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

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

Download Full-text

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

Blood ◽

10.1182/blood.v104.11.1244.1244 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1244-1244

Author(s):

Hildegard T. Greinix ◽

Robert M. Knobler ◽

Nina Worel ◽

Margit Mitterbauer ◽

Axel Schulenburg ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Acute Gvhd ◽

Complete Response ◽

Graft Versus Host ◽

Steroid Dependent ◽

Grade Ii ◽

Grade Iii ◽

Steroid Refractory ◽

Acute Graft

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

Download Full-text

Extracorporeal Photopheresis (ECP): Effective Therapy for Steroid Dependent and Refractory Acute Graft-Versus-Host Disease (GVHD)

Blood ◽

10.1182/blood.v118.21.1973.1973 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1973-1973

Author(s):

Ryan W Jacobs ◽

Madan H. Jagasia ◽

Bipin N. Savani ◽

Anne T. Neff ◽

Adetola A. Kassim ◽

...

Keyword(s):

Median Survival ◽

Salvage Therapy ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Randomized Study ◽

Median Number ◽

Systemic Steroids ◽

Steroid Dependent ◽

Grade 3 ◽

Steroid Refractory

Abstract Abstract 1973 Introduction: Outcome of patients with steroid refractory acute GVHD (aGVHD) remains poor and the optimal therapy remains ill-defined. ECP has been successfully used for treating steroid-resistant chronic GVHD. We studied the efficacy and outcome of ECP used as salvage therapy in patients with steroid refractory/dependent aGVHD at 2 centers: Vanderbilt University, USA and Nottingham, UK. Methods: Transplant and aGVHD characteristics of patients treated with ECP from 1/2006 to 8/2010 were reviewed. Steroid doses at onset and completion of ECP were available. Steroid refractory aGVHD was defined as progression after 3 days or no response after 7 days of systemic steroids. Steroid dependent aGVHD was defined as recurrence of aGVHD during steroid taper. Responses to ECP were abstracted from medical records and were determined at completion of ECP. Patients were transplanted for hematological malignancies on standard of care or IRB approved protocols. Results: Fifty two patients (Vanderbilt-29; Nottingham-23) were treated with ECP for steroid dependent (15, 29%) or steroid refractory (32, 63%) aGVHD at a median of 59 days (range, 12–99) after transplant. Indication for ECP was missing for 5 patients. aGVHD was seen after first transplant (44, 85%), second transplant (1, 2%) or after donor lymphocyte infusion (7, 13%), respectively. Grade 3–4 aGVHD was present at onset in 29 (57%) patients. Stage 3–4 skin, GI, and liver involvement occurred in 28 (37%), 15 (29%) and 9 (18%) patients, with three organ involvement at onset in 9 (17%) patients. All patients received systemic steroids prior to ECP for a median of 18 days (range, 10–91). Initial therapy consisted of 1 mg/kg or 2 mg/kg prednisone equivalent in 24 (46%) and 26 (50%) patients, respectively. Forty-one patients (79%) had either no or partial response after 7 days of steroid. ECP was administered as 2 treatments per week on a weekly to bi-weekly frequency and then stopped or tapered depending on response. Steroids were tapered at the discretion of the treating physician. Median number of ECP treatments was 12 (range, 2–45) given over a median duration of 55 days. Thirty-two (63%) patients responded to ECP (CR-26, 50%; PR-6, 12%). At the end of ECP treatment, grade 3–4 aGVHD was present in 17 patients (33%) with stage 3–4 involvement in skin (4, 8%), GI (10, 20%) and liver (10, 20%), respectively. The median steroid dose at termination of ECP in ECP-responders and non-responders was 0.15 mg/kg (range, 0–0.75) and 2 mg/kg (range, 0.15–2.3), respectively (P<0.001). ECP response: Donor type, stem cell source, aGVHD grade at onset, and organ –specific stage did not impact response. ECP response was superior for aGVHD developing after ablative regimen compared with reduced intensity/non-ablative regimens (76% vs. 48%, P=0.05). Patients with response at day 7 after initial steroid and subsequent steroid dependent aGVHD had a better response with ECP (80% vs. 50%, P=0.042). In logistic regression analyses, adjusted for regimen intensity, response at day 7 of initial steroid showed a trend for predicting ECP response (OR=4.22, 95% CI 0.95–18.7, P=0.058). Survival: Of the 52 patients, 28 (54%) are deceased (GVHD-19, relapse/progression-5, infections-4). The median follow up of the cohort after onset of ECP is 309 days (range, 12–1657). Median and 2-yr overall survival (measured from onset of ECP) is 442 days (95% CI, 0–993) and 42%. In univariate analyses, median survival after ECP onset was superior for patients who had an ablative transplant (not reached vs. 44 days, P=0.05), and had grade 2 or less aGVHD at onset (not reached vs. 79 days, P=0.028) (Fig. 1A). Indication of ECP (steroid dependent or refractory) did not impact survival. Patients with ECP response had a superior survival (measured from end of ECP) compared to non-responders (median survival, not reached vs. 14 days, P<0.001) (Fig. 1B) with a 65% 2-yr survival in ECP responders. In Cox proportional analyses, response to ECP was an independent predictor of survival (HR 0.091, 95% CI 0.034–0.263, P<0.001), after adjusting for regimen intensity and grade of aGVHD at onset. Conclusion: ECP is an effective steroid-sparing salvage therapy for patients with steroid dependent or refractory aGVHD with a response rate of 63% and 2-yr survival of 65% in responders. Based on this data, it is reasonable to undertake a prospective randomized study of ECP versus other agents, in patients with steroid dependent or refractory aGVHD. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽

10.1182/blood.v124.21.2570.2570 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2570-2570

Author(s):

Federica Giannotti ◽

Annalisa Ruggeri ◽

Gerard Michel ◽

Jean-Hugues Dalle ◽

Tracey O'Brien ◽

...

Keyword(s):

Single Unit ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Median Number ◽

Cell Dose ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Acute GVHD: think before you treat

Hematology ◽

10.1182/hematology.2021000300 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 642-647

Author(s):

Laura F. Newell ◽

Shernan G. Holtan

Keyword(s):

Clinical Trials ◽

Tissue Repair ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Classification Systems ◽

High Likelihood ◽

Graft Versus Host ◽

Steroid Dependent ◽

Steroid Sparing

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

Download Full-text

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

Blood Advances ◽

10.1182/bloodadvances.2019000362 ◽

2019 ◽

Vol 3 (19) ◽

pp. 2866-2869 ◽

Cited By ~ 10

Author(s):

Jonathan L. Golob ◽

Martha M. DeMeules ◽

Tillie Loeffelholz ◽

Z. Z. Quinn ◽

Michael K. Dame ◽

...

Keyword(s):

Stem Cells ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Epithelial Monolayer ◽

Graft Versus Host ◽

Key Points ◽

Colonic Stem Cells ◽

Steroid Refractory ◽

Acute Graft

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

Download Full-text

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

Blood ◽

10.1182/blood-2019-122674 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4456-4456

Author(s):

Sadeghi Behnam ◽

Remberger Mats ◽

Per Frisk ◽

Britt-Marie Frost ◽

Olle Ringden ◽

...

Keyword(s):

Stromal Cells ◽

Acute Gvhd ◽

Pediatric Population ◽

Chronic Gvhd ◽

Gi Tract ◽

Graft Versus Host ◽

Grade Ii ◽

Steroid Refractory ◽

Long Term Mortality

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

Download Full-text

Graft-Versus-Leukemia Effect after Haplo-Identical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with AML- No Association with Graft-Versus-Host Disease: A Study on Behalf of the Acute Leukemia Working Party of EBMT

Blood ◽

10.1182/blood-2018-99-110609 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4586-4586

Author(s):

Avichai Shimoni ◽

Myriam Labopin ◽

Emanuele Angelucci ◽

Didier Blaise ◽

Fabio Ciceri ◽

...

Keyword(s):

Multivariate Analysis ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Board ◽

Graft Versus Host ◽

Graft Versus Leukemia ◽

Grade Ii ◽

Landmark Analyses ◽

Subsequent Relapse ◽

Grade Iii

Abstract Introduction . Allogeneic stem-cell transplantation (SCT) is a curative approach in acute myeloid leukemia (AML) by providing dose-intensive chemo-radiotherapy and enhancing a graft-versus-leukemia (GVL) effect. The GVL effect is provided by alloimmune T- cells and is usually closely associated with graft-versus-host disease (GVHD). Patients with GVHD have a lower incidence of relapse, but at high grades a higher incidence of non-relapse mortality (NRM). However, GVL can also occur independently of GVHD. The use of haplo-identical SCT is rapidly increasing over the last decade due to the introduction of non-T depleted methods, in particular with post-transplant cyclophosphamide (PTCy), with expected outcomes that are similar to other donor sources. The GVL effect after T- depleted haplo-identical SCT is mostly related to natural-killer cell alloreactivity and is not necessarily associated with GVHD. However, there is no definite data whether GVL after SCT in the non-T depleted setting is similarly associated with GVHD as in the matched donor setting. Methods . We assessed the impact of acute and chronic GVHD on SCT outcomes in patients with AML following non-T depleted haplo-identical SCT with PTCy, by using a series of landmark analyses. Results . The study included 605 patients with AML in CR1 (73%) or CR2 (27%) after non-T depleted haplo-identical SCT with PTCy, given during the years 2009-2016. The median age was 53 years (range, 18-76). 71% had myeloablative conditioning and 29% had reduced-intensity conditioning . The overall rate of acute GVHD grade II-IV and III-IV was 28.4% and 8.0%, respectively. The rates of chronic GVHD all grades and extensive were 32.7% and 12.3%, respectively. The rate of relapse and NRM were 21.8% and 18.2% and the rates of leukemia-free survival (LFS) and overall survival, 2 years after SCT were 59.9% and 64.1%, respectively. 509 patients were alive and leukemia-free 100 days after transplant. 366 had no prior acute GVHD at this landmark, 107 had acute GVHD grade II and 36 had grade III-IV. The overall rate of subsequent relapse was 20.3%, 18.3% and 11.9%, respectively (P=0.60). The overall rates of subsequent NRM were 10.3%, 19.0% and 35.7%, respectively (P<0.001). The rates of LFS were 69.4%, 62.6% and 52.4%, respectively (P=0.01). Multivariate analysis showed that acute GVHD grade II before day 100 was not associated with subsequent relapse (Hazard ratio (HR) 1.02, P=0.93), had borderline association with NRM (HR 1.79, P=0.09) and no association with LFS (HR 1.28, P=0.27). Acute GVHD grade III-IV before day 100 was not associated with subsequent relapse (HR 0.92, P=0.87), while it was associated with higher NRM (HR 5.23, P<0.001) and inferior LFS (HR 2.35, P=0.003). Both acute GVHD grade II and grade III-IV were associated with subsequent extensive chronic GVHD, HR 2.02 (P=0.04) and 6.93 (P<0.001), respectively. 393 patients were alive and leukemia-free 6 months after transplant. Out of them 316 had no prior chronic GVHD at this landmark, 55 had limited and 22 extensive chronic GVHD. The overall rate of subsequent relapse was 14.3%, 9.2% and 23.9%, respectively (P=0.60). The overall rates of subsequent NRM were 7.3%, 10.4% and 31.7%, respectively (P=0.003). The rates of LFS were 78.4%, 80.4% and 44.4%, respectively (P=0.01). Multivariate analysis showed that limited grade chronic GVHD occurring before 6 months was not associated with subsequent relapse (HR 0.69, P=0.44), NRM (HR 1.43, P=0.55) or LFS (HR 0.88, P=0.74). Extensive chronic GVHD was not associated with subsequent relapse (HR 1.44, P=0.56) but was associated with higher NRM (HR 5.77, P=0.004) and inferior LFS (HR 2.75, P=0.01). Similar results were seen for prior chronic GVHD at the 1 year landmark. Conclusions. By a series of landmark analyses at 100 days, 6 months and 1 year after SCT, we did not find any association of acute GVHD grade II or III-IV or chronic GVHD (limited or extensive) with subsequent relapse. Acute GVHD grade III-IV was associated with a higher NRM and lower LFS rates after day100. All grades of acute GVHD were associated with a higher incidence of chronic GVHD. Previous extensive chronic GVHD was also associated with a higher NRM and a lower LFS. GVL is thus not associated with GVHD after non T-deleted haplo-identical SCT with PTCy. Future novel strategies for prevention of significant GVHD are warranted. Disclosures Angelucci: Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board. Mohty:MaaT Pharma: Consultancy, Honoraria.

Download Full-text

Pentostatin in Steroid-Refractory Chronic Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v106.11.1805.1805 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1805-1805 ◽

Cited By ~ 2

Author(s):

Javier Bolanos-Meade ◽

David Jacobsohn ◽

Viki Anders ◽

Megan Higman ◽

Allen Chen ◽

...

Keyword(s):

Partial Response ◽

Graft Versus Host Disease ◽

Calcineurin Inhibitor ◽

Chronic Gvhd ◽

Complete Response ◽

Main Concern ◽

Host Disease ◽

Graft Versus Host ◽

Mixed Response ◽

Steroid Refractory

Abstract Pentostatin, one of the purine nucleoside analogues, is known to decrease lymphocyte number and function. It has been successfully used to treat steroid refractory acute graft-versus-host disease (GVHD). We are currently investigating pentostatin for refractory chronic GVHD (cGVHD). Fifty-two patients were enrolled and 42 are assessable for response. All patients presented here failed at least two immunosuppressive regimens including steroids at a dose equivalent to at least 1 mg/kg/day prednisone for one month. The treatment protocol consists of giving pentostatin 4 mg/m2/dose IV every 2 weeks for 6 months. Patients with improving disease were permitted to continue pentostatin therapy at a 3 to 4 week interval. To reduce the risk of infection, steroids are tapered early in all patients and they received prophylactic antibiotics (antibiotics, fluconazole, sulfamethoxazole/trimethoprim and valcyclovir). At the end of 3 months, patients with stable or improving cGVHD are weaned off their other medications but maintained on a calcineurin inhibitor. Pentostatin is stopped at 6 months if complete response (CR) is achieved or continued if partial response (PR). Patients are followed for improvement in the skin/fascia, mouth, and liver. The severity of GVHD is scored for each system on a scale from 0 to 4. Complete response is resolution of symptoms (irreversible changes [such as long standing contractures] due to cGVHD were not required to improve to score a CR if all other changes improved); partial response is at least a 1 point improvement in this score system. Mixed response is improvement in 1 system but worsening in another. Fifty-two patients have received a median of 8.5 doses (range 1–34). Median age of the cohort is 40.5 years (range 5 to 67). Diagnoses include AML/MDS (6), ALL (7), hemoglobinopathy (2), aplastic anemia (3), CML (16), myelofibrosis (1), NHL (8), myeloma (4), paroxysmal nocturnal hemoglobinuria (3), CLL (1), and lymphohistiocytosis (1). Graft source included 20 patients: 6/6 sibling BMT; 10 patients: 6/6 sibling PBSCT; 10 patients: MUD BMT; 6 patients 5/6 MUD BMT; 2 patients: 6/6 MUD PBSCT; 1 patient 5/6 sibling BMT; 1 patient: 6/6 sibling BMT followed by DLI; 1 patient 5/6 BMT from a child; and 1 patient, unknown. Most patients were on calcineurin inhibitor, eleven on prednisone, seven on MMF, one on rapamycin, and one was receiving ECP at entry on the study. In the 42 assessable patients, 5 patients attained a CR, 16 a PR, 5 a mixed response (improvement in one organ with deterioration in another one), and 16 patients have progressed. The overall response rate is 50%. Therapy has been well-tolerated with infections being the main concern. Mucormycosis, pneumonia, disseminated fungal infection, fungal pneumonia, progressive disease were the causes of death of the 15 patients who have died and only infections could be related to the study drug. The results suggest that pentostatin has activity in the treatment of cGVHD and may be especially beneficial in children and adolescents as the 5 CR were in this group.

Download Full-text

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.

Download Full-text

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

Blood ◽

10.1182/blood.v110.11.2983.2983 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2983-2983

Author(s):

David Gomez-Almaguer ◽

Guillermo J. Ruiz-Arguelles ◽

Oscar Gonzalez-Llano ◽

Homero C. Gutierrez-Aguire ◽

Olga G. Cantu-Rodriguez ◽

...

Keyword(s):

T Lymphocytes ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Host Disease ◽

Graft Versus Host ◽

Grade Ii ◽

Steroid Refractory ◽

Acute Graft

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

Download Full-text