Bradley Augustson

Early Mortality After Diagnosis of Multiple Myeloma: Analysis of Patients Entered Onto the United Kingdom Medical Research Council Trials Between 1980 and 2002—Medical Research Council Adult Leukaemia Working Party

PURPOSE Early mortality in multiple myeloma (MM) is usually attributed to combined effects of active disease and comorbid factors. We have studied early deaths in a series of large multicenter trials to assess direct causes of death, their predictability, and whether current management strategies have reduced their frequency. PATIENTS AND METHODS A total of 3,107 newly diagnosed patients entered onto United Kingdom Medical Research Council MM trials from 1980 to 2002 were studied. Trial files, final clinical summaries, and postmortem reports were analyzed. RESULTS Death within 60 days of trial entry occurred in 299 patients (10%). Logistic regression modeling identified beta 2-microglobulin, performance status, and age as the most important predictors of early death, but only with 61% sensitivity and 73% specificity. Forty-five percent of deaths were attributable to infection, which was often associated with bone pain (particularly thoracic pain) and delay in presenting to medical care. Neutropenia was present at diagnosis in only 11 of the 135 deaths from infection. Renal failure was present in 28% of early deaths and was linked to light-chain MM, hypercalcemia, dehydration, and nonsteroidal anti-inflammatory drugs. There was no time related reduction in the percentage or nature of early deaths in 1,550 patients older than 65 years receiving similar therapy between 1982 and 2002. CONCLUSION A tenth of patients die within 60 days of diagnosis of MM. Infection and renal failure are the main direct causes of early mortality, which cannot be accurately predicted by presenting prognostic features. All patients should be considered at high risk of death during induction therapy.

Dasatinib therapy for systemic mastocytosis: four cases.

To the Editor: Systemic mastocytosis (SM) is an uncommon disorder characterised by clonal proliferation and tissue infiltration by mast cells. Effective treatment options for patients with this disease are currently limited. Malignant mast cells are derived from stem cells with activating mutations of the KIT receptor tyrosine kinase (1, 2). The KIT mutation has been implicated in a significant proportion of SM cases (3). Dasatinib (BMS-354825; Bristol-Myers Squibb, New York, NY, USA) is a novel tyrosine kinase inhibitor which has been proven effective in inhibiting D816V positive mast cells in vitro (4, 5). There are currently no published clinical studies evaluating dasatinib in patients with SM. We report four cases of SM treated with dasatinib. The clinical, histological and genetic features of each case are summarised in Table 1. D816V mutation was detected in unfractionated bone marrow cells using a PCR assay (6), while fluorescence in situ hybridisation (FISH) studies were performed for FIP1L1-PDGFRa (7). Mast cell tryptase was measured using the UniCAP 100 (Pharmacia & Upjohn Diagnostics, Uppsala, Sweden) immunoabsorbant assay. Bone marrow trephine biopsies were examined and graded for the extent of involvement by mast cells as outlined in Table 1. Dasatinib was obtained from Bristol-Myers Squibb on compassionate grounds. Case 1 is a 20-year-old female who presented with pruritic skin rash, anorexia, diarrhoea and weight loss of 15 kg (18% of total body weight). Treatment with dasatinib 50 mg daily commenced with concomitant hydrocortisone (100 mg intravenously) and anti-histamine for the first three doses. A moderate exacerbation of skin rash, pruritus and nausea occurred 1 h after the first dose and resolved at 4 d. Dasatinib dose was increased to 50 mg twice daily at 1 month. A moderate reduction in pruritus, improved appetite and weight gain of 10 kg occurred after 6 months, though there was not significant change on repeat bone marrow biopsy. Case 2 is a 52-year-old male who presented with symptomatic pericardial effusion, hepatomegaly and splenomegaly (6 cm). Bone marrow biopsy showed myelodysplasia and diffuse infiltrates of mast cells. Initial treatment with imatinib was not effective and the patient developed moderate diarrhoea and generalised pruritic skin rash. Treatment with dasatinib commenced at 70 mg twice daily with concomitant antihistamines. The patient suffered significantly worse diarrhoea, pruritus and headaches from day 2 to day 5. Complete remission of diarrhoea and skin rash occurred after day 5. Bone marrow examination at 7 months revealed histological response (see Table 1). After 11 months, the patient developed acute myeloid leukaemia and dasatinib therapy ceased. Case 3 is a 60-year-old female who presented with an 18-month history of pruritic skin rash, headaches and lethargy. Early treatment including prednisolone, cladribine, nilotinib, interferon-alpha and splenic radiotherapy was ineffective and the patient developed grade 4 pancytopenia. Dasatinib therapy commenced 5 yr after initial diagnosis. Dose was escalated from 20 mg twice daily to 70 mg twice daily over 3 d, with administration of corticosteroid (hydrocortisone 100 mg intravenously, one dose only) and anti-histamines prior to each dose. Prednisolone 37.5 mg daily was weaned over the following 6 wk. No adverse effects occurred during early treatment. There was no evidence of significant clinical or histological response despite dose increase to 90 mg twice daily and then 110 mg twice daily. Dasatinib therapy ceased after 2 months. Two months later the patient died of complications related to sepsis. Case 4 is a 49-year-old man who was diagnosed with indolent systemic mastocytosis with prominent mast cell degranulation symptoms (ISMSY) after presenting with anaphylactic shock on a background of four previous episodes of anaphylaxis. Interferon-alpha, cladribine, prednisolone and intravenous human immunoglobulin were ineffective and episodes of anaphylaxis occurred with increasing frequency. Dasatinib commenced at 4 yr after diagnosis. Concomitant therapy included ranitidine (ceased with first dasatinib dose), dexchlorpheniramine, sodium cromoglycate, ketolifen and montelukast. No adverse effects were observed. Episodes of anaphylaxis occurred with the same frequency. Dasatinib therapy ceased after 6 months. Dasatinib was generally well tolerated. Cases 1 and 2 suffered early adverse effects that are likely to have been mediated by mast cell mediator release. A similar phenomenon is observed with other cytoreductive agents in SM (8). Cases 3 and 4 showed no response to dasatinib therapy. Both had been heavily pretreated prior to commencing treatment. This small series suggests that dasatinib has some in vivo activity in SM, treating symptoms and reversing disease progression in some patients. The doi:10.1111/j.1600-0609.2008.01048.x European Journal of Haematology ISSN 0902-4441

Acute graft-versus-host disease after liver transplant: Novel use of etanercept and the role of tumor necrosis factor α 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 α 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. Liver Transpl 15:421–426, 2009.

Tacrolimus‐induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients

Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5–3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus‐induced TMA. We identified four patients with tacrolimus‐induced TMA post‐OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 ± 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post‐partum thrombotic thrombocytopenic purpura) and hepatitis C virus‐related cirrhosis. All patients had tacrolimus post‐OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 ± 7.5 months. There was no mortality 6 months post‐TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes.

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.

Management of systemic AL amyloidosis: recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Systemic AL amyloidosis is a plasma cell dyscrasia with a characteristic clinical phenotype caused by multi‐organ deposition of an amyloidogenic monoclonal protein. This condition poses a unique management challenge due to the complexity of the clinical presentation and the narrow therapeutic window of available therapies. Improved appreciation of the need for risk stratification, standardised use of sensitive laboratory testing for monitoring disease response, vigilant supportive care and the availability of newer agents with more favourable toxicity profiles have contributed to the improvement in treatment‐related mortality and overall survival seen over the past decade. Nonetheless, with respect to the optimal management approach, there is a paucity of high‐level clinical evidence due to the rarity of the disease, and enrolment in clinical trials is still the preferred approach where available. This review will summarise the Clinical Practice Guidelines on the Management of Systemic Light Chain (AL) Amyloidosis recently prepared by the Medical Scientific Advisory Group of the Myeloma Foundation of Australia. It is hoped that these guidelines will assist clinicians in better understanding and optimising the management of this difficult disease.

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.

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/m2; Day (D) 1, 4, 8, 11] and three 35 day cycles; Bz (1.3 mg/m2; 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/m2) 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. Am. J. Hematol. 90:E86–E91, 2015.

Prognostic nomogram for diffuse large B‐cell lymphoma incorporating the International Prognostic Index with interim‐positron emission tomography findings

Results from interim‐positron emission tomography (PET) studies in diffuse large B‐cell lymphoma (DLBCL) patients are varied. We evaluated the prognostic value of interim‐PET in our centre. To improve concordance, interim‐PET was combined with the International Prognostic Index (IPI).

The utility of an automated electronic system to monitor and audit transfusion practice

Background and Objectives  Transfusion laboratories with transfusion committees have a responsibility to monitor transfusion practice and generate improvements in clinical decision‐making and red cell usage. However, this can be problematic and expensive because data cannot be readily extracted from most laboratory information systems. To overcome this problem, we developed and introduced a system to electronically extract and collate extensive amounts of data from two laboratory information systems and to link it with ICD10 clinical codes in a new database using standard information technology.