Steroid-free Regimen Research Articles

343.8: The short- and long-term outcomes of steroid-free regimen in liver transplantation.

343.8: The short- and long-term outcomes of steroid-free regimen in liver transplantation.

Drug repurposing for glomerular diseases: an underutilized resource.

Drug repurposing in glomerular disease can deliver opportunities for steroid-free regimens, enable personalized multi-target options for resistant or relapsing disease and enhance treatment options for understudied populations (for example, children) and in resource-limited settings. Identification of drug-repurposing candidates can be data driven, which utilizes existing data on disease pathobiology, drug features and clinical outcomes, or experimental, which involves high-throughput drug screens. Information from databases of approved drugs, clinical trials and PubMed registries suggests that at least 96 drugs on the market cover 49 targets with immunosuppressive potential that could be candidates for drug repurposing in glomerular disease. Furthermore, evidence to support drug repurposing is available for 191 immune drug target-glomerular disease pairs. Non-immunological drug repurposing includes strategies to reduce haemodynamic overload, podocyte injury and kidney fibrosis. Recommended strategies to expand drug-repurposing capacity in glomerular disease include enriching drug databases with glomeruli-specific information, enhancing the accessibility of primary clinical trial data, biomarker discovery to improve participant selection into clinical trials and improve surrogate outcomes and initiatives to reduce patent, regulatory and organizational hurdles.

A comparative analysis of kidney allograft outcomes in steroid use versus steroid discontinuation after basiliximab and ATG induction: AUNOS database study.

The relative safety and efficacy of early steroid withdrawal in kidney transplant patients after basiliximab compared to anti-thymocyte globulin (ATG) induction therapy is unknown. We aimed to compare kidney allograft outcomes in steroid use versus steroid discontinuation after basiliximab and ATG induction from the United Network for Organ Sharing (UNOS) database. We conducted a retrospective cohort analysis of the UNOS database and included first kidney transplant recipients who received ATG or basiliximab induction therapy. We compared graft and patient outcomes in those who received steroid maintenance and those who were discharged off steroids. Of 106,061 patients, 25,344 (86.7%) received basiliximab induction and were maintained on steroids (B-Sm), and 3,880 (13.3%) were on a steroid-free regimen (B-Sf). Graft failure rate was significantly higher in the B-Sf compared to B-Sm at 1-year (4.1 vs. 1.8%, p<0.001), 3-year (6.0 vs. 4.3%, p<0.001) and 5-year follow-up (7.7 vs. 6.4%, p=0.0004). The mortality rate was significantly higher in B-Sf at 1-year (3.3 vs. 2.4%, p=0.0005), 3-year (7.6 vs. 5.5%, p<0.001) and 5-year follow-up (11.5 vs. 8.8%, p<0.001) when compared to the B-Sm. 76,837 recipients received ATG induction therapy, 51,745 (72.4%) were on steroid maintenance therapy (A-Sm) and 25,092 (32.6%) were on a steroid-free regimen (A-Sf). The graft failure rate was significantly higher in A-Sf compared to A-Sm at 1-year follow-up (2.6 vs. 2.3%, p=0.0006), however, there was no difference at 3-year (5.0 vs. 5.0%, p=0.53) or 5-year follow-up (7.2 vs. 8.1%, p=0.17). There was no difference in mortality rates between A-Sf vs. A-Sm at 1 year (2.5 vs. 2.4%, p=0.98) and at 3 years (5.5 vs. 5.4%, p=0.45), respectively. Patients who were maintained on steroids after basiliximab induction had better 5-year allograft survival and patient survival compared to those who were not maintained on steroids. However, steroid maintenance conferred no additional benefit after ATG induction and was associated with higher mortality.

Patient-reported treatment-related symptoms and use of the PRO-CTCAE for multiple myeloma clinical trials: A qualitative interview study.

e19516 Background: Therapeutic regimens for multiple myeloma (MM) involve multiple pharmacological agents, including steroids. Many cause treatment-related symptoms that add to patient burden or may trigger treatment cessation. This study gathered qualitative data about the patient experience with MM treatments, including regimens with steroids. Findings were summarized and compared to the Patient Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), to assess its comprehensiveness and relevance in MM clinical trials. Methods: Individual, semi-structured interviews were conducted virtually with a diverse sample of 16 US-based, English-speaking adults (38% male, 25% Black, 13% Hispanic) to explore their experiences with MM and treatments, including perspectives on steroids and potential benefits of steroid-sparing regimens. Content analysis was used to summarize and compare terminology participants used to describe their experiences with treatments. Results: Participants reported a diverse set of treatment-related symptoms impacting their overall experience, indicating the importance of assessing regimen tolerability in clinical trials. Steroids were linked to increased energy that interfered with sleep or functioning, irritability, taste changes, weight gain, increased appetite, and cognitive symptoms like brain fog. Participants reported that most symptoms were tolerable, but they would prefer to avoid steroids if treatment benefits did not diminish. Many reported symptoms were included in the PRO-CTCAE items (see Table), but several symptoms related to regimens with steroids are not covered: excess energy, bitter/metallic taste, taste sensitivity, brittle nails, irritability, hunger/increased appetite, and muscle weakness. Conclusions: MM patients experience a range of treatment-related symptoms, many of which impact their quality of life. If given the option, patients would prefer a steroid-free regimen if there was proven clinical benefit. While the PRO-CTCAE covers most of the treatment-related symptoms, proving to be an option for multiple myeloma clinical trials, additional PRO instruments may be needed to cover specific gaps in the PRO-CTCAE item library content coverage. [Table: see text]

NAVIGATING THE UNCHARTED WATERS: MANAGING CONCURRENT CYTOMEGALOVIRUS MYOCARDITIS AND ALLOGRAFT REJECTION IN A PATIENT WITH HEART TRANSPLANTATION

Abstract A 49–year–old female with hypertrophic cardiomyopathy underwent orthotopic heart transplantation. She was cytomegalovirus(CMV)–positive and received a heart from a CMV–negative donor, so prophylaptic therapy was not administered. Initial immunosuppression included cyclosporine and induction with Basiliximab in a steroid–free regimen. The first routine biopsy (EMB) showed mild focal cellular rejection (grade 1A) and C4d positivity with granular aspect. Mycophenolate mofetil (MMF) was added. The second EMB, 7 days later, showed mild diffuse cellular rejection (grade 1B) and diffuse C4d positivity. Anti–HLA donor–specific antibodies (DSA) had increased anti–B13 levels (MFI=21298) compared to pre–transplantation tests. Echocardiography showed a normal ejection fraction (LVEF) and mild concentric hypertrophy (LVH). Treatment included pulse methylprednisolone therapy (1 g/day for three days) followed by oral prednisone with a slow tapering regimen, and increased MMF. CMV count weekly monitored was negative. The next two EMBs performed one week apart from each other described a grade 1A mild focal pattern while the 5th EMB (1 month and 2 weeks post–transplant) showed a grade 1A rejection together with focal mild fibrosis and eosinophils, so we replaced cyclosporine with tacrolimus, increased MMF and prednisone. At this time, the patient had no overt clinical signs of CMV infection but a CMV–PCR of 100847 IU/mL so ganciclovir 5 mg/Kg bid was started and CMV–PCR decreased to 42308 IU/mL after 1 week. Subsequently, she developed sinus tachycardia, mildly reduced LVEF, moderate LVH and diastolic dysfunction. Troponin was elevated. A new EMB revealed interstitial edema, diffuse ischemic injury, and eosinophilic inclusions suggesting CMV myocarditis. Treatment involved down–titrating MMF and Prednisone, administering standard intravenous immunoglobulin (IVIG), and high–dose Ganciclovir (7.5 mg/Kg bid). Leukopenia subsequently led to Ganciclovir down–titration. In the next days, the patient improved, CMV cleared, and leukocyte count normalized. She was discharged on Tacrolimus, MMF, Prednisone and Valganciclovir. Subsequent tests showed no cellular or antibody–mediated rejection (AMR), no CMV inclusions, recovered cardiac function, and markedly reduced anti–B13 DSA (MFI 3000). This case raises some concerns: in this context, the use of IVIG in the treatment of CMV infection and AMR appears reasonable, in support of antiviral and immunosuppressive therapy.

Long-term outcomes of two-dose alemtuzumab induction in pediatric kidney transplantation.

Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse. We performed a single-center retrospective cohort study of 57 pediatric kidney transplant recipients receiving alemtuzumab 20 mg/m2/dose ×2 doses for induction immunosuppression. All patients underwent surveillance biopsies, and 91.3% underwent steroid withdrawal by day 4 post-transplant. Outcomes of interest included graft survival, development of donor specific antibodies (DSA), incidence of viremia and PTLD, and duration of lymphopenia. Median follow-up time was 7.9 years (IQR 5-13.6 years). Median graft survival was 16.5 years (95% CI 11.6-unknown). DSA developed in 36.5% at a median of 944 days (IQR 252-2113 days). Incidences of BK polyomavirus DNAemia (BKPyV-DNAemia), CMV DNAemia, and EBV DNAemia were 38.6%, 22.8%, and 14%, respectively; one patient developed PTLD at 13.3 years post-transplant. Median duration of lymphopenia was 365 days (IQR 168-713 days); 19.3% of patients remained lymphopenic at 3 years post-transplant. There was no association between duration of lymphopenia and graft survival, rejection, DSA detection, or viremia. A two-dose alemtuzumab induction protocol can have excellent outcomes with a steroid-free maintenance immunosuppression regimen. More comprehensive, multicenter, comparative studies of pediatric kidney transplant are needed to improve long-term outcomes.

Comparison of the efficacy of steroid-free versus classic steroid-containing regimens in primary membranous nephropathy.

Objective: To compare the efficacy of a steroid-free regimen with steroid-based treatment in managing primary membranous nephropathy (PMN) and investigate the potential benefits of steroid-free regimens in PMN therapy. Methods: This was a single-centre prospective cohort study. A total of 81 patients were divided into two groups according to their medication regimen: a rituximab (RTX)/tacrolimus (TAC) group (low-dose RTX combined with low-dose TAC group, without steroids, n = 31) and a prednisone (P)/TAC group (P combined with TAC group, n = 61). The changes in 24-h urine protein quantification, levels of blood albumin, blood creatinine, total cholesterol, triglyceride and fasting blood glucose as well as anti-phospholipase A2 receptor antibody titres were observed in both groups before treatment and after 1, 3, 6 and 12months of treatment. Clinical remission (complete and partial remission), serological remission and recurrence were assessed in both groups after treatment, and the occurrence of adverse reactions was observed. Results: 1) Before treatment, there was no significant difference in baseline values between the two groups (p > 0.05). 2) After 12months of treatment, the 24-h proteinuria and total cholesterol levels in the RTX/TAC group were significantly lower than those in the P/TAC group (p < 0.05). 3) After 6months of treatment, the clinical remission rate of the RTX/TAC group was significantly higher than that of the P/TAC group (p < 0.05). After 12months of treatment, the clinical remission rate of the RTX/TAC group was significantly higher than that of the P/TAC group (p < 0.05). (4) After 3, 6 and 12months of treatment, serological remission rates in the RTX/TAC group were significantly higher than those in the P/TAC group (p < 0.05). During treatment, the anti-PLA2R antibody titres in the RTX/TAC group remained lower than those in the P/TAC group (p < 0.05). Conclusion: The low-dose RTX combined with low-dose TAC steroid-free regimen induces serological remission in patients with PMN earlier than the classic regimen of P combined with TAC, and there was no significant difference in adverse effects between the two groups. Besides, the long-term clinical remission effect of low-dose RTX combined with low-dose TAC is better than that of P combined with TAC.

Randomized controlled trial of sustained release tacrolimus vs twice daily tacrolimus in adult living donor liver transplantation

BackgroundTo compare the safety and efficacy of once-daily tacrolimus (ODT) versus twice-daily tacrolimus (BDT) in adult live donor liver transplantation (LDLT). MethodsIn this open-labelled randomized trial, 174 adult patients undergoing LDLT were randomized into ODT or BDT, combined with basiliximab induction and mycophenolate mofetil (steroid-free regimen). Tacrolimus was started at a total dose of 1 mg and the trough level was aimed at 3–7 ng/ml. The primary endpoint was eGFR at 1,3- and 6 months post-transplant, using CKD- EPI equation. Secondary endpoints included biopsy-proven acute rejection (BPAR), metabolic complications, post-operative bilio-vascular complications and patient survival. ResultsThere was no statistically significant difference in eGFR between the two groups at 6 months (ODT –96 ± 19, BDT –91 ± 21, p value-0.164). BPAR was comparable (18/84 in ODT, 19/88 in BDT, p value-0.981). For a similar dosage of tacrolimus, the median trough tacrolimus levels attained were significantly lower for ODT than BDT during the first-month post-transplant (p value-0.001). Metabolic complications due to immunosuppression, post-operative bilio-vascular complications and patient survival was similar between the two groups at 6 months. ConclusionOnce-daily tacrolimus has similar renal safety and efficacy as twice-daily tacrolimus when used in combination with basiliximab induction and mycophenolate in adult LDLT.

Medium-term Outcomes in Pediatric Heart Transplant Recipients Managed Using a Steroid Avoidance Immune Suppression Protocol.

Short-term outcomes using steroid avoidance immune suppression are encouraging in pediatric heart transplant (HT) recipients at low risk of antibody-mediated rejection. We assessed medium-term outcomes in pediatric HT recipients initiated on a steroid avoidance protocol at our institution using surveillance biopsies. All primary HT recipients during 2006-2020 who did not have a donor-specific antibody were eligible for immune suppression consisting of 5-d Thymoglobulin/steroid induction followed by a tacrolimus-based, steroid-free regimen. We assessed freedom from graft failure (death or retransplant), acute rejection, posttransplant lymphoproliferative disease, and cardiac allograft vasculopathy. Overall, 150 of 181 primary HT recipients were eligible for steroid avoidance regimen. Their median age was 8.7 y, 41% had congenital heart disease, 23% were sensitized, and 35% were on a mechanical support. The median follow-up was 6.1 y. Eleven patients (8%) were on maintenance steroids at discharge and 13% at 1 y. Graft survival was 94% at 1 y and 87% at 5 y. Freedom from rejection was 73% at 1 y and 64% at 5 y. Freedom from posttransplant lymphoproliferative disease was 96% at 1 y and 95% at 5 y. Freedom from moderate cardiac allograft vasculopathy was 94% at 5 y. Eight patients developed diabetes. Estimated glomerular filtration rate was <60 mL/min/1.73 m2 in 5% of the cohort at 5 y. Pediatric HT recipients at low risk of antibody-mediated rejection have excellent medium-term survival and relatively low incidence of posttransplant morbidities when managed using a steroid avoidance immune suppression protocol.

COVID-19 Outcomes in Kidney Transplant Recipients in a German Transplant Center.

Kidney transplant recipients (KTRs) show higher morbidity and mortality from COVID-19 than the general population and have an impaired response to vaccination. We analyzed COVID-19 incidence and clinical outcomes in a single-center cohort of approximately 2500 KTRs. Between 1 February 2020 and 1 July 2022, 578 KTRs were infected with SARS-CoV-2, with 25 (4%) recurrent infections. In total, 208 KTRs (36%) were hospitalized, and 39 (7%) died. Among vaccinated patients, infection with the Omicron variant had a mortality of 2%. Unvaccinated patients infected with the Omicron variant showed mortality (9% vs. 11%) and morbidity (hospitalization 52% vs. 54%, ICU admission 12% vs. 18%) comparable to the pre-Omicron era. Multivariable analysis revealed that being unvaccinated (OR = 2.15, 95% CI [1.38, 3.35]), infection in the pre-Omicron era (OR = 3.06, 95% CI [1.92, 4.87]), and higher patient age (OR = 1.04, 95% CI [1.03, 1.06]) are independent risk factors for COVID-19 hospitalization, whereas a steroid-free immunosuppressive regimen was found to reduce the risk of COVID-19 hospitalization (OR = 0.51, 95% CI [0.33, 0.79]). This suggests that both virological changes in the Omicron variant and vaccination reduce the risk for morbidity and mortality from COVID-19 in KTRs. Our data extend the knowledge from the general population to KTRs and provide important insights into outcomes during the Omicron era.

State-of-the-art paradigm of corticosteroid therapy for immune-mediated inflammatory kidney diseases

Since 1950's corticosteroids (CS) have remained the cornerstone of immunosuppressive therapy for immune-mediated kidney diseases. However multiple adverse events, associated with the prolonged CS therapy, became the basis for the development of novel treatment approaches. Current evidence supports the implementation of the steroid-sparing regimens for the treatment of different types of glomerulonephritis. Randomised controlled trial PEXIVAS demonstrated the efficacy and safety of early steroid tapering, starting from the second week of therapy, in patients with ANCA-associated vasculitis with kidney involvement. Several trials showed the efficacy of oral prednisolone 0.3-0.5 mg/kg/daily as a part of multitarget therapy for severe proliferative lupus nephritis. A combination of calcineurin inhibitors and low-dose CS are effective for remission induction in membranous nephropathy, as well as the steroid-free rituximab regimen for the patients with moderate risk of disease progression. Medium dose CS showed promising effect in patients with IgA-nephropathy. Long-term high dose CS remain the standard-of-care for the treatment of minimal change disease and focal segmental glomerulosclerosis, however patients with steroid-dependent and relapsing disease tacrolimus and rituximab can help to achieve steroid-sparing effect. The role of CS pulse-therapy is currently debated, nevertheless it remains a compulsory treatment in several conditions. Thus, overall trend is directed towards the minimization of the maximal doses of CS and/or treatment duration. However, to implement this approach morphological verification of the diagnosis and personalized assessment of the potential risk and benefit are required.

Body Composition in Patients with Follicular Lymphoma: Asso-Ciations between Changes in Radiomic Parameters in Patients Treated with R-CHOP-like and R-B Regimens: LyRa 01F

In patients with follicular lymphoma (FL), therapeutic advances have led to improved survival, and within this framework, it is important to identify treatment strategies offering a better quality of life. Using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), in patients treated with R-CHOP-like or R-Bendamustine regimens, we assessed changes in the bone mineral density (BMD), musculoskeletal index (SMI), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) at disease onset and at the end of therapy. We evaluated whether the high-steroid regimen could lead to more significant radiological changes than those induced by the steroid-free regimen and whether a low BMD at disease onset is an unfavorable prognostic index. Seventy-nine patients between 60 and 80 years old with a new diagnosis of FL were included in the study. Evaluation of Delta values (pre- and post-therapy mean values) in the two immunochemotherapy regimens showed differences in radiomic parameters within the two patient cohorts. The R-CHOP-like regimen was associated with a significant reduction in BMD, an increase in SAT and VAT, and a reduction in skeletal muscle density (SMD) and SMI. Moreover, patients with high FLIPI showed a BMD below the cut-off value. This study represents the first study demonstrating a prognostic correlation between FLIPI and low BMD.

Treatment of De Novo Renal Transplant Recipients With Calcineurin Inhibitor-free, Belatacept Plus Everolimus-based Immunosuppression.

Patients who were de novo renal transplant recipients seropositive for Epstein-Barr virus were randomized to receive BELA+EVL or TAC+MMF maintenance therapy after rabbit antithymocyte globulin induction and up to 7 d of corticosteroids. The primary endpoint was the rate of biopsy-proven acute rejection at month 6. Because of an unanticipated BELA supply constraint, enrollment was prematurely terminated at 68 patients, of whom 58 were randomized and transplanted (intention-to-treat [ITT] population: n = 26, BELA+EVL; n = 32, TAC+MMF). However, 25 patients received BELA+EVL' and 33 received TAC+MMF (modified ITT population). In the ITT population, the 6-mo biopsy-proven acute rejection rates were 7.7% versus 9.4% in the BELA+EVL versus TAC+MMF group. The corresponding 24-mo biopsy-proven acute rejection rates were 19.2% versus 12.5% in the ITT population and 16.0% versus 15.2% in the mITT population; all events were Banff severity grade ≤IIA and similar between groups. One patient in each group experienced graft loss unrelated to acute rejection. The 24-mo mean unadjusted estimated glomerular filtration rates were 71.8 versus 68.7 mL/min/1.73 m2 in the BELA+EVL versus TAC+MMF groups. Posttransplant lymphoproliferative disorder was reported for 1 patient in each group. No deaths or unexpected adverse events were observed. A steroid-free maintenance regimen of BELA+EVL may be associated with biopsy-proven acute rejection rates comparable to TAC+MMF.

Early calcineurin-inhibitor to belatacept conversion in steroid-free kidney transplant recipients.

Belatacept (Bela) was developed to reduce nephrotoxicity and cardiovascular risk that are associated with the chronic use of Calcineurin inhibitors (CNIs) in kidney transplant recipients. The use of Bela with early steroid withdrawal (ESW) and simultaneous CNI avoidance has not been formally evaluated. At 3 months post-transplant, stable kidney transplant recipients with ESW on Tacrolimus (Tac) + mycophenolate (MPA) were randomized 1:1:1 to: 1) Bela+MPA, 2) Bela+low-dose Tac (trough goal <5 ng/mL), or 3) continue Tac+MPA. All patients underwent surveillance graft biopsies at enrollment and then at 12, and 24 months post-transplant. Twenty-seven recipients were included; 9 underwent conversion to Bela+MPA, 8 to Bela+low-dose Tac and 10 continued Tac+MPA. Serial blood samples were collected for immune phenotyping and gene expression analyses. The Bela+MPA arm was closed early due to high rate of biopsy proven acute rejection (BPAR). The incidence of BPAR was 4/9 in Bela+MPA, 0/8 in Bela+low dose Tac and 2/10 in Tac+MPA, P= 0.087. The Bela+low-dose Tac regimen was associated with +8.8 mL/min/1.73 m2 increase in eGFR compared to -0.38 mL/min/1.73 m2 in Tac+MPA, P= 0.243. One graft loss occurred in the Bela+MPA group. Immunophenotyping of peripheral blood monocyte count (PBMC) showed that CD28+CD4+ and CD28+CD8+ T cells were higher in Bela+MPA patients with acute rejection compared to patients without rejection, although the difference did not reach statistical significance. Our data indicate that, in steroid free regimens, low-dose Tac maintenance is needed to prevent rejection when patients are converted to Bela, at least when the maneuver is done early after transplant.

First-line steroid-free systemic treatment of acute and chronic graft-versus-host disease after novel prophylaxis regimens.

In the early randomized trials the efficacy of calcineurin inhibitors (CNI) in the treatment of graft-versus-host disease (GVHD) was comparable to corticosteroids (CS), but these results became obsolete with the introduction of CNIs in prophylaxis. Recently several effective CNI-free GVHD prophylaxis regimens were introduced based on posttransplantation cyclophosphamide (PTCY) and αβ ex vivo T-cell depletion (αβ-TCD). Among patients treated under these protocols 34 patients with grade II-IV acute (aGVHD) and 40 with moderate and severe chronic (cGVHD) disease were treated with CNIs or other CS-free regimens as the first line. Overall response rate (ORR) was significantly higher in cGVHD than in aGVHD: 80% (95% CI 68-92) vs 47% (95% CI 30-64%), p = 0.0031. In aGVHD it was almost completely restricted to isolated stage III skin GVHD. In cGVHD patients with moderate disease ORR was higher than in severe: 96% (95% CI 88-100%) vs 56% (95%CI 32-81%), p = 0.0022. Two-year overall survival was 76% (95% CI 58-87%) in aGVHD and 95% (95% CI 81-99%) in cGVHD. Failure-free survival was 21% (95% CI 9-37%) in aGVHD and 81% (95% CI 64-91%) in cGVHD. Patients responding to steroid-free regimens had lower use of systemic antibiotics (p = 0.0095), antifungals (p = 0.0319) and antivirals (p < 0.0001).

P888: REPLACING STEROIDS IN TRANSPLANT-INELIGIBLE MULTIPLE MYELOMA: THE PHASE 2 ISATUXIMAB-BORTEZOMIB-LENALIDOMIDE-DEXAMETHASONE REST STUDY

Background: Standard therapies for newly diagnosed multiple myeloma (NDMM) patient’s ineligible for autologous stem-cell transplantation (ASCT) have been lenalidomide-dexamethasone (Rd), bortezomib-lenalidomide-dexamethasone (VRd) or bortezomib-melphalan-prednisone (VMP). The benefit of adding an anti-CD 38 monoclonal antibody (mAb) to the standard treatments of VMP and Rd has been demonstrated in two large phase 3 studies (Facon, 2019. Mateos, 2018). Isatuximab is an anti-CD38 mAb approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone to treat relapsed/refractory MM, and has also shown clinical responses as combination therapy to treat NDMM (Trudel, 2019). Corticosteroids have been the backbone of most myeloma targeted therapies since the discovery of their effectiveness. Due to the continuous treatment paradigm, the cumulative dose of corticosteroids in patients is substantial. Steroids inflict reduction in both short- and long-term quality of life and increase patients’ receptiveness for infections. Infections are one of the main reasons for complications and death during active first line treatment, and the rate rises with age. Both steroid-free regimens and regimens with reduced corticosteroids have demonstrated improved safety and similar efficacy as regimens containing steroids. Aims: The study will evaluate isatuximab (Isa) in combination with bortezomib (V) and lenalidomide (R) with minimal dexamethasone (d) as first-line treatment in transplant-ineligible patients. The primary endpoint is the number of patients who achieve measurable residual disease negative (Euroflow NGF 10-5) complete response during and/or after 18 cycles of study treatment. Secondary endpoints include progression free survival, overall survival, overall response rate (ORR), safety evaluations and patient-reported outcome. Methods: The REST study is an academic, single arm, open-label, phase 2 study of NDMM patients ineligible for ASCT. 50 patients will be included and receive Isa-VRd (Isa:10 mg/kg IV Days 1, 8, 15, 22 during cycle 1, QW cycle 2-18; V: 1,3 mg/m2 SC Days 1,8,15 during cycle 1-8; R: 25 mg PO Days 1-21 during all cycles; d: 20 mg PO Days 1,8,15,22 only for the first 2 cycles), all 28-day cycles. Results: As of January 31, 2022, 17 patients have been enrolled. Baseline characteristics can be found in Table 1. At data-cutoff, the median number of cycles started by patients was 3.6 (range 1-8) and the median duration of exposure was 16 (range 3-28) weeks. 8 patients developed 14 grade ≥3 non-hematological adverse eventd (AE), including infections (n=7), fever (n=1), skeletal pain (n=2), acute renal failure (n=1), peripheral sensory neuropathy (n=1), diarrhea (n=1) edema (n=1). There were no AEs leading to definitive treatment discontinuation. At a follow up of 6 months, the ORR was 100% (15/15) and the ≥very good partial response rate was 53.3% (8/15 patients). Image:Summary/Conclusion: Isa-VRd in the transplant ineligible population has a tolerable safety profile. Isa-VRd is showing encouraging preliminary efficacy in NDMM ineligible for transplant. Enrollment and follow-up is ongoing. Acknowledgements: Sanofi sponsors the REST study.

Role of Immunosuppression on Efficacy of Anti-SARS-CoV-2 Vaccines in Heart Transplanted (HT) Patients

PurposeVaccines against COVID-19 have a lower efficacy in HT patients (pts); factors influencing their immunogenicity are unknown. The aim of this study is to investigate the role of immunosuppression on mRNA vaccines efficacy.MethodsWe included all HT pts followed in our Center completing the vaccine cycle (03-06/21), for whom levels of IgG anti-RBD after the second dose were known, excluding those with a previous COVID infection. Demography, immunosuppression (drugs and trough blood level), lymphocyte count, previous rejection episodes were collected before the first dose. The endpoint was vaccine-induced immunization after the second dose according to our laboratory's threshold of IgG anti-RBD.ResultsAmong 201 vaccinated, IgG anti-RBD values were available for 63 pts at 2± 1 months after the second dose (22±3 days after the first; 89% BNT162b2; 60±11 yrs, 5±1 yrs from HT, 75% males, 3 with rejection > 1R in the previous 6 months). All pts were on CNI-inhibitors (35% tacrolimus, TAC, 65% cyclosporine, CyA), 57% on MMF, 23% mTOR, 69% steroids (CS). 41.7% had no response to vaccine. At univariate analysis the predictors of lack of response to vaccine were: MMF (43% vs 71%), TAC vs CSA (27% vs 73%), steroids (46% vs 76%), steroid dose > 5mg, lymphocytes <18% of leukocytes (both identified by ROC), more than 5 years from HT; mTOR was more likely associated with protection (80% vs 49%), p<0.05 all. Importantly, age was not predictive of immunogenicity. At stepwise multivariate analysis all these factors maintained statistical significance (p<0.05 all). IgG anti-RBD values were influenced by low lymphocytes, steroids and TAC trough levels (p< 0.05 all).Response to vaccine was the lowest for MMF+TAC+CS (23.1%), intermediate for MMF+CyA+CS (53.3%) and steroid-free regimens (68.7%), highest (87.5%) for mTOR+CNI+CS (20%,23%,24%,23% of pts, p=0.01). No rejection episodes were registered 3 months after the second dose of vaccine.ConclusionWhile confirming a low response to COVID-19 vaccines a in HT pts, our study underscores the negative effect of immunosuppression, particularly of MMF, high doses of steroids and TAC. Given that MMF is a cornerstone of most protocols, from these results it arises the hypothesis (to be tested in larger studies) if switching stable patients from TAC to Cya or to lower steroid doses may favor the attempts to increase the response to vaccines.

Novel Immunosuppression in Solid Organ Transplantation.

Solid organ transplantation and survival has improved tremendously in the last few decades, much of the success has been attributed to the advancements in immunosuppression. While steroids are being replaced and much of the immunosuppressive strategies focus on steroid free regimens, novel agents have introduced in the induction, maintenance, and treatment of acute rejection phase. MTOR inhibitors have helped with the renal sparing side effect from the calcineurin inhibitors, newer agents such as rituximab have decreased the incidence of donor-specific antibodies which led to decreased incidence of acute rejection reactions. In this chapter we discuss the newer therapies directed specifically for solid organ transplantation.

Characterization of Kidney Retransplantation Following Graft Failure Due to BK Virus Nephropathy

Immunosuppression following kidney transplantation increases risk of BK polyomavirus reactivation, a common cause of graft dysfunction and failure. Subsequent retransplantation is a viable option that has not been extensively studied. This study further characterizes BK Virus Nephropathy (BKVN) and retransplantation in the most expansive population to date, geographically, temporally, and in magnitude. The OPTN/UNOS database was used to identify patients who received kidney or kidney-pancreas transplantation between 1987 and 2018 that resulted in BKVN-attributed failure (n=1587). This population was divided into those who underwent retransplantation (n=495) and those who did not (n=1092). The retransplanted cohort was younger (45 vs. 53 yr; P<0.0001) and had fewer prior kidney transplants (P<0.003), lower expected post-transplant survival (P<0.001), lower rates of delayed graft function (DGF) (14.1% vs. 22.2%; P=0.0008), a greater proportion of white patients (55.4% vs. 43.2%; P=0.0002), a greater proportion of living donors (35.8% vs. 23.0%; P<0.0001), and longer allograft lifespan (2.95 vs. 2.41 yr; P<0.0001), compared to those not retransplanted. Among retransplants, DGF and high kidney donor profile index (KDPI) were associated with decreased allograft lifespan (P=0.001, P=0.0005, respectively). Steroid induction had no effect on allograft lifespan when compared to steroid-free regimens (P=0.915). Retransplanted allografts lasted longer than previous BKVN-failed grafts (10.44 and 3.70 years, respectively; P<0.0001). Retransplantation following BKVN-associated graft failure has been associated with favorable outcomes. To maximize allograft lifespan in retransplantation, clinicians may consider selection of low KDPI donors, prevention of delayed graft function, and tailored immunosuppressive regimens that minimize steroids.

Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients-Results From the SAILOR Study.

Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse.Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed.Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43–69 mg*h/L, min: 24—max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2–20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days–2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: −4.8%−12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2–0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC.Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.