Combination Of Mycophenolate Mofetil Research Articles

IMPDH2 suppression impedes cell proliferation by instigating cell cycle arrest and stimulates apoptosis in pediatric hepatoblastoma

BackgroundHepatoblastoma (HB) is the most common pediatric liver tumor, presenting significant therapeutic challenges due to its high rates of recurrence and metastasis. While Inosine Monophosphate Dehydrogenase 2(IMPDH2) has been associated with cancer progression, its specific role and clinical implications in HB have not been fully elucidated.MethodsThis study utilized Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Tissue Microarray (TMA) for validation. Following this, IMPDH2 was suppressed, and a series of in vitro assays were conducted. Flow cytometry was employed to assess apoptosis and cell cycle arrest. Additionally, the study explored the synergistic therapeutic effects of mycophenolate mofetil (MMF) and doxorubicin (DOX) on HB cell lines.ResultsThe study identified a marked overexpression of IMPDH2 in HB tissues, which was strongly correlated with reduced Overall Survival (OS) and Event-Free Survival (EFS). IMPDH2 upregulation was also found to be associated with key clinical-pathological features, including pre-chemotherapy alpha-fetoprotein (AFP) levels, presence of preoperative metastasis, and the pre-treatment extent of tumor (PRETEXT) staging system. Knockdown of IMPDH2 significantly inhibited HB cell proliferation and tumorigenicity, inducing cell cycle arrest at the G0/G1 phase. Notably, the combination of MMF, identified as a specific IMPDH2 inhibitor, with DOX, substantially enhanced the therapeutic response.ConclusionThe overexpression of IMPDH2 was closely linked to adverse outcomes in HB patients and appeared to accelerate cell cycle progression. These findings suggest that IMPDH2 may serve as a valuable prognostic indicator and a potential therapeutic target for HB.ImpactThe present study unveiled a significant overexpression of inosine monophosphate dehydrogenase 2 (IMPDH2) in hepatoblastoma (HB) tissues, particularly in association with metastasis and recurrence of the disease. The pronounced upregulation of IMPDH2 was found to be intimately correlated with adverse outcomes in HB patients. This overexpression appears to accelerate the progression of the cell cycle, suggesting that IMPDH2 may serve as a promising candidate for both a prognostic marker and a therapeutic target in the context of HB.

Orbital radiotherapy with combined intravenous methylprednisolone and mycophenolate mofetil in moderate-to-severe thyroid eye disease

PurposeTo report the clinical outcomes of orbital radiotherapy (ORT) with combined intravenous methylprednisolone (IVMP) and mycophenolate mofetil (MMF) in thyroid eye disease (TED) patients with restrictive myopathy. DesignProspective comparative case series of patients managed at The Chinese University of Hong Kong from 2015 to 2021. MethodsThe primary outcome was the change in Gorman diplopia score at 52 weeks. Secondary outcomes were the changes in extraocular muscle motility (EOMy), area of extraocular muscle (EOM) on MRI, exophthalmos, and marginal reflex distance (MRD) 1 and MRD2 at 52 weeks. ResultsA total of 40 (29 females) TED patients, medium age 56 years, were treated with the double regimen: combined IVMP and MMF (17) or triple regimen: IVMP, MMF, and ORT (23). The triple group has a higher age (P = 0.028). Sex, smoking history, thyroid, and pre-treatment orbital status were comparable between the 2 groups. EOMy improved more after the triple regimen(P = 0.026). Nine patients from the triple group showed a significant reduction in the size of the inferior rectus (both eyes: P < 0.05), while five from the double group showed no significant reduction of any EOM on MRI. The improvement of CAS, diplopia score, exophthalmos, MRD1, and MRD2 were similar. No patient reported any severe or organ-threatening side effects from IVMP, MMF, or ORT requiring discontinuation of treatment. ConclusionThe triple regimen demonstrates better structural and functional outcomes in TED-related restrictive myopathy. Future randomized clinical trials are warranted to clarify the adjuvant role of ORT in this specific indication of TED management.

P060 Multi-targeted therapy better in achieving a complete response in Lupus Nephritis: A systematic review and meta-analysis

Abstract Background/Aims Overall management of SLE and Lupus Nephritis (LN) has significantly improved over the last four decades. Recently great therapeutic strides have been made in management of LN using newer agents alone or combination of older therapies. With the availability of increased number of options choosing the optimal treatment regimen for LN has become challenging. Identifying the treatment regimen most effective in achieving complete response while minimizing adverse events is crucial for improving patient outcomes. We performed a systematic review and meta-analysis of clinical trials to explore optimal treatment regimen for LN. Methods The systematic review and meta-analysis were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search was conducted using public databases, such as the Cochrane Library, Web of Science and PubMed. Only randomized controlled clinical trials with either active comparator or placebo arms were included. Studies were excluded if they were retrospective, with no comparative drug arm, or less than 20 subjects per treatment response arm. Due to lack of agreed upon outcome measures, complete response (CR) and partial response (PR) criteria were determined as per the definition used by individual studies. Severe adverse reaction (SAE) frequencies were determined for each study for safety evaluation. Publication bias was detected by using funnel plots. Forest plots were used to summarize data, generate frequencies, odds ratio (OR), relative risks (RR) and corresponding 95% confidence intervals (CI) for each subgroup. Heterogeneity was evaluated using the I2 statistic, and labelled as low (25%), moderate (50%) and high (75%). All analyses were performed using R Statistical Software meta package (v4.2.1; R Core Team 2022). Results 31 eligible studies comprising 5495 SLE patients were included in analyses, the study characteristic features are shown in Table 1. Overall significant OR for achieving CR was reported by 10 studies (Figure 1). The highest effect was reported from study by Bao et.al using a combination of tacrolimus(TAC) and mycophenolate mofetil (MMF) compared to cyclophosphamide (CYC) (OR = 10.5, 95% CI 2.27; 48.76), another study using TAC+MMF combo reported OR = 2.49, 95% CI 1.59;3.88. The study by Ginzler et.al reported OR = 5.06 (95% CI 1.6:16.02) in favor of using MMF. Studies using CYC, voclosporin + MMF, and belimumab also reported significant OR for achieving CR. Data for the frequency of SAE were available in 22 studies. The frequency of SAE was not significantly different between treatments arms (OR: 1.07, 95%CI: 0.93-1.23, p &amp;gt; 0.05) Conclusion Our meta-analysis suggests multi-target treatment strategies, by adding calcineurin inhibitors to MMF may be better for achieving complete response in LN. Furthermore, using this combination treatment did not seem to increase the risk of side effects. Heterogenous treatment response criteria and variable comparator arms were major limiting factors of this study. Disclosure O. Pamuk: None. B. Shaikh: None. S. Khan: None. S. Abi Doumeth: None. S. Hasni: None.

Effectiveness and safety of mycophenolate mofetil and rituximab combination therapy for immune idiopathic myopathies

IntroductionIdiopathic inflammatory myopathies (IIM) represent a rare and heterogenous group diseases, and their treatment is not fully defined yet. According to previous small case series, the combination of mycophenolate mofetil (MMF) and rituximab (RTX) may be effective in controlling difficult-to-treat patients. Our aim was to further explore the efficacy and safety of this combined approach in patients with IIM.MethodsPatients with IIM treated with the RTX/MMF combination in our Center were retrospectively identified. After the start of combination therapy, the efficacy was evaluated at 12 months (T12) according the 2016 ACR/EULAR response criteria for IIM. Cardiac imaging and pulmonary function tests were used to monitor disease activity in patients with myocarditis and interstitial lung disease, respectively. Adverse events were recorded over the follow-up period.ResultsAmong the 20 patients (median age 61 years; 70% female) included in the study, anti-synthetase syndrome was the most prevalent IIM subgroup (60%). At treatment start, muscle, heart, and lung were the most commonly actively affected organs. After 12 months, a moderate or major response was observed in all patients, and creatine kinase was significantly decreased (p-value = 0.012). Cardiac imaging and enzymes monitoring showed a reduction of heart inflammation, while pulmonary function tests improved in patients with lung involvement. No severe side effects were observed.ConclusionOur data show that combination of RTX and MMF is effective and safe in patients with severe and refractory IIM. Therefore, this combined treatment might represent a feasible approach for difficult-to-treat IIM cases.

Treatment outcome and survival status among adult patients treated for lupus nephritis in selected tertiary hospitals of Ethiopia

Lupus nephritis (LN) is kidney involvement of systematic lupus erythematous that ranges from mild to severe and occurs in 60% of adult patients. Despite advances in therapy, LN morbidity and mortality remains high. There is a paucity of data regarding adult LN patient's treatment outcome, survival status, and associated factors in developing countries, particularly in Ethiopia. This study aimed to assess the treatment outcome, survival status, and associated factors of adult patients treated for LN in two selected tertiary hospitals [Tikur Anbessa Specialized Hospital (TASH) and St. Paul’s Hospital Millennium Medical College (SPHMMC)] of Addis Ababa, Ethiopia. A hospital-based retrospective cross-sectional multicenter study was conducted from January 1, 2016 to January 1, 2021. Socio-demographic, clinical, and treatment-related data were collected from patient’s medical records by using a structured abstraction checklist. Descriptive statistics were used to summarize the quantitative data as appropriate. The modified Aspreva Lupus Management Study (mALMS) criteria was applied to categorize LN treatment outcomes into complete, partial, and non-response. Multinomial logistic regression analysis was performed to identify predictors of LN treatment outcome. Patients’ survival was estimated by using Kaplan–Meier and Cox proportion regression analysis. P value < 0.05 was considered to declare statistical significance. A total of 200 LN patients were included in the final analysis. Amongst these, the majority of them (91.5%) were females. The median age of the patients was 28 (15–60) years. The mean duration of treatment follow-up was 28 months. The commonly prescribed immunosuppressive drugs during both the induction (49.5%) and maintenance (60%) phases were a combination of mycophenolate mofetil with prednisolone. Complete, partial, and non-responses at the last follow-up visit accounted for 66.5%, 18.0%, and 15.5%, respectively. Patient survival at the last follow-up visit was more than 90% for patients with complete response to the induction therapy. Non-response at the last follow-up visit was significantly associated with severe disease activity index (adjusted odds ratio [AOR] = 6.25, 95% confidence interval [CI] 1.49–26.10), presence of comorbidity (AOR = 0.21, 95% CI 0.05–0.92), baseline leucopenia (AOR = 14.2, 95% CI 1.04–201.3), partial response at the end of induction therapy (AOR = 32.63, 95% CI 1.4–736.0), and duration of induction therapy of greater than 6 months (AOR = 19.47, 95% CI 1.5–258.8). This study unveiled that lower numbers of LN patients were presented with non-response at the last follow-up visit and non-response to induction therapy was associated with lower patients’ survival rates compared with complete or partial response.

Five-Year study on renal outcomes in biopsy-proven focal segmental glomerulosclerosis patients in Shiraz, Iran.

Focal segmental glomerulosclerosis (FSGS) is a prevalent glomerular disease that often leads to nephrotic syndrome. It is characterized by consolidating a portion of the glomerular capillary tuft connected to Bowman's capsule. This retrospective cohort study aimed to determine the demographic characteristics, risk factors, and prognostic indicators associated with FSGS in Shiraz, Iran. The study included 53 primary FSGS patients aged over 18 years who were referred to clinics affiliated with Shiraz University of Medical Sciences. Data were collected through a comprehensive data-gathering sheet encompassing demographic information, medical history, laboratory test results, and histopathological findings. Statistical analysis was performed using SPSS 18, considering a significance level of p<0.05. A five-year follow-up was conducted on the 53 patients, with the mean age of 41.0±13.3 years. The most common FSGS variants observed were "not otherwise specified" (NOS, 13.2%) and tip variant (7.5%). Older patients exhibited higher disease activity, whereas remission rates were higher among younger individuals (P=0.012). Patients achieving remission had lower creatinine and Pro/Cr ratios and higher glomerular filtration rates (p<0.05). Treatment involving a combination of corticosteroids and mycophenolate mofetil showed a significant correlation with remission (P=0.036). Older patients with higher creatinine levels, higher Pro/Cr ratios, and lower glomerular filtration rates at disease onset may require more aggressive treatment. Combination therapy with mycophenolate mofetil and corticosteroids yields better outcomes, leading to increased remission rates. These findings provide valuable insights for managing FSGS patients.

Retrospective evaluation of prognosis and survival with various immunosuppressants in 82 dogs diagnosed with meningoencephalitis of unknown etiology (2010–2021)

BackgroundMeningoencephalomyelitis of unknown etiology (MUE) is a comprehensive term for non-infectious inflammatory brain diseases of the central nervous system (CNS) caused by abnormal autoimmune responses. This study aims to compare the differences in survival and clinical response of MUE according to the adjuvant immunosuppressant use. Medical records of 82 dogs diagnosed with MUE were reviewed retrospectively.ResultsThe overall survival time was 769 days (range 14–2687 days). The median survival time for each adjunctive was: leflunomide 1035 days (range 126–2163 days), mycophenolate mofetil 865 days (range 39–2191 days), cyclosporin 441 days (range 11–2176 days), cytosine arabinoside 754 days (range 6–1898 days) and a combination of mycophenolate mofetil and cytosine arabinoside 132 days (range 23–1227 days). There was no significant difference in the incidence rate of adverse events according to the immunosuppressants, but moderate to severe anemia was confirmed in 3 patients (18.7%) in the leflunomide group.ConclusionsThe survival time and response rate of MUE dogs differed depending on which adjunctive immunosuppressants were used. Leflunomide showed a long survival time and a relatively good response rate in dogs with MUE. However, a large-scale further study with standardized doses of immunosuppressants and supportive treatment and constant monitoring interval is needed.

Clinical analysis of sirolimus as an alternative GVHD prophylaxis for patients with kidney injury undergoing allo-HSCT

Objective: To explore the feasibility of sirolimus as an alternative graft versus host disease (GVHD) prophylaxis in patients with kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Retrospective case series study. Medical records of 11 patients in Peking University People's Hospital from 1 August 2008 to 31 October 2022, who received sirolimus instead of cyclosporine to prevent GVHD, due to renal insufficiency after allo-HSCT, were analyzed retrospectively. Incidence of GVHD, infection, and transplant-associated thrombotic microangiopathy (TA-TMA), as well as renal function, were evaluated. Results: Among the 11 patients who received sirolimus, 6 were treated with haploidentical donor HSCT, and 5 were treated using matched sibling donor HSCT. The median (range) time of sirolimus administration was 30 (7-167) days after allo-HSCT, and the median (range) sirolimus course duration was 52 (9-120) days. During sirolimus treatment, 1 case did not undergo combined treatment with other prophylactic drugs, 3 cases received combined mycophenolate mofetil (MMF), and 1 case underwent combined CD25 monoclonal antibody treatment, while 6 cases had combined therapy with both MMF and CD25 monoclonal antibody. Of the 11 patients, 2 developed Grade Ⅲ acute GVHD, 1 developed severe pneumonia and died, and 1 developed TA-TMA, while nine patients had normal or improved renal function. Median (range) follow-up time was 130 (54-819) days. Non-relapse mortality was observed in 1 patient. Relapse mortality was also observed in 1 patient. Conclusion: Sirolimus-based alternative GVHD prophylaxis is a potentially viable option for patients undergoing allo-HSCT who cannot tolerate cyclosporine, but its efficacy and safety require further optimization and verification in prospective studies.

Nephroprotective Effects of Mycophenolate Mofetil and Glibenclamide on Streptozotocin-induced Diabetic Renal Injury in Rats: An Experimental Study.

Diabetic renal injury is a microvascular complication associated with inflammation and oxidative stress, culminating in renal dysfunction. Conventionally, it is treated with hypoglycemic agents to address metabolic perturbations. However, the way to mitigate immunological, inflammation, and oxidative stress have seldom been studied. Hence, in the present study, the nephroprotective role of immunosuppressive and anti-inflammatory drugs, mycophenolate mofetil (MMF) in combination with the oral hypoglycemic agent glibenclamide, on streptozotocin (STZ)- induced diabetic renal damage was studied. Bodyweight, fasting blood glucose, and glycosylated hemoglobin levels were altered in the diabetic rats. Furthermore, renal injury was indicated by abnormal levels of urinary protein and creatinine and serum markers of renal function in diabetic rats. Hyperglycemia-induced oxidative stress and inflammation were also observed in the diabetic rats. The combination of MMF and glibenclamide treatment significantly attenuated the abnormal effects of hyperglycemia, oxidative stress, and inflammation-induced renal injury in diabetic rats. Histopathological studies confirmed the nephroprotective role of MMF and glibenclamide by reversing renal injury in diabetic rats. The present study suggests that MMF and glibenclamide have a protective role in STZ-induced diabetic renal damage.

Evaluation of neutropenia secondary to mycophenolate mofetil associated with valganciclovir in liver transplant patients

ObjectiveImmunosuppressive drugs are necessary to avoid or reduce the risk of rejection of transplanted organs. The immunosuppression generated may result in these patients needing antibiotics and antivirals to be prescribed to them in conjunction with their immunosuppressants to avoid the risk of infection. This has generated an increase in neutropenia in patients treated with mycophenolate mofetil in combination with valganciclovir. The purpose of this study is to estimate the risk of neutropenia attributable to combination treatment of mycophenolate mofetil with valganciclovir in patients with a transplanted liver. MethodThis is a retrospective cohort study. It included patients who received a liver transplant between 2012 and 2017 and who were treated with mycophenolate mofetil or with a combination of mycophenolate mofetil and valganciclovir. Minimum follow-up was 100 days post-transplantation. Children under 16 years of age and patients who died during follow-up were excluded. Binary logistic regression analysis was used to determine the association of neutropenia with sex, age, diabetes, creatinine at baseline and at discharge, and concomitant treatment of mycophenolate mofetil with valganciclovir. Relative risk and 95% CI were calculated using logistic regression coefficients. Results144 patients were analyzed, 87 were treated with mycophenolate mofetil and 57 received mycophenolate mofetil and valganciclovir together. An overall risk of neutropenia of 37% [95% CI (29-45)] was observed. The risk was significantly higher in patients who received the combination of mycophenolate mofetil and valganciclovir (56%) than in those treated with mycophenolate mofetil alone (24%), p = 0.001. Binary-logistic-regression analysis revealed that concomitant use of mycophenolate mofetil with valganciclovir was associated with an increased risk of neutropenia: Relative risk = 4.97, 95% CI [2.25-11.00]. ConclusionsOur study shows that concomitant use of mycophenolate mofetil and valganciclovir increases the risk of neutropenia in patients with a transplanted liver.

Efficacy and safety of immunosuppressive agents for adults with lupus nephritis: a systematic review and network meta-analysis.

Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN. We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer. Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%). This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.

Association Between Mycophenolate Mofetil Use and Subsequent Infections Among Hospitalized Patients with Systemic Lupus Erythematosus: A Nested Case-Control Study.

The association between mycophenolate mofetil (MMF) and infection in patients with systemic lupus erythematosus (SLE) has not been clarified. This study evaluated the degree and factors in effect of MMF use on infection in patients with SLE. A hospitalized-based observational study was conducted to collect medical records on patients with SLE during 2010-2021. A nested case-control study was performed among 3339 patients with SLE, including 1577 cases and 1762 controls by whether they developed any type of infection. The exposure of MMF use was determined within 1year before diagnosed infection or the end of follow-up. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for association between MMF and subsequent infection. MMF was significantly associated with the risk of overall infection (adjusted OR 1.90, 95% CI 1.48-2.44) and different types of infections, including bacterial infection (adjusted OR 2.07, 95% CI 1.55-2.75), viral infection (adjusted OR 1.92, 95% CI 1.23-3.01), and opportunistic infection (adjusted OR 2.13, 95% CI 1.31-3.46). The top three risks of specific types of infections were bacteremia/septicemia, urinary tract infection/pyelonephritis, and herpes zoster. Stratification analysis showed risk of overall infection increased especially in MMF users with age over 55years, diabetes, central nervous system involvement, and thrombocytopenia. Moreover, the risk of infection increased with increasing dosage and duration of MMF use. Additionally, the combination of MMF with CYC and other immunosuppressants significantly increases the risk of infections compared to using a single one. MMF use is associated with various type of infections in patients with SLE, particularly in those with longer use, older age, complications with comorbidities, and concomitant use of CYC or other immunosuppressants.

Outcomes in progressive systemic sclerosis treated with autologous hematopoietic stem cell transplantation compared with combination therapy.

Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to improve long-term survival for early diffuse progressive SSc compared with CYC. CYC, however, does not provide a long-term benefit in SSc. The combination of MMF and rituximab is a potent alternative regimen. We aimed to retrospectively compare the outcomes of SSc patients who underwent AHSCT to patients who met the eligibility criteria for AHSCT but received upfront combination therapy with MMF and rituximab. Repeated assessments of modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), and diffusing capacity (DLCO) values were conducted. Clinical improvement was defined as an mRSS decrease >25% or an FVC increase >10%. Event-free survival (EFS) was defined in the absence of persistent major organ failure or death. Twenty-one SSc patients in the combination therapy group were compared with 16 in the AHSCT group. Age, sex and disease duration were similar between the two groups. Clinical improvement at 12 months was seen in 18 (86%) patients in the combination group compared with 13 (81%) in the AHSCT group (P = 0.7). The hazard ratio for EFS at 24 months favoured the combination group (HR = 0.09, P = 0.04). During follow-up, both groups exhibited a significant and comparable reduction in mRSS and an increase in FVC values at each time interval up to 24 months. MMF and rituximab compared with AHSCT in SSc patients eligible for AHSCT resulted in similar skin and lung clinical improvement with a better safety profile at 24 months.

Evaluation of Treatment with a Combination of Prednisolone and Mycophenolate Mofetil for Dogs with Immune-Mediated Polyarthritis

Evaluation of Treatment with a Combination of Prednisolone and Mycophenolate Mofetil for Dogs with Immune-Mediated Polyarthritis

Comparative Efficacy and Safety of Mycophenolate Mofetil and Azathioprine in Combination with Corticosteroids in the Treatment of Lymphocytic Myocarditis.

This paper aimed to study the efficacy and safety of mycophenolate mofetil (MM) in combination with corticosteroids in the treatment of lymphocytic myocarditis (LM) when compared to the standard combination of corticosteroids and azathioprine. The study included 50 adult patients (47.8 ± 10.8 y.o.) in a NYHA III functional class due to LM who were verified using endomyocardial biopsy. The main group included 29 patients who received MM at 2 g/day. The comparison group comprised 21 patients who received azathioprine at 150 [50; 150] mg/day. Both groups were administered with methylprednisolone. The average follow-up period was 30 [22; 35] months, but no less than 6 months. The groups were comparable in the baseline parameters and standard drug therapy. In both groups, there was a comparable significant increase in the ejection fraction (from 30.6 ± 7.7% to 44.0 ± 9.4% vs. 29.2 ± 7.7% to 46.2 ± 11.8%, p < 0.001), and a decrease in systolic pressure in the pulmonary artery and the dimensions of the left ventricle and atrium. The frequency of death was two (6.9%) and two (9.5%), transplantation was one (3.4%) and one (4.8%) patient and the "death + transplantation" endpoint was three (10.3%) and three (14.3%) without differences between the groups. The presence of the parvovirus B19 in the myocardium in 6/5 patients did not affect the results. The incidence of infectious complications was comparable. The most severe infectious complications were pneumonia and fatal purulent encephalitis (both cases in the azathioprine group), leptospirosis meningitis (in the mycophenolate mofetil group). In the patients with LM, the combination of corticosteroids with MM at a dose of 2 g/day was at least no less effective than with azathioprine. There was a tendency toward a better tolerance using MM.

Impact of everolimus versus mycophenolate mofetil in combination with reduced tacrolimus on oncologic outcome after liver transplantation for hepatocellular carcinoma

Impact of everolimus versus mycophenolate mofetil in combination with reduced tacrolimus on oncologic outcome after liver transplantation for hepatocellular carcinoma

Abstract 1093: Measuring and inhibiting purine metabolism in patients with glioblastoma

Abstract Introduction: We have previously found that purine metabolism is an important metabolic mediator of treatment resistance in glioblastoma (GBM). Mycophenolate mofetil (MMF), an inhibitor of purine synthesis, synergizes with radiation and temozolomide in mouse models of GBM. No measurements of purine synthesis have been performed in human cancer patients, nor has the purine inhibitor MMF been used clinically for patients with GBM. Methods: We infused clinical-grade 13C6 glucose into patients undergoing craniotomy for presumed GBM and used mass spectrometry to measure carbon incorporation into purines in cortex and disparate tumor regions. We are conducting a phase 0/1 trial (NCT04477200) to determine the safety and potential efficacy of the purine inhibitor MMF in patients with GBM. In the phase 0 arm, patients with recurrent GBM needing tumor re-resection receive MMF for one week prior to surgery and tumor and brain tissue is analyzed by mass spectrometry to determine drug concentrations and target engagement. In the phase 1 portions, patients (age &amp;gt;18, KPS ≥ 60) with recurrent GBM are treated with MMF and a second course of radiation while patients with newly diagnosed GBM are treated with radiation (RT), temozolomide (TMZ) and MMF followed by cyclic MMF and TMZ. A TITE-CRM algorithm is employed to dose-escalate MMF (range 500-2000 mg BID) and determine its maximum tolerated dose in combination with RT and/or TMZ. Results: Stable isotope tracing has been performed on 8 patients with suspected GBM. Purine synthesis was increased in tumor tissue compared to normal cortex in all patients, with most patients having 10-30-fold increased purine labeling in tumor. We have enrolled 8 patients on our phase 0 peri-surgical study and all had active concentrations of mycophenolic acid (the active metabolite of MMF) in enhancing and non-enhancing GBM tissue. We have enrolled 28 evaluable phase 1 patients (13 recurrent, 15 new). No dose-limiting toxicities have been observed with MMF (1000-2000 mg BID) in combination with re-irradiation or cyclic TMZ. In concurrent chemoradiation with MMF, we have observed two dose limiting grade 3 toxicities at 2000 mg, both improved with treatment break. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 patients is 15.6 months, which compares favorably with typical survival time of 8-10 months in this population. In the newly diagnosed cohort, median survival is not yet reached, but 14 of 15 patients are alive and without progressive tumor. Conclusions: Glucose-derived purine synthesis is elevated in human GBM compared to cortex, which could provide a favorable therapeutic index for purine synthesis inhibition. The purine synthesis inhibitor MMF achieves active concentrations in human GBM, is reasonably well tolerated in combination with standard GBM treatments, and is associated with promising preliminary clinical outcomes. Citation Format: Yoshie Umemura, Andrew J. Scott, Wajd Al-Holou, Anjali Mittal, Weihua Zhou, Kari Wilder-Romans, Jie Xu, Nathan Qi, Maureen Kachman, Michelle Kim, Larry Junck, Denise Leung, Nathan Clarke, Jason Heth, Bo Wen, Amit Pai, Vijay Tarnal, Deepak Nagrath, Theodore Lawrence, Costas A. Lyssiotis, Daniel R. Wahl. Measuring and inhibiting purine metabolism in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1093.

The Combination Therapy of Glucocorticoids, Tacrolimus, and Mycophenolate Mofetil in Primary Membranous Nephropathy Coexisting with Type 2 Diabetes Mellitus: A Retrospective Study

ABSTRACT Background: Primary membranous nephropathy (pMN) is treated with glucocorticoids or immunosuppressive agents, depending on the disease severity. However, treating pMN with type 2 diabetes mellitus (T2DM) remains challenging. Methods: We retrospectively collected and analyzed the data of patients diagnosed with pMN and T2DM. The low-dose multitarget regimen consists of prednisone (10 mg/d), tacrolimus (0.05 mg/kg/d, blood concentration 5–10 ng/mL), and mycophenolate mofetil (1 g/d); The cyclophosphamide (CTX) regimen consists of prednisone (initial dose 1 mg/kg/d) and CTX (0.8–1.0 g/month, cumulative dose 6–9 g). Results: Sixty-seven patients were diagnosed with pMN and T2DM, and 28 were enrolled in this study, with 14 cases each in the low-dose multitarget and CTX groups. Urinary protein excretion decreased significantly in both groups after treatment, which was significantly greater in the low-dose multitarget group than that in the CTX group (2 months: −4800.48 ± 3002.65 mg/24h versus −1663.32 ± 4113.98 mg/24h, P −BH = 0.045; 12 months: −7289.25 ± 2520.92 mg/24h versus −4512.79 ± 3448.85 mg/24h, P −BH = 0.044). Serum albumin levels increased more in the low-dose multitarget group than in the CTX group, although the difference was not significant. Patients treated with glucocorticoids plus CTX had worse glycemic control in two months. Conclusion: The combination of glucocorticoids, tacrolimus, and mycophenolate mofetil was effective for treating pMN with T2DM and not inferior to the CTX regimen in proteinuria reduction. Further studies are needed to confirm the regimen's influence on blood glucose and long-term efficacy.

Successful Use of Mycophenolate Mofetil as Adjunct to Prednisolone for Treatment of Acute Kidney Injury Secondary to Human Serum Albumin Administration in a Dog.

The use of human serum albumin (HSA) is described in dogs receiving critical care. However, despite the high degree of homology, anaphylactic and delayed hypersensitivity reactions are reported. Delayed type III hypersensitivity reactions can lead to glomerulonephritis and acute kidney injury (AKI). Undiluted 20% HSA was administered to a 4.8 yr old intact male Labrador Retriever with severe hypoalbuminemia, following surgical management of septic peritonitis of gastrointestinal origin. Nineteen days after HSA administration, the dog developed peracute high magnitude renal proteinuria and AKI. Rapid immunosuppression, using a combination of prednisolone and mycophenolate mofetil, resulted in full resolution of AKI, hypoalbuminemia, and proteinuria. Addition of mycophenolate mofetil may have resulted in the first documented case of full renal recovery from hypersensitivity-induced AKI caused by HSA administration.

Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703

Introduction: Controlling both GVHD and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success. For three decades, the standard GVHD prophylaxis strategy has been a calcineurin inhibitor such as tacrolimus (Tac) plus methotrexate (MTX). Although several approaches have been tried in recent years to improve upon Tac/MTX, intensifying immunosuppression frequently comes with an increased risk of serious infections or relapse and usually no effect on chronic GVHD even if acute GVHD is reduced. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) previously completed a phase II study comparing three novel GVHD prophylaxis regimens to contemporaneous controls receiving Tac/MTX (BMT CTN 1203) in order to determine the most promising novel GVHD prophylaxis approach with reduced intensity conditioning (RIC). The most promising GVHD prophylaxis regimen in BMT CTN 1203 was a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF). Here, we report the results of the randomized phase III study comparing outcomes of alloHCT in those randomized to receive PTCy/Tac/MMF versus standard Tac/MTX. Patients and Methods: Eligible adults (age 18+) with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (N=128), 8/8 matched unrelated (N=288), or 7/8 single mismatch (N=15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status were randomized 1:1 to receive PTCy/Tac/MMF (N=214) or Tac/MTX (N=217), stratified by transplant center and Disease Risk Index (DRI). The primary endpoint of the study was GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause. The primary hypothesis was that PTCy/Tac/MMF has a ≥15% higher GRFS at 1 year than Tac/MTX in the intent-to-treat population. Secondary endpoints included the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival. Results: The 2 study arms were well balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy (Figure panel A). In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GRFS than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted 1-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm, Figure panel B). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GVHD. The Day 100 grade III-IV acute GVHD was 6.3% vs 14.7% (p=0.001), and chronic GVHD rate at 1 year was 21.9% vs 35.1% (p=0.005) for PTCy vs Tac/MTX, respectively. There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%, p=0.9), or OS rate at 1 year post transplant (76.8% vs 72.6% , p=0.3), in PTCy vs Tac/MTX. The cumulative incidence of engraftment was lower for PTCy for neutrophils ≥ 500/mm3 by day +28 (90.3% vs 93.4%, p=0.03), platelets ≥ 50,000/mm3 by day +100 (79.5% vs 83.7%, p<0.001), and lymphocytes ≥ 1000/mm3 by 1 year (47.1% vs 63.2%, p<0.001). Grade 3 infection rates were similar between the arms (12.2% for PTCy vs 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% vs 23.5%, p=0.002). There was no difference in CMV reactivation between the treatment arms (7.3% for PTCy vs 7.1%, p=0.8). There was no significant difference in proportion of chimerism at day +100 (>95% donor in 68.6% for PTCy vs 67.8%, p=0.2) or secondary graft failure between the arms (2.9% for PTCy vs 0.9%, p=0.2). Conclusions: BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal