A New Standard in Graft-versus-Host Disease Prophylaxis? An Introduction to Blood and Marrow Transplant Clinical Trials Network 1703

Abstract Q-learning is a method of reinforcement learning that employs backwards stagewise estimation to identify sequences of actions that maximize some long-term reward. The method can be applied to sequential multiple-assignment randomized trials to develop personalized adaptive treatment strategies (ATSs)—longitudinal practice guidelines highly tailored to time-varying attributes of individual patients. Sometimes, the basis for choosing which ATSs to include in a sequential multiple-assignment randomized trial (or randomized controlled trial) may be inadequate. Nonrandomized data sources may inform the initial design of ATSs, which could later be prospectively validated. In this paper, we illustrate challenges involved in using nonrandomized data for this purpose with a case study from the Center for International Blood and Marrow Transplant Research registry (1995–2007) aimed at 1) determining whether the sequence of therapeutic classes used in graft-versus-host disease prophylaxis and in refractory graft-versus-host disease is associated with improved survival and 2) identifying donor and patient factors with which to guide individualized immunosuppressant selections over time. We discuss how to communicate the potential benefit derived from following an ATS at the population and subgroup levels and how to evaluate its robustness to modeling assumptions. This worked example may serve as a model for developing ATSs from registries and cohorts in oncology and other fields requiring sequential treatment decisions.

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Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study

Blood ◽

10.1182/blood-2009-05-224840 ◽

2009 ◽

Vol 114 (20) ◽

pp. 4354-4360 ◽

Cited By ~ 32

Author(s):

David A. Jacobsohn ◽

Andrew L. Gilman ◽

Alfred Rademaker ◽

Brittan Browning ◽

Michael Grimley ◽

...

Keyword(s):

Confidence Interval ◽

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Joint Damage ◽

Normal Growth ◽

Marrow Transplant ◽

Host Disease ◽

Graft Versus Host ◽

Blood And Marrow Transplant ◽

Steroid Refractory

Abstract There is no standard therapy for steroid-refractory chronic graft-versus-host disease (GVHD). This problem is particularly daunting in children with chronic GVHD, whereby the effects of the disease and its treatment may impair normal growth and development. Children are also particularly vulnerable to failure and/or toxicity of therapy; for example, joint contractures or joint damage may result in life-long disability. The Pediatric Blood and Marrow Transplant Consortium performed a phase 2 trial of pentostatin for steroid-refractory chronic GVHD in 51 children (median age, 9.8 years) from 24 institutions. Overall response was 53% (95% confidence interval, 40%-64%), with a response of 59% (95% confidence interval, 42%-75%) in sclerosis. Thirteen subjects (25%) had toxicity requiring them to stop pentostatin. The drug had a significant steroid-sparing effect in those that responded. A trend was also observed toward increased survival at 3 years in responders versus nonresponders (69% vs 50%; P = .06). The intravenous administration of the drug ensures compliance in a patient group in which oral therapy is difficult to monitor. Pentostatin has activity in refractory chronic GVHD in children, and future studies, including treatment of children newly diagnosed with high-risk chronic GVHD, are warranted. The trial was registered at www.Clinicaltrials.gov as #NCT00144430.

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