Pharmacodynamic monitoring of calcineurin inhibitor therapy: Is there a clinical benefit?

17 Background: The advent of checkpoint inhibitor therapy (CIT) has dramatically changed the oncology landscape, but is associated with significant costs. A positive randomized clinical trial (RCT) may not translate to meaningful outcomes for patients. The American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) have developed frameworks to quantify the value of cancer treatment. We applied these frameworks to RCTs involving CIT in order to explore the relationship between trial outcomes and magnitude of clinical benefit. Methods: A literature search was conducted to identify CIT RCTs. Data extracted included study characteristics, pre-specified estimated hazard ratios (eHR) and observed HR (oHR). ASCO Value Framework version 2016 and ESMO Magnitude of Clinical Benefit (MCB) scale v1.1 were applied to each publication by 2 authors independently. Results: 30 RCTs (3 adjuvant, and 27 advanced setting) using CIT were identified between January 2010- October 2018. The majority of trials were in lung cancer (37%) and melanoma (36%). The eHR was 0.71±0.06 (range: 0.55-0.78), and oHR was 0.76±0.15 (range: 0.49 – 1.11). 54% RCTs did not achieve eHR, with a difference of 0.16±0.12 (range: 0.01 – 0.41). ASCO framework scores ranged -24.0 to 71.3, far below the maximum potential score of 180. 18 RCTs formed the basis for FDA approvals. The mean ASCO framework score was 45.6 ± 16.6 (range: 14.4 - 71.3) for FDA approved indications, and 14.0 ± 18.4 (range: -24 – 49) for non-FDA approvals (p < 0.001). All FDA approvals scored grade 4 or 5 on the ESMO MCB scale, indicating a meaningful clinical benefit. Many non-FDA approved RCTs did not receive an MCB grade as they were negative trials. There was no difference in the ASCO framework scores between MCB grade 4 and 5 RCTs. 3 adjuvant RCTs had an ASCO framework score ranging from 20.5 to 38.7 despite an MCB Grade A. Conclusions: Many trials did not meet the pre-specified eHR. FDA approval had statistically significantly higher NHB scores than non-FDA approvals, and they were deemed to have a meaningful clinical benefit according to the ESMO MCB scale. ASCO framework scores may require re-calibration since the highest score achieved in CIT RCTs was only 40% of the maximum score.

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Everolimus in Heart Transplantation: An Update

Journal of Transplantation ◽

10.1155/2013/683964 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 17

Author(s):

Stephan W. Hirt ◽

Christoph Bara ◽

Markus J. Barten ◽

Tobias Deuse ◽

Andreas O. Doesch ◽

...

Keyword(s):

Wound Healing ◽

Heart Transplantation ◽

Heart Transplant ◽

Calcineurin Inhibitor ◽

De Novo ◽

Relevant Information ◽

Evidence Base ◽

Left Ventricular ◽

Inhibitor Therapy ◽

Transplant Patients

The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, allde novoheart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.

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Treatment Outcomes of Topical Calcineurin Inhibitor Therapy for Patients With Vitiligo

JAMA Dermatology ◽

10.1001/jamadermatol.2019.0696 ◽

2019 ◽

Vol 155 (8) ◽

pp. 929 ◽

Cited By ~ 10

Author(s):

Ji Hae Lee ◽

Hyuck Sun Kwon ◽

Han Mi Jung ◽

Hyunyong Lee ◽

Gyong Moon Kim ◽

...

Keyword(s):

Treatment Outcomes ◽

Calcineurin Inhibitor ◽

Inhibitor Therapy ◽

Topical Calcineurin Inhibitor

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P0126RENAL TRANSPLANT PATIENTS UNDER CALCINEURIN INHIBITOR THERAPY RAPIDLY ACQUIRE AN ABERRANT LYSOSOMAL LESION IN PROXIMAL TUBULAR CELLS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0126 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Benjamin Vervaet ◽

Nika Kojc ◽

Cynthia Nast ◽

Gerd Schreurs ◽

Patrick D'Haese ◽

...

Keyword(s):

Renal Transplantation ◽

Renal Transplant ◽

Renal Allograft ◽

Calcineurin Inhibitor ◽

Deceased Donor ◽

Inhibitor Therapy ◽

Transplant Patients ◽

Protocol Biopsies ◽

Proximal Tubular ◽

Renal Transplant Patients

Abstract Background and Aims Calcineurin inhibitor therapy has changed the field of (renal) transplantation by considerably prolonging graft survival. Yet, all immunosuppressive calcineurin inhibitors are nephrotoxic that eventually contribute to complete scarring of the renal allograft. In renal biopsy analysis many histopathological features have been considered indicative of CNI nephrotoxicity, i.e. striped fibrosis, vascular hyalinosis, isometric tubular vacuolization, glomerulosclerosis, cellular infiltration and tubular atrophy, however, all are rather aspecific and can be secondary to many other causes. During the course of evaluating the specificity of a recently discovered proximal epithelial lysosomal lesion (i.e. multiple enlarged (>1,2µm) dysmorphic lysosomes containing dispersed electron dense non-membrane bound aggregates) in patients with Chronic Interstitial Nephropathy in Agricultural Communities (CINAC), we observed it to be present in renal transplant patients treated with cyclosporine or tacrolimus. Here, we test the hypothesis whether this lysosomal lesion is acquired during CNI therapy. Method A retrospective transmission electron microscopic analysis was performed to evaluate the presence of the typical lysosomal lesion on the following biopsies from renal transplant patients: 20 deceased donor implantation biopsies; 5 living donor implantation biopsies. For another 10 additional deceased donor renal allograft recipients, we evaluated implantation as well as protocol biopsies taken after 6 and 12 months of CNI treatment that started immediately after transplantation. Also included were 24 indication biopsies of CNI treated renal transplants. Results Of the total set of implantation biopsies (n=35), 2 (6%) were positive for the aberrant lysosomal phenotype on EM, whereas in the protocol and indication biopsies prevalence of the lesion was considerably higher ranging between 56% (protocol) and 80% (indication) of cases. Conclusion CNI therapy is associated with the fairly rapid appearance of a particular proximal tubular lysosomal phenotype observable on EM, that was not (or rarely) present at implantation. Whether this lesion is related to CNI toxicity and indicative for the outcome for the graft and/or patient survival after renal transplantation has to be investigated in a prospective trial.

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