Carfilzomib, thalidomide, and dexamethasone is safe and effective in relapsed and/or refractory multiple myeloma: final report of the single arm, multicenter phase II ALLG MM018/AMN002 study.

This multicentre, phase II study of the Australian Lymphoma and Leukaemia Group (ALLG) and the Asian Myeloma Network (AMN) investigated fixed-duration (18-month) treatment with carfilzomib (K), thalidomide (T), and dexamethasone (d; KTd) in patients with relapsed and/or refractory multiple myeloma and 1-3 prior lines of therapy. Patients received induction with up to twelve 28-day cycles of K [20mg/m2 IV cycle 1 day 1 and 2, 56mg/m2 (36mg/m2 for patients ≥75 years) from day 8 onwards), T 100mg PO nocte and weekly dexamethasone 40mg (20mg for patients ≥75 years). During maintenance T was omitted, while K continued on days 1,2,15,16 with fortnightly dexamethasone. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate, overall survival (OS), duration of response, safety, and tolerability. Ninety-three patients (median age 66.3 years (41.9 - 84.5)) were enrolled with a median follow-up of 26.4 (1.6 - 54.6) months. The median PFS was 22.3 months (95% CI 15.7 - 25.6) with a 46.3% (95% CI 35.1 - 52.8) 2-year PFS. Median OS was not reached and was 73.8% (95% CI 62.9 - 81.9) at 2 years. The overall response rate was 88% (≥ VGPR 73%). There was no difference in the depth of response, PFS or OS comparing Asian and Non-Asian cohorts (p=0.61). The safety profile for KTd was consistent with each individual drug. KTd is well tolerated and effective in patients with RRMM irrespective of Asian or non-Asian ethnicity and provides an alternative option particularly where use of KRd is limited by access, cost, or renal impairment.

Treatment of patients with Waldenström macroglobulinaemia: clinical practice update from the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Waldenström macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of IgM paraprotein, bone marrow infiltration by clonal small B lymphocytes with plasmacytic differentiation and the MYD88 L265P mutation in >90% of cases. Traditionally, WM has been treated with chemoimmunotherapy. Recent trials have demonstrated the efficacy and safety of Bruton tyrosine kinase inhibitors in WM, both as monotherapy and in combination with other drugs. There is emerging evidence on the use of other agents including B-cell lymphoma 2 inhibitors and on the treatment of rare presentations of WM. In this update, the Medical and Scientific Advisory Group of Myeloma Australia reviews the available evidence on the treatment of WM since the last publication in 2017 and provides specific recommendations to assist Australian clinicians in the management of this disease.

Predictors of early mortality in multiple myeloma: Results from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR).

The frequency and causes of early mortality in patients with newly diagnosed multiple myeloma (NDMM) have not been well described in the era of novel agents. We investigated early mortality in a prospective cohort study of all patients with NDMM registered on the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) at 36 institutions between July 2011 and March 2020. Early mortality was defined as death from any cause within the first 12 months after diagnosis. A total of 2377 patients with NDMM were included in the analysis, with a median (interquartile range) age of 67.4 (58.9-74.60 years, and 60% were male. Overall, 216 (9.1%) patients died within 12 months, with 119 (4.5%) having died within 6 months. Variables that were independent predictors of early mortality after adjustment in multivariable regression included age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.05-1.08; p < 0.001), Eastern Cooperative Oncology Group performance status (OR 1.50, 95% CI 1.26-1.79; p < 0.001), serum albumin (OR 0.95, 95% CI 0.93-0.98; p < 0.001), cardiac disease (OR 1.96, 95% CI 1.35-2.86; p < 0.001) and International Staging System (OR 1.40, 95% CI 1.07-1.82; p = 0.01). For those with a primary cause of death available, it was reported as disease-related in 151 (78%), infection 13 (7%), other 29 (15%). Infection was listed as a contributing factor for death in 38% of patients.

Imaging of patients with multiple myeloma and associated plasma cell disorders: consensus practice statement by the Medical Scientific Advisory Group to Myeloma Australia.

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.

Patients with multiple myeloma over a large catchment of 2.5 million square kilometres: a Western Australia retrospective survival review.

Multiple myeloma is an incurable malignancy of plasma cells. We retrospectively reviewed the survival outcomes of patients with multiple myeloma in Western Australia (WA) public hospitals over a 10-year period. We did not detect a difference in survival between patients residing the metropolitan Perth and regional areas, despite a paucity of haematology services in regional WA due to low population density in a large geographic area. Patients with R-ISS Stage 3 had the poorest survival in our cohort with median survival of 24 months.

'It is a journey of discovery': living with myeloma.

PURPOSE: Although multiple myeloma (MM) is incurable, many people live with the disease for a number of years. Thus, understanding the effect of the disease and its therapies on the lives of those with MM is important. This qualitative study explores the impact of MM and its treatments on patients. METHODS: People with newly diagnosed or relapsed MM were recruited from a tertiary institution. Participants were interviewed using a semi-structured approach. The questions were designed to obtain insight into how participants viewed their diagnosis, treatment, and symptoms and how these had impacted on their lives. Data were analysed using a phenomenological approach. RESULTS: Fifteen people with MM with a mean age of 62 were recruited. Participants' mean time since diagnosis was 2.7 years and they had received a mean of 1.7 lines of therapy. The first major theme to emerge was lifestyle changes. Interviewees described MM as causing changes to all aspects of their lives, including substantial functional changes, as well as changes to employment, relationships, and their sense of self. The second major theme was 'adjust, adjust, adjust'. Alongside challenging life changes, participants described a range of practical, psychological, and relational approaches to adjusting to living with MM. CONCLUSION: This study highlights the importance of and the need for improved supportive care in patients with MM, ideally with a multidisciplinary approach. It also identifies the potential for further investigation of patient approaches to adjusting to MM and development of support strategies.

Considerations for pre-transfusion immunohaematology testing in patients receiving the anti-CD38 monoclonal antibody daratumumab for the treatment of multiple myeloma.

In recent years, the anti-CD38 monoclonal antibody daratumumab (Darzalex; Janssen-Cilag Pty Ltd) has been shown to be highly efficacious in relapsed and refractory multiple myeloma, with the final results of treatment in newly diagnosed patients awaited. Despite awareness of the potential interference of daratumumab in pre-transfusion immunohaematology testing during phase I and II clinical studies, there was a degree of unpreparedness in the community upon the introduction of this drug into the clinics, particularly the impact that it has on the operational processes in hospital transfusion laboratories and timely issue of red blood cells (RBCs). Anti-CD38 interference in pre-transfusion immunohaematology tests is a particular problem in patients being treated with daratumumab for multiple myeloma as many will require RBC transfusions during their disease treatment. Panagglutination caused by anti-CD38 monoclonal antibody during the indirect antiglobulin test may mask the presence of a clinically significant RBC alloantibody in the patient's plasma during the antibody screen and identification process, which may be overlooked, particularly in urgent situations, subsequently resulting in a delayed or acute haemolytic transfusion reaction. Here, we summarise daratumumab's effects on pre-transfusion immunohaematology testing and its impact on clinical practice and make practical recommendations based on a consensus from medical and scientific transfusion experts and myeloma specialists on behalf of the Australian and New Zealand Society of Blood Transfusion and Myeloma Scientific Advisory Group to Myeloma Australia, respectively.

Bisphosphonate guidelines for treatment and prevention of myeloma bone disease.

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk of skeletal-related events such as pathologic fracture, spinal cord compression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activation of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the standard of care. Pamidronate and zoledronic acid are the most commonly used BP to treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD.

Treatment of patients with Waldenström macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Waldenström macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease.

Clinical characteristics and outcomes of patients with Hodgkin lymphoma with central nervous system involvement: An international multicenter collaboration.

Central nervous system (CNS) involvement is rare in patients with Hodgkin lymphoma (HL). Thus, the clinical features and outcomes are not well described. Cases of histologically confirmed CNS HL diagnosed between 1995 and 2015 were retrospectively identified in institutional (n = 7), national (n = 2), and cooperative group (n = 1) databases. We screened 30,781 patients with HL in our combined databases and identified 21 patients meeting eligibility criteria, an estimated frequency of 0.07%. CNS involvement was present at initial diagnosis in 10 patients (48%) and a feature of relapsed/refractory disease in 11 (52%). Among these 11 patients, the median time from initial diagnosis of HL to development of CNS involvement was 1.9 years (range 0.4-6.6) and the median number of prior lines of therapy was 2 (range 1-7). Altogether, treatments included radiation, multiagent systemic chemotherapy, combined modality therapy, and subtotal resection. The overall response rate was 65%. After a median follow-up of 3.6 years (range 0.8-13.2) from diagnosis of CNS HL, the median PFS and OS were 7.6 and 29 months, respectively. CNS involvement as a feature of relapsed/refractory disease was adversely prognostic for both PFS and OS; however, four patients remain alive and free of relapse at 7-78 months follow-up. CNS involvement in HL is exceedingly rare and has a distinct clinical presentation with predilection for parenchymal lesions with dural extension. Around one-quarter of patients, mostly with CNS involvement at initial HL diagnosis, experience prolonged disease-free survival. Am. J. Hematol. 91:894-899, 2016. © 2016 Wiley Periodicals, Inc.

Design and development of the Australian and New Zealand (ANZ) myeloma and related diseases registry.

BACKGROUND: Plasma cell dyscrasias (PCD) are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ) for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR) was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process. METHODS: The MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources. RESULTS: More than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and 'real world' outcome data, to support the conduction of high quality studies. In addition, the Myeloma 1000 sub-study is establishing a repository of paired peripheral blood specimens from registry patients to study mechanisms underlying disease progression. CONCLUSION: Establishment of the MRDR has been challenging, but it is a valuable investment that will provide a platform for coordinated national and international collaboration for clinical research in PCD in ANZ.

The addition of dexamethasone to bortezomib for patients with relapsed multiple myeloma improves outcome but ongoing maintenance therapy has minimal benefit.

Despite the common practice of combining dexamethasone (Dex) with bortezomib (Bz) in patients with multiple myeloma (MM), until now there has been few prospective trials undertaken. We undertook a trial that recapitulated the original APEX study except that dexamethasone was incorporated from cycle 1. We also incorporated an exploratory maintenance component to the study. Twenty sites enrolled 100 relapsed/or refractory MM patients utilizing eight 21 day cycles of IV Bz [1.3 mg/m(2) ; Day (D) 1, 4, 8, 11] and three 35 day cycles; Bz (1.3 mg/m(2) ; Day (D) 1, 8, 15, 22). Our study was registered at www.clinicaltrials.gov (NCT00335348). Patients with stable disease or better received maintenance Bz (1.3 mg/m(2) ) every 14 days until progression. Dexamethasone (20 mg) was given for 2 days with each Bz dose. A prospectively defined matched-analysis of primary (overall response rate; ORR) and secondary endpoints [Complete Response (CR) and time to progression (TTP)] compared our cohort to those on the Bz arm of the APEX trial. The addition of Dex improved ORR by 20% (56% vs. 36%) [odds ratio 0.44 (0.24-0.80)]. The median TTP was also significantly longer (10.1 vs. 5.1 months) (hazard ratio 0.50, 95% CI: 0.35-0.72, P = 0.0002) and our landmark analysis demonstrated that this was largely due to the early use of dexamethasone, as we were unable to demonstrate any benefit of bortezomib/dexamethasone maintenance therapy.

Automated digital enumeration of plasma cells in bone marrow trephine biopsies of multiple myeloma.

AIMS: Determination of the number of plasma cells in bone marrow biopsies is required for the diagnosis and ongoing evaluation of plasma cell neoplasms. We developed an automated digital enumeration platform to assess plasma cells identified by antigen expression in whole bone marrow sections in multiple myeloma, and compared it with manual assessments. METHODS: Bone marrow trephine biopsy specimens from 91 patients with multiple myeloma at diagnosis, remission and relapse were stained for CD138 and multiple myeloma oncogene 1 (MUM1). Manual assessment and digital quantification were performed for plasma cells in the entire trephine section. Concordance rates between manual and digital methods were evaluated for each antigen by intraclass correlation analyses (ICC) with associated Spearman's correlations. RESULTS: The digital platform counted 16 484-1 118 868 cells and the per cent CD138 and MUM1-positive plasma cells ranged from 0.05% to 93.5%. Overall concordance between digital and manual methods was 0.63 for CD138 and 0.89 for MUM1. Concordance was highest with diffuse plasma cell infiltrates (MUM1: ICC=0.90) and lowest when in microaggregates (CD138: ICC=0.13). Manual counts exceeded digital quantifications for both antigens (CD138: mean=26.4%; MUM1: mean=9.7%). Diagnostic or relapse threshold counts, as determined by CD138 manual assessments, were not reached with digital counting for 16 cases (18%). CONCLUSIONS: Automated digital enumeration of the entire, immunohistochemically stained bone marrow biopsy section can accurately determine plasma cell burden, irrespective of pattern and extent of disease (as low as 0.05%). This increases precision over manual visual assessments which tend to overestimate plasma burden, especially for CD138, and when plasma cells are in clusters.

Adjusting for patient crossover in clinical trials using external data: a case study of lenalidomide for advanced multiple myeloma.

OBJECTIVES: In some trials, particularly in oncology, patients whose disease progresses under the comparator treatment are crossed over into the experimental arm. This unplanned crossover can introduce bias in analyses because patients who crossover likely have a different prognosis than those who do not cross over; for instance, sicker patients not responding to standard therapy or those expected to benefit the most may be selectively chosen to receive the experimental treatment. Standard statistical methods cannot adequately correct for this bias. We describe an approach designed to minimize the impact of crossover, and illustrate this by using data from two randomized trials in multiple myeloma (MM). METHODS: The MM-009/010 trials compared lenalidomide and high-dose dexamethasone (Len+Dex) with dexamethasone alone (Dex). Nearly half (47%) of the patients randomized to Dex crossed over to Len with or without Dex (Len+/-Dex) at disease progression or study unblinding. Data from these trials was used to predict survival in an economic model evaluating the cost-effectiveness of lenalidomide. To adjust for crossover, the prediction equations were calibrated to match survival with Dex or Dex-equivalent therapies in trials conducted by the Medical Research Council (MRC) in the United Kingdom. To adjust for differences between the MM and MRC trial populations, a prediction equation was developed from the MRC data and used to predict survival by setting predictors to mean values for patients in the MM-009/010 trials. The expected survival with Dex without crossover was then predicted from the calibrated MM-009/010 equation (i.e., adjusted to match survival predicted from the MRC equation). RESULTS: The adjusted median overall survival predicted by the MRC equation was 19.5 months (95%CI, 16.6-22.9) for patients with one prior therapy, and 11.6 months (95% CI, 9.5-14.2) for patients with >1 prior therapy. These estimates are considerably shorter than was observed in the clinical trials: 33.6 months (27.1-NE) and 27.3 months (95% CI, 23.3-33.3) as of December 2005. CONCLUSION: The calibration method described here is simple to implement, provided that suitable data are available; it can be implemented with other types of endpoints in any therapeutic area.

Real-world utilisation of ASCT in multiple myeloma (MM): a report from the Australian and New Zealand myeloma and related diseases registry (MRDR).

Supported by clinical trial proven survival benefit, clinical guidelines recommend upfront autologous stem cell transplantation (ASCT) for eligible MM patients. However, reported real-world utilisation is lower than expected (40-60%). We reviewed ASCT utilisation, demographics and outcomes for MM patients (≤70 years, ≥12-month follow-up) enroled onto the Australian/New Zealand MRDR from June 2012 to May 2020. In 982 patients (<65 years: 684, 65-70 years: 298), ASCT utilisation was 76% overall (<65 years: 83%, 65-70 years: 61%, front-line therapy: 67%). Non-ASCT recipients were older (median age: 65 years vs 60 years, p < 0.001), had more comorbidities (cardiac disease: 16.9% vs 5.4%, p < 0.001; diabetes: 19.1% vs 7.0%, p < 0.001; renal dysfunction: median eGFR(ml/min): 68 vs 80, p < 0.001), inferior performance status (ECOG ≥ 2: 26% vs 13%, p < 0.001) and higher-risk MM (ISS-3: 37% vs 26%, p = 0.009, R-ISS-3 18.6% vs 11.8%, p = 0.051) than ASCT recipients. ASCT survival benefit (median progression-free survival (PFS): 45.3 months vs 35.2 months, p < 0.001; overall survival (OS): NR vs 64.0 months, p < 0.001) was maintained irrespective of age (<65 years: median PFS: 45.3 months vs 37.7 months, p = 0.04, OS: NR vs 68.2 months, p = 0.002; 65-70 years: median PFS: 46.7 months vs 29.2 months, p < 0.001, OS: 76.9 months vs 55.6 months, p = 0.005). This large, real-world cohort reaffirms ASCT survival benefit, including in 'older' patients necessitating well-designed studies evaluating ASCT in 'older' MM to inform evidence-based patient selection.

The association of mobilising regimen on immune reconstitution and survival in myeloma patients treated with bortezomib, cyclophosphamide and dexamethasone induction followed by a melphalan autograft.

G-CSF only mobilisation has been shown to enhance immune reconstitution early post-transplant, but its impact on survival remains uncertain. We undertook a retrospective review of 12 transplant centres to examine overall survival (OS) and time to next treatment (TTNT) following melphalan autograft according to mobilisation method (G-CSF only vs. G-CSF and cyclophosphamide [CY]) in myeloma patients uniformly treated with bortezomib, cyclophosphamide and dexamethasone induction. Six centres had a policy to use G-CSF alone and six to use G-CSF + CY. Patients failing G-CSF only mobilisation were excluded. 601 patients were included: 328: G-CSF + CY, 273: G-CSF only. Mobilisation arms were comparable in terms of age, Revised International Staging System (R-ISS) groups and post-transplant maintenance therapy. G-CSF + CY mobilisation generated higher median CD34 + yields (8.6 vs. 5.5 × 106/kg, p < 0.001). G-CSF only mobilisation was associated with a significantly higher lymphocyte count at day 15 post-infusion (p < 0.001). G-CSF only mobilisation was associated with significantly improved OS (aHR = 0.60, 95%CI 0.39-0.92, p = 0.018) and TTNT (aHR = 0.77, 95%CI 0.60-0.97, p = 0.027), when adjusting for R-ISS, disease-response pre-transplant, age and post-transplant maintenance therapy. This survival benefit may reflect selection bias in excluding patients with unsuccessful G-CSF only mobilisation or may be due to enhanced autograft immune cell content and improved early immune reconstitution.

Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis.

PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

Acute graft-versus-host disease after liver transplant: novel use of etanercept and the role of tumor necrosis factor alpha inhibitors.

Acute graft-versus-host disease following orthotopic liver transplantation is a rare but feared complication arising in 1% to 2% of cases with a dismal prognosis. It most often presents as fever, rash, and diarrhea with or without pancytopenia. Patients die from complications of marrow failure such as sepsis or bleeding. Because of its low incidence, there is no clear treatment protocol for this complication. Both increasing and withdrawing immunosuppression have been attempted with variable success. Although anti-tumor necrosis factor alpha therapy has been widely used for the treatment of steroid-resistant acute graft-versus-host disease in the hematopoietic stem cell transplant setting, there previously have been no reported cases of its use in liver transplantation. The aim of this report is to review a case of acute graft-versus-host disease and the use of etanercept to manage this complication. Etanercept has never previously been used in liver transplantation complicated by acute graft-versus-host disease. In the hematology literature, the success of its use is offset by significant rates of serious infectious (especially fungal) complications. However, preliminary results are encouraging and offer insight into its use as a potentially viable therapeutic option. We report the first successful use of etanercept in liver transplantation-associated graft-versus-host disease, albeit complicated by invasive aspergillosis, and recommend concurrent antifungal prophylaxis when the drug is used in this setting.