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Case-cohort design in hematopoietic cell transplant studies.

ABSTRACT:

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Imagine you and your colleagues have done 1000 transplants in persons with acute myeloid leukaemia (AML) in 1st remission. 5 percent of the 20 percent of recipients relapsing posttransplant have an isolated central nervous system relapse. You are curious and want to know whether there is anything special about this 5 percent, specifically whether this risk corelates with any pretransplant clinical and laboratory co-variates. You have extensive clinical data and some typical laboratory data on all 1000 but you suspect the culprit is mutation topography. What to do? Fortunately you have bio-banked DNA from the 1000. If resources and monies are not limiting you can do targeted or next generation sequencing on all 1000 DNA samples and off you go. However, most of us lack unlimited resources and monies. How can you sensibly and efficiently tackle this research problem? The answer is a case-cohort design study. In the typescript which follows Profs. Cai and Kim explain how to accomplish this. If you follow their advice you may need only to analyze samples from < 300 recipients rather than 1000 to test your hypothesis. They explain how to design such a study and provide references to estimate sample size.Sadly, their typescript will not tell you how to get funding for the study, whish poor devil who will have to write the protocol, worse, who will shepherd it though endless committees for approval and the like. Help on these issues is outside the scope of our statistics series. In this context we suggest advice from Woody Allen's article in the New Yorker: The Kugelmass Episode (April 24, 1977). When Prof. Kugelmass (English, City College) tells his analyst Dr. Mandel he has fallen in love with Emma Bovary who died of arsenic poisoning near Rouen, France 120 years earlier the analyst says: After all, I'm an analyst, not a magician. Kugelmass' reply: Then perhaps what I need is a magician and is off to Coney Island to find one. Good luck, the magician may still be there! (Note: This typescript is R-rated. It contains an equation.)Robert Peter Gale, Imperial College London, and Mei-Jie Zhang, Medical College of Wisconsin and CIBMTR.

SUBMITTER: Cai J

PROVIDER: S-EPMC8738130 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Autoimmune cytopenias (AICs) are potentially life-threatening complications following hematopoietic cell transplantation (HCT), yet little is understood about the mechanism by which they develop. We hypothesized that discordant B cell and T cell recovery is associated with AICs in transplant patients, and that this might differ based on transplant indication. Methods: In this case control study of children who underwent HCT at our institution, we evaluated the clinical and transplant characteristics of subjects who developed AICs compared to a control group matched by transplant indication and donor type. In cases, we analyzed the state of immune reconstitution, including B cell recovery, T cell recovery, and chimerism, immediately prior to AIC onset. Subjects were stratified by primary indication for transplant as malignancy (n = 7), primary immune deficiency (PID, n = 9) or other non-malignant disease (n = 4). We then described the treatment and outcomes for 20 subjects who developed AICs. Results: In our cohort, cases were older than controls, were more likely to receive a myeloablative conditioning regimen and had a significantly lower prevalence of chronic GVHD. There were distinct differences in the state of immune recovery based on transplant indication. None of the patients (0/7) transplanted for primary malignancy had T cell recovery at AIC onset compared to 71% (5/7) of patients with PID and 33% (1/3) of patients with non-malignant disease. The subset of patients with PID and non-malignant disease who achieved T cell reconstitution (6/6) prior to AIC onset, all demonstrated mixed or split chimerism. Subjects with AIHA or multi-lineage cytopenias had particularly refractory courses with poor treatment response to IVIG, steroids, and rituximab. Conclusions: These results highlight the heterogeneity of AICs in this population and suggest that multiple mechanisms may contribute to the development of post-transplant AICs. Patients with full donor chimerism may have early B cell recovery without proper T cell regulation, while patients with mixed or split donor chimerism may have residual host B or plasma cells making antibodies against donor blood cells. A prospective, multi-center trial is needed to develop personalized treatment approaches that target the immune dysregulation present and improve outcomes in patients with post-transplant AICs.

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Case-cohort design in hematopoietic cell transplant studies.

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