Research Spotlight

Shadman, M., D. G. Maloney, B. Storer, B. M. Sandmaier, T. R. Chauncey, N. Smedegaard Andersen, D. Niederwieser, J. Shizuru, B. Bruno, M. A. Pulsipher, R. T. Maziarz, E. D. Agura, P. Hari, A. A. Langston, M. B. Maris, P. A. McSweeney, R. Storb and M. L. Sorror (2020). “Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience.” Bone Marrow Transplant 55(1): 172-181.

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Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.

Serper, M. and S. K. Asrani (2019). “Liver transplantation and chronic disease management: Moving beyond patient and graft survival.” Am J Transplant Dec 17. [Epub ahead of print].

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With advances in surgical techniques, multidisciplinary care and immunosuppression, patient and graft survival continue to improve in liver transplantation (LT). Excellent patient and graft survival have translated into an aging liver transplant recipient (LTRs) cohort that resembles a general chronic disease population. LTRs are becoming more medically complex related to LT indication (e.g. non-alcoholic fatty liver disease) and with increased prevalence of relevant chronic conditions such as chronic kidney disease.(Excerpt from text of this editorial.)

Sengupta, A., S. Zaid, N. Kamioka, J. Terre, M. Miyasaka, S. A. Hirji, M. Hensey, N. Geloo, G. Petrossian, N. Robinson, E. Sarin, L. Ryan, S. H. Yoon, C. W. Tan, O. K. Khalique, S. K. Kodali, T. Kaneko, P. B. Shah, S. C. Wong, A. Salemi, K. Sharma, J. A. Kozina, M. A. Szerlip, C. W. Don, S. Gafoor, M. Zhang, Z. Newhart, S. R. Kapadia, S. L. Mick, A. Krishnaswamy, A. Kini, H. Ahmad, S. L. Lansman, M. J. Mack, J. G. Webb, V. Babaliaros, V. H. Thourani, R. R. Makkar, M. B. Leon, I. George and G. H. L. Tang (2019). “Mid-Term Outcomes of Transcatheter Aortic Valve Replacement in Extremely Large Annuli With Edwards SAPIEN 3 Valve.” JACC Cardiovasc Interv Dec 18. [Epub ahead of print].

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OBJECTIVES: The aim of this study was to report the 1-year results of transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN 3 (S3) valve in extremely large annuli. BACKGROUND: Favorable 30-day outcomes of S3 TAVR in annuli >683 mm(2) have previously been reported. Pacemaker implantation rates were acceptable, and a larger left ventricular outflow tract and more eccentric annular anatomy were associated with increasing paravalvular leak. METHODS: From December 2013 to December 2018, 105 patients across 15 centers with mean area 721.3 +/- 36.1 mm(2) (range: 683.5 to 852.0 mm(2)) underwent TAVR using an S3 device. Clinical, anatomic, and procedural characteristics were analyzed. One-year survival and echocardiographic follow-up were reached in 94.3% and 82.1% of patients, respectively. Valve Academic Research Consortium-2 30-day and 1-year outcomes were reported. RESULTS: The mean age was 76.9 +/- 10.4 years, and Society of Thoracic Surgeons predicted risk score averaged 5.2 +/- 3.4%. One-year overall mortality and stroke rates were 18.2% and 2.4%, respectively. Quality-of-life index improved from baseline to 30 days and at 1 year (p < 0.001 for both). Mild paravalvular aortic regurgitation occurred in 21.7% of patients, while moderate or greater paravalvular aortic regurgitation occurred in 4.3%. Mild and moderate or severe transvalvular aortic regurgitation occurred in 11.6% and 0%, respectively. Valve gradients remained stable at 1 year. CONCLUSIONS: S3 TAVR in annular areas >683 mm(2) is feasible, with favorable mid-term outcomes.

Schinstock, C. A., R. B. Mannon, K. Budde, A. S. Chong, M. Haas, S. Knechtle, C. Lefaucheur, R. A. Montgomery, P. Nickerson, S. G. Tullius, C. Ahn, M. Askar, M. Crespo, S. J. Chadban, S. Feng, S. C. Jordan, K. Man, M. Mengel, R. E. Morris, I. O’Doherty, B. H. Ozdemir, D. Seron, A. R. Tambur, K. Tanabe, J. L. Taupin and P. J. O’Connell (2019). “Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: the 2019 Expert Consensus From the Transplant Society Working Group.” Transplantation Dec 27. [Epub ahead of print].

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With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low level evidence. The number of prospective randomized trials for the treatment of AMR is small and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated.At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes and outcomes were discussed. The evidence for different treatments was reviewed and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented.Whilst it was agreed that the aims of treatment are to preserve renal function, reduce histological injury and reduce the titer of donor specific antibody (DSA), there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

Schiller, L. R. (2020). “Good News about BAD.” Clin Gastroenterol Hepatol 18(1): 45-47.

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In this issue the Canadian Association of Gastroenterology (CAG) presents its official guidelines for the management of bile acid diarrhea (BAD). The American Gastroenterological Association (AGA) recently published its clinical guidelines for the laboratory diagnosis of chronic diarrhea, and the British Society of Gastroenterology (BSG) published its guidelines for investigation of chronic diarrhea in 2018. All 3 guidelines and the reviews that present the underlying evidence highlight the importance of bile acid malabsorption (BAM) as a potential mechanism for chronic diarrhea. The concept that bile acid entering the colon might cause secretory diarrhea goes back more than 50 years. In 1967 Alan F. Hofmann, then at the Mayo Clinic, synthesized what was known about the physiology of bile acids with several clinical reports of diarrhea occurring in patients who had evidence of BAM into the concept of “cholegenic diarrhea” or “cholerheic enteropathy.” These patients had several features in common, including ileal disease or resection, diarrhea, steatorrhea, and evidence of accelerated bile acid turnover. Bile acids were known to be cathartic, and Hofmann postulated that the excess bile acid in the colon inhibited water transport and caused diarrhea through that mechanism . . . [R]esearch during the last 50 years has established that BAD is a real mechanism for chronic diarrhea, not just with ileal disease or resection but in patients with functional diarrhea or IBS-D. It is incumbent on physicians now to consider this diagnosis in patients with chronic diarrhea. Whether one tests and then treats or just empirically treats, we will do a great service for many of our patients with chronic diarrhea by addressing this mechanism of disease. (Excerpts from text, p. 45-46, summarizing Sadowski D.C. et al: Canadian Association of Gastroenterology clinical practice guideline on the management of bile acid diarrhea; no abstract available.)