Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?

The drugs cyclosporine A (CsA) and tacrolimus (FK506) revolutionized organ transplantation. Both compounds are still widely used in the clinic as well as for basic research, even though they have dramatic side effects and modulate other pathways than calcineurin-NFATc, too. To answer the major open question - whether the adverse side effects are secondary to the actions of the drugs on the calcineurin-NFATc pathway - alternative inhibitors were developed. Ideal inhibitors should discriminate between the inhibition of (i) calcineurin and peptidyl-prolyl cis-trans isomerases (PPIases; the matchmaker proteins of CsA and FK506), (ii) calcineurin and the other Ser/Thr protein phosphatases, and (iii) NFATc and other transcription factors. In this review we summarize the current knowledge about novel inhibitors, synthesized or identified in the last decades, and focus on their mode of action, specificity, and biological effects

Treatment Change as a Predictor of Outcome among Patients with Classic Chronic Graft-versus-Host Disease

We analyzed outcomes for 668 patients who had systemic treatment for chronic graft-versus-host disease (cGVHD) to assess the utility of early treatment change for exacerbation of cGVHD as a surrogate for survival endpoints in clinical trials. Fifty-six percent of patients had treatment change within 2 years after diagnosis of cGVHD. The median onset of treatment change was 4.4 months (range: 0.3-50 months). The cumulative incidence of nonrelapse mortality (NRM) at 2 years was 16%, and overall survival (OS) at 2 years was 74%. In time-dependent Cox models, treatment change was associated with an increase in risk of NRM (hazard ratio, 2.53; 95% confidence interval, 1.7-3.7; P < .0001). The hazard ratio was attenuated by 6% per month of delay in treatment change. Our results confirm that exacerbation of cGVHD is associated with an increased risk of NRM and with decreased OS, but the strength of this association is not large enough to allow the use of early exacerbation as a surrogate for survival endpoints in clinical trials. Other measures of clinical benefit, such as response, will need to be developed as endpoints in phase 11 trials for patients with cGVHD.141213801384National Institutes of Health [CA 118953-01A1, CA78902]Department of Health and Human ServicesNational Institutes of Health [CA 118953-01A1, CA78902

Dose-adapted post-transplant cyclophosphamide for HLA-haploidentical transplantation in Fanconi anemia

We developed a haploidentical transplantation protocol with post-transplant cyclophosphamide (CY) for in vivo T-cell depletion using a novel adapted-dosing schedule (25 mg/kg on days +3 and +4) for Fanconi Anemia. With median follow-up of 3 years (range, 37 days to 6.2 years), all six patients engrafted. Two patients with multiple co-morbidities and late referrals to transplant died from sepsis (n=2) and chronic graft-versus-host disease (GVHD) (n=1). Four patients without pre-existing co-morbidities and early transplant referrals are alive with 100% donor chimerism and excellent performance status. We conclude that modulated-dosing post-transplant CY is effective in vivo T-cell depletion to promote full donor engraftment in patients with Fanconi anemia