Organ-specific management and supportive care in chronic graft-versus-host disease

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation has reviewed the available literature and made recommendations for the supportive care and management of organ-specific complications of chronic graft-versus-host disease (cGvHD). This guideline includes recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular and genital manifestations of cGvHD and for the supportive care of these patients, including vaccinations and prophylaxis against infection. The goal of treatment should be effective control of GvHD while minimizing the risk of toxicity and relapse.     

Diagnosis and management of acute graft-versus-host disease

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of acute graft-versus-host disease. This guideline includes recommendations for the diagnosis and grading of acute graft-versus-host disease as well as primary treatment and options for patients with steroid-refractory disease. The goal of treatment should be effective control of graft-versus-host disease while minimizing risk of toxicity and relapse.     

The role of extracorporeal photopheresis in the management of cutaneous T‐cell lymphoma,graft‐versus‐host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society

Extracorporeal photopheresis (ECP ) has been used for over 35 years in the treatment of erythrodermic cutaneous T‐cell lymphoma (CTCL ) and over 20 years for chronic and acute graft‐versus‐host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP . The recent literature has been reviewed and considered when writing this update. Most notably, the national transition from the UVAR XTS ^® machine to the new CELLEX machine for ECP with dual access and a shorter treatment time has led to relevant changes in these schedules. This consensus statement updates the previous statement from 2007 on the treatment of CTCL and GvHD with ECP using evidence based medicine and best medical practise and includes guidelines for both children and adults.     

Extracorporeal photopheresis for graft-vs-host disease: A literature review and treatment guidelines proposed by the Nordic ECP Quality Group

Extracorporeal photopheresis (ECP) is one of the most used and established therapies for steroid-refractory graft-vs-host disease (GvHD), with a good effect to side effect profile. In this review, we present a summary of present literature and provide evidence-based treatment guidelines for ECP in GvHD. The guidelines constitute a consensus statement formed by the Nordic ECP Quality Group representing all ECP centres in the Nordic countries, and aims to facilitate harmonisation and evidence-based practice. In developing the guidelines, we firstly conducted a thorough literature search of original articles and existing guidelines. In total, we identified 26 studies for ECP use in acute GvHD and 36 in chronic GvHD. The studies were generally small, retrospective and heterogeneous regarding patient characteristics, treatment schedule and outcome assessment. In general, a majority of patients achieved partial response or better, but response rates varied by the organs affected. Head-to-head comparisons to other treatment modalities were lacking. Overall, we consider the quality of evidence to be low–moderate (GRADE) and encourage future prospective multi-armed trials to strengthen the present recommendations. However, despite limitations in evidence strength, standardised treatment schedules and regular follow-up are imperative to ensure the best possible patient outcome.     

Graft‐versus‐host disease or toxic epidermal necrolysis: diagnostic dilemma after liver transplantation

Graft‐versus‐host disease (GvHD) and toxic epidermal necrolysis (TEN) are rare and severe complications after liver transplantation. While mild acute GvHD is quite different from TEN and easy to distinguish, severe acute GvHD and TEN can be hard to differentiate because of similar clinical symptoms. We herein report a case with rapid progression of critical illness, after liver transplantation, caused by GvHD or TEN, although between those, diagnosis was not possible during the clinical course. Although, based on the timing/progression of the symptoms and the chimerism of >40%, the case seemed much more clinically consistent with GVHD, the combination of clinical symptoms together with skin rashes and the histologic appearance of skin lesions indicated diagnosis of a Stevens‐Johnson syndrome/TEN overlap. The true diagnostic dilemma in such cases is discussed in detail, as these cases emphasize the need for more advanced diagnostic techniques.     

Mycophenolate mofetil for the treatment of acute and chronic steroid-refractory graft-versus-host disease

Corticosteroid-resistant graft-versus-host disease (GvHD) is difficult to manage and is associated with high morbidity and mortality. The purpose of our study was to evaluate the safety and efficacy of mycophenolate mofetil (MMF) as the salvage therapy for steroid-refractory GvHD. Twenty one patients (10 with acute GvHD and 11 with chronic GvHD) were studied retrospectively. Steroid-resistant GvHD was defined as acute or chronic GvHD not responding to a first-line regimen of cyclosporine A and corticosteroids in a dose equivalent to 2 mg/kg methylprednisolone for at least 7 days. MMF was added at a dose of 2 g daily, and corticosteroids were tapered. Thirteen (62%) of 21 patients responded to the treatment with MMF, including 6 (60%) of 10 patients with acute refractory GvHD and 7 (64%) of 11 patients with chronic refractory GvHD. The most common adverse effects were infectious complications (67%, 14 of 21 patients) and hematological toxicity (29%, 6 of 21 patients). Median duration of MMF administration was 6 months (range 1–27 months). Sixteen of 21 patients were alive after the median follow-up of 27 months (range 1–72 months) after the initiation of MMF therapy. All 16 surviving patients were in good clinical condition and in remission of their hematological malignancy. Five patients died—two of relapses of leukemia and three of refractory intestinal GvHD. These results suggest that MMF can be an effective treatment for some cases of steroid-refractory GvHD.     

Case Report: A Cryptosporidium infection in a patient with relapsed T‐lymphoblastic lymphoma undergoing allogeneic stem cell transplantation

Cryptosporidium infection is a rare cause of enterocolitis. In immunocompromised patients, cryptosporidiosis may lead to debilitating and life‐threatening diarrhea and malabsorption, occasionally with multi‐organ involvement. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) requires long‐term immunosuppressive therapy, while cellular immunity is usually compromised due to intensive conditioning chemotherapy. Diarrhea in patients who underwent allo‐HSCT may be a sign of an infection, but can also be the result of intestinal graft‐versus‐host disease (GvHD). Here, we describe the case of a patient who developed severe diarrhea following allo‐HSCT for relapsed T‐lymphoblastic lymphoma. Initially, GvHD was suspected and treatment was initiated accordingly. However, a colon biopsy showed signs of cryptosporide oocysts alongside only low‐grade GvHD. Following molecular confirmation of the diagnosis of cryptosporidiosis, an intensive treatment regimen was started. Despite the severe clinical course, the patient recovered and was discharged with only residual symptoms.     

Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Société Française de Greffe de Moëlle (SFGM)

Increasing numbers of patients are surviving after allogeneic bone marrow transplantation and are therefore at risk for developing late complications. Among these complications, avascular necrosis of bone has been reported, but only two single-centre studies included sufficient patients to enable analysis of the risk factors for developing avascular necrosis. In this multicentre retrospective study the aim was to assess risk factors for this complication in a large number of patients. The population consisted of 4388 patients, recorded in the Société Française de Greffe de Moelle (SFGM) data base, who had undergone a single allogeneic bone marrow transplant between January 1974 and December 1993. 77 patients developed avascular necrosis leading to a 4.3% projected incidence at 5 years. Symptoms developed 2–132 months after transplantation. In these 77 patients a mean of 1.87 joints per patient were affected (range 1–7). The hip joint was the most often affected (88% of patients) and 48% of the patients required joint replacement. All but two patients received steroids for acute and/or chronic graft-versus-host disease (GvHD) over a mean period of 15 months. In univariate analysis, among eight factors tested as risk factors for developing avascular necrosis, six were shown to be linked to an increased risk: older age, diagnosis of aplastic anaemia or acute leukaemia, an irradiation-based conditioning regimen, type of GvHD prophylaxis regimens, acute and chronic GvHD. In multivariate logistic regression analysis, five factors remained significantly associated with an increased risk for developing avascular necrosis: chronic GvHD (odds ratio (OR) 3.52), acute GvHD (OR 3.73), age>16 years (OR 5.81), aplastic anaemia (OR 3.90), and acute leukaemia (OR 1.72). Avascular necrosis is not a rare late complication of allogeneic bone marrow transplantation causing significant morbidity. In this study, older age, initial diagnosis, and GvHD and/or its treatment with steroids emerged as significant risk factors.     

The use of thalidomide in chronic refractory graft versus host disease

BACKGROUND: Chronic graft versus host disease (GvHD) is a serious complication of allogenic bone marrow transplantation. As prednisone and ciclosporine A are not always effective in its treatment, we investigated the value of thalidomide. METHODS: We describe the results of thalidomide in 12 patients with chronic prednison/ciclosporin A refractory GvHD seen in our clinic since 1991. A case history is given as illustration. RESULTS: Four patients had a complete remission of chronic GvHD on thalidomide; five patients showed a partial response. Of these five patients, three died eventually of respectively ongoing GvHD, pneumonia and recurrent leukemia. There were no serious side effects, except for one patient who had to stop thalidomide because of polyneuropathy. CONCLUSIONS: It is worthwhile to give thalidomide in prednison/ciclosporin A refractory chronic GvHD. Probably thalidomide should be given earlier in the course of GvHD, this needs further study.     

Dissociation of putative graft-versus-haematopoiesis and graft-versus-myeloma effects in patients with rapidly progressive multiple myeloma

This study evaluates the immunological effects in 21 patients with multiple myeloma (MM) following allogeneic stem cell transplantation with a non-myeloablative conditioning regimen. Patients were heavily pretreated, most of them having progressed despite one to three courses of high dose chemotherapy followed by autologous stem cell rescue. For patients conditioned with low dose total body irradiation and Fludarabine, development of full (100%) donor chimerism (FDC) within the first 3-4 months strongly depended on the number of T cells transplanted. This putative graft-versus-haematopoiesis effect, however, did not coincide with clinical response. Rather, 10 of 17 patients progressed although FDC in peripheral blood was achieved. In contrast, clinical graft-versus-host disease (GvHD) of grade III-IV was associated with disease remission. Four of six patients achieved complete remission (CR) and one patient achieved a partial remission (PR) in close temporal relation with their acute GvHD. Two of four patients in CR succumbed to the consequences of this side effect. One patient in PR progressed soon after successful treatment of the GvHD, one of two patients with a long-lasting CR developed chronic GvHD. Our observations suggest the existence of two distinct immune effects in MM following allogeneic transplantations with reduced conditioning regimen. First, the putative graft-versus-haematopoiesis effect that induced FDC was observed in all patients receiving unmanipulated grafts. Secondly, the graft-versus-myeloma effect that induced CR did not correlate with FDC but was associated with grade III-IV GvHD in our group of heavily pretreated patients.     

Management of acute graft versus host disease (GvHD)

Graft versus host disease (GvHD) is a frequent complication of allogeneic hemopoietic stem cell transplantation (HSCT), and of donor lymphocyte infusions (DLI): the acute form occurs within 100 days from HSCT or DLI, the chronic form beyond day +100. GvHD should be prevented rather than treated. There are several ways to prevent GvHD: remove donor T cells from the transplant (ex vivo T-cell depletion), administer T-cell antibodies to the patient (in vivo T-cell depletion), administer immunosuppressive drugs such as methotrexate, cyclosporin, tacrolimus, and mycofenolate (post-transplant immunosuppression). New strategies of GvHD prophylaxis include the infusion of expanded mesenchymal stem cells and downregulation of host antigen-presenting cells. First-line treatment of established GvHD is based on low-dose corticosteroids (0.5-2 mg/kg). Second-line therapy for steroid refractory GvHD is unsatisfactory. The early administration of T-cell antibodies and/or TNF antibodies and TNF soluble receptor may be successful in some cases, but they do not seem to fulfill the expectations. High-dose chemotherapy has not been explored thoroughly. Acute GvHD is complicated by infections that cause significant morbidity and mortality: prophylaxis, early diagnosis and treatment of infections are an integral part of GvHD management. We have considerably reduced the risk of acute GvHD over the past three decades: we need to further improve these results, with the final goal of dissecting, if possible, the graft versus host from the graft versus tumor effect.     

Treatment of graft-versus-host disease with monoclonal antibodies and related fusion proteins

Allogeneic hematopoietic stem cell transplantation has evolved from an experimental treatment approach to a widely used, curative therapy to treat malignant and nonmalignant diseases of the hematopoietic system. Despite advances in donor selection, conditioning regimens and supportive care, acute and chronic graft-versus-host disease (GvHD) remain a major cause of morbidity and mortality. Steroids are the standard first-line treatment and are able to control GvHD in approximately 50% of patients. Those who fail on steroids have a poor long-term prognosis. Therefore, a large number of drugs and procedures have been evaluated as second-line therapy. Monoclonal antibodies have increasingly been used to treat malignancy and autoimmune disease during the last 20 years. Their unique ability to target specific antigens theoretically enables them to directly interfere with cellular mechanisms that are involved in GvHD pathology. For this reason, monoclonal antibodies have been studied extensively as a second-line treatment for acute and chronic GvHD. The purpose of this article is to collect published data on clinical trials from the current literature and to give an overview on efficacy and toxicity of monoclonal antibody treatment for GvHD.     

Update on extracorporeal photochemotherapy for graft-versus-host disease treatment

Pediatric experience with extracorporeal photochemotherapy (ECP) for graft-versus-host disease (GvHD) has mainly been reported by Italian and French groups. Data concerning 41 children with acute GvHD and 63 children affected by chronic GvHD are available. In 73 and 63% of them, respectively, improvement was observed, with addition of ECP to their immunosuppressive regimen. Treatment with ECP was associated with minimal side effects, even in the smallest of patients. In all responded pediatric patients, both with acute and chronic GvHD, ECP allowed progressive reduction or discontinuation of the concomitant pharmacological immunosuppressive therapy without an increase in GvHD activity. These data show that ECP is a useful therapy for children affected by GvHD resistant to conventional treatment and can be safely used.     

Prognostic factors in chronic myeloid leukemia: allografting

Risk assessment for allografting differs from that for conventional therapy mainly because the transplant intervenes far from initial diagnosis and generates a new source of morbidity and mortality, graft-versus-host disease (GvHD). Major well-defined pre-, peri- and post-transplant risk factors influence two endpoints: transplant-related mortality (TRM) and relapse incidence (RI), which in turn determine the principal outcomes-leukemia-free survival (LFS) and survival. Some factors have concordant effects on both endpoints, like disease stage. Other risk factors have divergent effects: histocompatibility, intensity of conditioning, or GvHD prevention. The impact of risk factors with divergent effects differs in various time periods post-transplant. The main pretransplant factors are disease stage, patient age and sex, donor-recipient sex combination, histocompatibility, and time from diagnosis to transplant. The primary peritransplant factors are the intensity of conditioning and of GvHD prevention. The main post-transplant factor is severity of acute and chronic GvHD. Determination of the risk profile for an individual patient is reliable and should form an integral part of pretransplant counseling. The management strategies for patients with high-risk disease and low TRM risk profiles and for patients with low-risk disease and high TRM risk profiles should be different.     

T-cell precursor frequencies and long-term outcome following unrelated hematopoietic stem cell transplantation

Functional assays measuring alloreactivity of donor cells are desired to detect either cryptic epitopes inducing graft-vs.-host disease (GvHD) after human leukocyte antigen (HLA)-identical hematopoietic stem cell transplantation (HSCT) or permissible HLA mismatches. However, their value in predicting GvHD and survival is still limited. We determined the cytotoxic and helper T-cell precursor (CTLp and HTLp) frequencies by limiting dilution analysis (LDA) in 40 unrelated recipient/donor combinations. The median observation period at the time of this writing was 4.44 years (range from 0.1 to 11.28). Better overall survival was observed in patients with rather low host-specific CTLp and HTLp frequencies, whereas a trend toward high CTLp frequencies was seen in patients with higher incidence of acute GvHD, especially in patients mismatched in HLA-C. CTLp and HTLp frequencies did not correlate with the incidence of chronic GvHD and relapse. In conclusion, we detected a trend toward better overall survival of patient/donor pairs with low CTLp and HTLp frequencies, however, recommend to use LDA as an additional tool for identifying the most suitable donor when more than one fully HLA-matched stem cell donor is available.     

Chronic graft versus host disease

The ability to cure increasing numbers of individuals for malignant and non-malignant diseases with the use of stem cell transplantation has resulted in a growing number of long-term survivors with unique medical issues. Chronic graft versus host disease (GvHD) continues to be a significant problem in the allogeneic stem cell transplant setting and, as we continue to use alternative stem cell sources and attempt to modulate the immune system to increase an anti-tumour effect, we will probably see rising numbers of patients with this complication. The capacity to treat this problem and improve both the immediate quality of life as well as long-term effects is imperative and requires the ability of haematologists/oncologists to identify chronic GvHD and its multi-organ system presentations. We describe the risk factors for developing chronic GvHD, its presentation and the current treatment options for both initial therapy and secondary treatment.     

Fecal but not serum calprotectin is a potential marker of GVHD after stem cell transplantation

Gastrointestinal graft-versus-host disease (GvHD) represents a life-threatening complication after stem cell transplantation. Differential diagnosis between gut GvHD and other causes of diarrhea after HSCT is still subjected to endoscopy and histological findings. The research for a reliable biomarker for gut GvHD might allow an early diagnosis of this condition and a consequent prompt treatment that could reduce unfavorable outcomes. Recently, fecal calprotectin was reported as reliable marker of gut involvement. We would evaluate if serum instead of fecal calprotectin could be considered a possible biomarker of gut GvHD. Serum calprotectin was measured in a cohort of 54 patients submitted to allogeneic stem cell transplantation using ELISA assay. For a subset of 21 patients, calprotectin serum levels were compared with fecal calprotectin detection. Contrary to fecal calprotectin, we found only a trend to high level of serum calprotectin for GvHD development and gut involvement, but statistical difference was not reached. Fecal but not serum calprotectin could be considered as possible biomarker for gut GvHD.     

A clinical comparison of unrelated cord blood transplantation and unrelated bone marrow transplantation for adult patients with acute leukaemia in complete remission

We performed a clinical comparison of unrelated cord blood transplantation (UCBT) and unrelated bone marrow transplantation in adult acute leukaemia patients in complete remission (CR) who received the same conditioning regimen, graft-versus-host disease (GvHD) prophylaxis and supportive treatment. The incidence of acute GvHD was almost the same between the two groups, but the haematopoietic recovery was delayed and the incidence of chronic GvHD was higher in the UCBT group. The probability of 2 year disease-free survival was similar between the two groups. These results suggest that adult acute leukaemia patients in CR without a suitable donor should be considered as candidates for UCBT.     

Correlation between donor cytomegalovirus immunity and chronic graft-versus-host disease after allogeneic bone marrow transplantation

Chronic graft-versus-host disease (GvHD) in bone marrow allograft recipients is frequently preceded by a cytomegalovirus (CMV) infection. To elucidate whether an immune reaction of transplanted donor cells against CMV was involved in the pathogenesis of chronic GvHD, the effect of donor pretransplant CMV immune status on chronic GvHD incidence was analyzed. In 43 bone marrow recipients at risk, the 2-yr cumulative chronic GvHD probability was 55% when the donor was immune, in contrast to 16.5% when the donor was non-immune (p less than 0.002). No correlation between recipient pretransplant CMV immunity and chronic GvHD was observed. Donor CMV immunity did not correlate with acute GvHD or posttranplant CMV infection and seemed to predispose for chronic GvHD regardless of donor and recipient age. However, the proportion of CMV immune donors increased with increasing donor and recipient age. This may account for the higher incidence of chronic GvHD in older patients. The present study suggests that chronic GvHD may be mediated by a reaction of immune donor cells against CMV infected recipient cells.     

Post‐transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation

Advances in haploidentical bone marrow transplantation (h‐BMT) have drastically broadened the treatment options for patients requiring BMT. The possibility of significantly reducing the complications resulting from graft‐versus‐host disease (GvHD) with the administration of post‐transplant cyclophosphamide (PT‐CY) has substantially improved the efficacy and applicability of T cell‐replete h‐BMT. However, higher frequency of disease recurrence remains a major challenge in h‐BMT with PT‐CY. There is a critical need to identify novel strategies to prevent GvHD while sparing the graft‐versus‐leukaemia (GvL) effect in h‐BMT. To this end, we evaluated the impact of bendamustine (BEN), given post‐transplant, on GvHD and GvL using clinically relevant murine h‐BMT models. We provide results indicating that post‐transplant bendamustine (PT‐BEN) alleviates GvHD, significantly improving survival, while preserving engraftment and GvL effects. We further document that PT‐BEN can mitigate GvHD even in the absence of Treg. Our results also indicate that PT‐BEN is less myelosuppressive than PT‐CY, significantly increasing the number and proportion of CD11b⁺Gr‐1^hi cells, while decreasing lymphoid cells. In vitro we observed that BEN enhances the suppressive function of myeloid‐derived suppressor cells (MDSCs) while impairing the proliferation of T‐ and B‐cells. These results advocate for the consideration of PT‐BEN as a new therapeutic platform for clinical implementation in h‐BMT.