-5474
Author(s):  
Audrey Scholoff ◽  
Gloria Obi ◽  
Kelty R. Baker ◽  
George Carrum ◽  
Rammurti T Kamble
Keyword(s):  
Graft Versus Host Disease ◽  
Complete Resolution ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Oral Ulcers

Abstract We herein document a complete response of extensive chronic graft-versus-host disease (cGvHD) to a Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib. A 41 years old female with primary refractory MCL underwent mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation in December 2011 (conditioning with CY/TBI and alemtuzumab, graft=6.6x 106/kg CD-34+ cells, tacrolimus alone for GVHD prevention). Following engraftment on day 11, she developed grade III acute GvHD involving the skin and gut on day 17 of transplantation that persisted beyond 100 days post-transplant. Her cGvHD was treated with steroids, but remained active and extensive. Despite persistent cGvHD and 100% donor chimerism she relapsed in July 2012. Treatment with radiation and bendamustine with rituximab failed. By December 2013, the patient had extensive cGvHD manifesting as scleromatous skin thickening, oral ulcers and sclerosis of the buccal mucosa, ocular dryness and diarrhea, and was started on ibrutinib1 560 mg once daily for relapsed MCL. After 8 weeks of therapy, cGvHD had begun to improve. Oral steroids were reduced and ultimately stopped after 26 weeks of ibrutinib; after 30 weeks treatment all cGvHD manifestations resolved completely. A complete remission for MCL was documented at 8 weeks of ibrutinib initiation. Currently she continues to be on 560 mg daily ibrutinib without cGvHD exacerbation or MCL relapse for 22 weeks and 52 weeks, respectively. Chronic graft versus host disease (cGvHD) is mediated donor T cells. The role of B cells in the pathogenesis of cGvHD is increasingly recognized. Two murine studies have explored the role of ibrutinib in cGVHD-like syndromes, one in which there is T cell driven sclerodermatous cGvHD and a second in which there is Ab driven multiorgan system cGvHD that includes bronchiolitis obliterans (BO). Administration of ibrutinib decreased the incidence and severity of sclerodermatous, and improved pre-existing lesions and also improved pulmonary fibrosis and reduced BO. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Our report provides the evidence that BTK inhibition led to complete resolution of cGvHD and supports exploration of its role in future clinical trials. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression

2010 ◽  
Vol 207 (12) ◽  
pp. 2551-2559 ◽  
Author(s):  
Jörn C. Albring ◽  
Michelle M. Sandau ◽  
Aaron S. Rapaport ◽  
Brian T. Edelson ◽  
Ansuman Satpathy ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
T Lymphocyte ◽  
Graft Versus Host Disease ◽  
Cell Expansion ◽  
Tumor Necrosis Factor Receptor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Life Threatening

Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non–life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4+ forkhead box P3− (Foxp3−) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4+ Foxp3+ regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non–life-threatening diseases.

scholarly journals Anti-LFA-1 Antibody Treatment of a Patient with Steroid-Resistant Severe Graft-Versus-Host Disease.

1992 ◽  
Vol 167 (4) ◽  
pp. 297-299 ◽  
Author(s):  
YOSHIYUKI OHASHI ◽  
SHIGERU TSUCHIYA ◽  
HIROMI FUJIE ◽  
MASAYOSHI MINEGISHI ◽  
TASUKE KONNO
Keyword(s):  
Graft Versus Host Disease ◽  
Antibody Treatment ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

scholarly journals Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10) [see comments]

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 1017-1023 ◽  
Author(s):  
P Herve ◽  
J Wijdenes ◽  
JP Bergerat ◽  
P Bordigoni ◽  
N Milpied ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Complete Response ◽  
Host Disease ◽  
Graft Versus Host ◽  
In Vivo Administration ◽  
Acute Graft ◽  
Receptor Monoclonal Antibody

Abstract In a multicenter pilot study, 32 patients showing steroid-resistant acute graft-versus-host disease (GVHD) were treated by in vivo administration of anti-interleukin-2 (IL-2) receptor monoclonal antibody (MoAb B-B10). Twenty-three patients received marrow from HLA- matched related donors, four from matched unrelated donors and five from partially matched related donors. The overall grade of GVHD was II in 16 patients, III in two, and IV in five. Five milligrams of B-B10 MoAb was infused in bolus daily for 10 days and then every second day for a further 10 days in an attempt to reduce GVHD recurrence. No clinical side effects were noted during the B-B10 treatment period. A complete response (CR) acute GVHD was achieved in 21 patients (65.6%). Six patients (18.7%) showed partial improvement (PR) and 5 patients (15.6%) no response (NR). A significant factor associated with GVHD response was the delay between the onset of the GVHD and the first day of B-B10 infusion. The earlier B-B10 was introduced, the greater the probability of CR (P = .03). There was no correlation between the serum B-B10 level and GVHD response (P = .69). There was, however, a significant correlation between the clinical response and the B-B10 kinetics as a function of time: serum B-B10 levels attained a plateau level more rapidly in the CR group than in the PR/NR group. Among the 26 complete and partial evaluable responders, GVHD recurred in 10 cases (38.4%). Host anti-B-B10 MoAb immune response occurred in only one (7.1%) of the 14 patients analyzed. Fourteen of the 32 patients (43.7%) are currently alive between 2 and 14 months after GVHD treatment with B- B10 was completed.

Tocilizumab In The Treatment Of Steroid Refractory Graft Versus Host Disease: A Single Institutional Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2067-2067 ◽  
Author(s):  
Julianna V.F. Roddy ◽  
Bradley M. Haverkos ◽  
Ali McBride ◽  
Kathryn M Leininger ◽  
Leslie A. Andritsos ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Graft Versus Host Disease ◽  
Interleukin 6 ◽  
Complete Response ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Off Label ◽  
Proinflammatory Activity ◽  
Steroid Refractory

Abstract Introduction Acute graft-versus-host-disease (aGVHD) is a frequent and often lethal complication of allogeneic hematopoeitic stem cell transplant (allo HSCT) despite current prophylactic regimen. It is fueled by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6), leading to damage of host tissues. Front-line treatment with glucocorticoids provide 30-40% complete response. Tocilizumab is a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody that binds to both soluble and membrane-expressed IL-6R, inhibiting IL-6–mediated proinflammatory activity. A case report and a recent small series (8 patients) with steroid refractory GVHD(SR GVHD) showed encouraging single agent activity of tocilizumab(Gergis et al, 2010; Drobyski et al, 2011). We report our experience on 9 patients who had SR aGVHD and received tocilizumab therapy. Method Tocilizumabwas administered intravenously at a dose of 8 mg/kg every 2 to 3 weeks. aGVHD grading and responses were based on consensus criteria (Przepiorka et al, 1995). Patients were monitored for toxicities and infections. Results The median age at transplant was 48 years (range 25-61). Four patients had double cord allo HSCT, 2 had matched related, 2 unrelated (with one 9/10 matched) and 1 haploidentical after a failed cord HSCT. Six patients had received myeloablative and 3 reduced intensity allo HSCT. All but one patient received tacrolimus and methotrexate for aGVHD prophylaxis, and all were in complete remission of their underlying disease at time of aGVHD. Table 1 includes responses and outcomes to tocilizumab therapy. All patients had GI involvement and 6 patients had two organs involved. Median aGVHD grade was 3 (range 3-4). The median time from first aGVHD onset to tocilizumab administration was 44 days (range 14-176). The median number of infusions was 2(1-6). There were no allergic or infusion-related events. Two patients (22%) had a complete response (CR), and two had mixed responses with CR in one organ, but no response in another. Only one of nine patients survived. Six patients (67%) died from aGVHD and its complications, one from CMV and one from septic shock. The median survival from start of tocilizumab was 26 days (range 13-759). Conclusions While the few tocilizumab treated patients with SR aGVHD reported in the literature have experienced a high response rate of 67%(CR and PR), our limited experience showed a less impressive 22% CR. Although tocilizumab has some activity in the treatment of SR aGVHD, it may not be significantly better than other available agents. Disclosures: Off Label Use: There is currently no standard of practice of steroid-refractory GVHD, every treatment option besides steroids are considered off-label. However, there is evidence to support its use. Tocilizumab Tocilizumab is a humanized anti–IL-6 receptor (anti–IL-6R) monoclonal antibody that binds both soluble and membrane-expressed IL-6R, inhibiting IL-6–mediated proinflammatory activity. In this study, we report our experience with the administration of tocilizumab, an anti-interleukin 6 receptor antibody, in the treatment of steroid refractory GVHD.

Anti-α4β7 integrin monoclonal antibody (vedolizumab) for the treatment of steroid-resistant severe intestinal acute graft-versus-host disease

2018 ◽  
Vol 54 (7) ◽  
pp. 987-993 ◽  
Author(s):  
Ivetta Danylesko ◽  
Adomas Bukauskas ◽  
Martin Paulson ◽  
Valdas Peceliunas ◽  
Tobias Gedde-Dahl d.y ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Graft Versus Host Disease ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft
Sign in / Sign up

Export Citation Format

Share Document