Stephanie J. Lee

INTRODUCTION Approximately 4,000 patients have allogeneic hematopoietic cell transplantation (HCT) annually throughout the world, and 40% to 60% of those who survive beyond the first 3 months develop chronic graft versus host disease (GVHD). Even though nearly 1,500 people develop chronic GVHD each year, no drugs have been approved for its treatment. New therapies are needed, since chronic GVHD has major adverse effects on long-term morbidity and late nonrelapse mortality after allogeneic HCT. The complexity of chronic GVHD, however, has made it difficult to design, conduct, and analyze clinical trials involving these patients, even when promising treatment options are available. The National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease clarified organized and codified a number of issues in this disease that are vital for successful drug development, and material in this chapter draws heavily from those recommendations. For design of a successful clinical trial in this complex disorder, three critically important questions must be considered (1) who will be enrolled in the trial, (2) how will subjects be treated, and (3) how will results be evaluated? The following sections address the selection of participants, treatment methods, data collection, primary and secondary endpoints, biostatistical considerations, and overall assessment of safety and efficacy, as applied to clinical trials of treatments for chronic GVHD. SELECTION OF PARTICIPANTS General Considerations The prestudy evaluation is critical to defining the patient population of the clinical trial.

Previous studies of quality of life (QOL) note compromised QOL after stem cell transplantation (HCT), but do not usually consider the impact of pre-transplantation deficits in QOL on post transplantation outcomes. To examine these associations, multivariate models for six self-reported QOL outcomes at 6 and 12 months were constructed, considering pre-transplantation clinical status and QOL, and subsequent clinical events. Outcomes measured overall subjective health, social functioning and agreement with statements such as 'Life has returned to normal.' Of 320 autologous and allogeneic HCT recipients who completed pre-transplantation surveys, 197 completed 6-month surveys and 175 completed 12-month surveys. Pre-transplantation overall health and mental health were independent predictors of all QOL outcomes at 6 months. Baseline physical health was also predictive of four of six outcomes at 12 months. In contrast, disease risk was predictive only of enjoying normal activities at 6 months. Relapse and chronic graft-versus-host disease were associated with poorer QOL. In conclusion, pre-transplantation self-reported physical and mental health are more strongly associated with QOL after HCT than commonly noted baseline clinical predictors such as age and disease risk. Measurement of baseline QOL can help place the effects of the transplantation procedure in context.

Despite improvements in the practice of allogeneic hematopoietic stem cell transplantation (HCT) over the last 25 years, chronic graft-versus-host disease (GVHD) remains a substantial problem with little change in the incidence, morbidity, and mortality of this complication. In fact, with increased use of peripheral blood, transplantation of older patients, and less immediate transplantation-related mortality, the prevalence of chronic GVHD may increase. One of the difficulties in combating chronic GVHD is a lack of understanding about the pathophysiology of the syndrome. Inherent difficulties in conducting human clinical trials also contribute to the lack of meaningful progress. This review covers potential new approaches to the prevention and treatment of chronic GVHD.

The diagnosis and treatment of cancer is often associated with high levels of psychosocial distress, yet exploration of these issues is rarely included in routine oncologic care. We conducted a pilot study to evaluate the feasibility of screening for psychosocial distress after autologous and allogeneic stem cell transplantation. A total of 80 adults were enrolled in Boston, MA, USA. Subjects completed self-administered assessments prior to hospital admission, at their first clinic visit after hospital discharge, and at 100 days post transplant. Assessments included validated instruments assessing psychosocial distress and quality of life (QOL). Elevated levels of anxiety and/or depression were detected in 55% of those providing pre-transplant assessments and were associated with compromised QOL. Post transplant screening was successfully performed in 69% of subjects and identified that 44% had symptoms of depression, anxiety or post traumatic stress disorder. Pre-transplant distress was associated with detection of distress after transplantation (81 vs 13%, P<0.0001). In summary, we detected high levels of distress in transplant patients using self-administered tools. Pre-transplant distress appears to be highly predictive of distress post transplant and is a feasible marker to target screening and intervention programs.

Studies investigating quality of life (QOL) after hematopoietic stem cell transplantation demonstrate the spectrum of QOL outcomes awaiting survivors. Nevertheless, how transplantation physicians interpret and apply QOL information to clinical practice is poorly understood. We conducted a cross-sectional survey of transplantation physicians to address these issues and received 180 (24%) responses from physicians in 29 countries. Seventy-two percent reported that their patients are willing to accept poor QOL for a small chance of cure. Only 28% said that QOL considerations "often" or "almost all the time" enter into patients' decisions about transplantation. This contrasted with physicians' reported attention to QOL in their discussions with patients. Although 53% of physicians reported using QOL results to modify practice, 55% would be more likely to use these data if they were more understandable. To ensure generalizability of the results, a validation sample was randomly selected, and these 85 physicians (response rate, 76%) confirmed the findings of the original survey. Given the extensive data regarding posttransplantation QOL, resources should be devoted to exploring how patients and physicians use these data in clinical care and in devising methods to ensure that QOL results are interpretable and relevant to patients and physicians.

Fludarabine and rituximab combination therapies in chronic lymphocytic leukemia (CLL) have yielded promising early results, but no comparative efficacy data relative to standard fludarabine treatment regimens have been reported. To assess the effect of the addition of rituximab to fludarabine therapy, we retrospectively compared the treatment outcome of patients with similar clinical characteristics enrolled on 2 multicenter clinical trials performed by the Cancer and Leukemia Group B and the US Intergroup that used fludarabine and rituximab (CALGB 9712, n = 104) or fludarabine (CALGB 9011, n = 178). In multivariate analyses controlling for pretreatment characteristics, the patients receiving fludarabine and rituximab had a significantly better progression-free survival (PFS; P < .0001) and overall survival (OS; P = .0006) than patients receiving fludarabine therapy. Two-year PFS probabilities were 0.67 versus 0.45, and 2-year OS probabilities were 0.93 versus 0.81. Infectious toxicity was similar between the 2 treatment approaches. These comparative data are retrospective and could be confounded by differences in supportive care or dissimilar enrollment of genetic subsets on each trial. Confirmation of these findings will require a prospective randomized trial comparing fludarabine and rituximab to fludarabine.

Multiple myeloma is an incurable malignancy of plasma cells. People with multiple myeloma may experience a variety of disease-related symptoms because of bony destruction, bone marrow infiltration, renal failure, immunodeficiency, and the psychosocial burden of a cancer diagnosis. Exciting new therapies and treatment approaches are becoming available but often bring unwanted side effects. Because the goal of treating multiple myeloma is still symptom palliation and prolongation of life rather than cure, it is important to consider the tradeoffs between treatment toxicity and disease control when caring for the person with myeloma. The traditional end-points of clinical trials are disease response, prolongation of disease-free and overall survival, and other objective criteria. However, subjective patient-reported measures, such as symptoms, quality of life, and functional status, are increasingly recognized as important dimensions by which to judge the impact of cancer and its treatment. In multiple myeloma, several patient-reported measures have been used to enrich our understanding of the disease's impact on patients' lives and the risks and benefits of specific treatments.

T-cell depletion (TCD) and immunosuppressive medications (ISTs) are 2 methods used for graft-versus-host disease (GVHD) prophylaxis in unrelated donor (URD) transplantation. However, comparisons of the clinical outcomes including quality of life and direct medical costs associated with each type of procedure have not been reported. We reviewed 48 TCD and 98 IST procedures performed from 1/1/97 to 12/31/99 at the Dana-Farber Cancer Institute, Boston, MA. With a median follow-up of 1.5 years for survivors, no differences were seen in relapse, acute GVHD, and overall survival between TCD and IST patients. Multivariable Cox modeling showed that age of 50 years or less (P = .002) and low-risk disease (P = .001) predicted survival, but method of GVHD prophylaxis (P = .6) and degree of human leukocyte antigen (HLA) matching (P = .8) did not. A subset of patients (53%) completed quality of life surveys prior to and at 6 and 12 months after transplantation; participation in the quality of life study was not associated with clinical characteristics and outcomes. No differences were seen in quality of life scores prior to transplantation, and changes over time were similar between groups. Costs ($113 000 vs $155 000, P < .0001) and total hospital days (34 vs 46, P = .0006) were significantly lower for patients undergoing TCD procedures. As prospective, randomized studies comparing methods of GVHD prophylaxis are performed, assessment of quality of life and costs should be included to fully understand the overall impact of each intervention.