Addition Of Mycophenolate Mofetil Research Articles

Clinical characteristics analysis of 24 cases of pediatric MOG antibody-associated diseases

ObjectiveTo investigate the clinical characteristics of children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). MethodsA retrospective analysis was conducted on the clinical data, antibody tests, imaging, and factors associated with recurrence in 24 children diagnosed with MOGAD at Wuxi Children's Hospital from December 2017 to December 2023. ResultsAmong the 24 included children, the clinical characteristics at the onset of the first episode included fever (12 cases), headache (8), decreased vision (7), drowsiness (6), convulsions (5), ataxia (3), paralysis of both lower limbs (2), urinary and fecal incontinence (2), and central facial palsy (1). Among them, one case started with paralysis of both lower limbs and urinary retention, and electromyography suggested the involvement of peripheral nerves, leading to the diagnosis of MOG antibody-associated central and peripheral demyelinating syndrome (MOGAD-CCPD). Cranial MRI abnormalities were observed in 20 children, and spinal MRI abnormalities were noted in 6 children. All children responded well to corticosteroids and intravenous immunoglobulin, but 7 children experienced a relapse. Among them, 3 children achieved disease control after the addition of mycophenolate mofetil (CellCept), with no further relapses observed during follow-up. ConclusionThe disease course of MOGAD can be monophasic or relapsing. Most children have a good response to acute phase treatments. For those who relapse, immunosuppressants can be added as maintenance therapy, and the clinical prognosis is generally good. This article reports the first highly rare case in China of MOGAD-CCPD in childhood, suggesting that MOG IgG may serve as a potential biomarker associated with CCPD.

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.

Mending Broken Hearts

Mending Broken Hearts

Comparison of mycophenolate mofetil and calcineurin inhibitor versus calcineurin inhibitor-based graft-versus-host-disease prophylaxis for matched unrelated donor transplant in acute myeloid leukemia. A study from the ALWP of the EBMT.

The association of Cyclosporine A (CsA) and mycophenolate mofetil (MMF) has increased in the setting of reduced intensity conditioning (RIC). Nevertheless, the use of CsA or CsA+MMF has not been reported in a large and uniform cohort. We analyzed 497 patients with acute myeloid leukemia in complete remission (CR) who underwent matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). All patients received a fludarabine busulfan RIC regimen and anti-thymocyte globulin (ATG) with either CsA alone or in combination with MMF. The cumulative incidence (CI) of grade II-IV acute GvHD was 27% (95% CI 21-33%) for CsA and 33% (95% CI 27-38%) for CsA+MMF (p = 0.25). The 2-year CI of chronic GvHD was 38% (95% CI 31-45%) and 33% (95% CI 28-39%) for the CsA and the CsA+MMF group, respectively (p = 0.26). On multivariate analysis, no statistically significant differences with respect to relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), acute and chronic GvHD were found between the two groups, also when conducting a subgroup analysis in peripheral blood stem cells (PBSC) recipients. Our results support the importance of randomized trial to identify patients who could benefit from the addition of MMF in MUD HSCT.

EP05 COVID-19 and the biliary tree: atypical manifestations of disease during the pandemic

Case report - IntroductionCOVID-19, the infectious disease caused by the novel coronavirus SARS-CoV-2, and first described in Wuhan, China in December 2019, has affected more than 19 million patients worldwide and resulted in more than 700,000 deaths at the time of writing1. Patients with rheumatic diseases and those receiving immunosuppressive treatment are felt to be at greater risk of complications from this illness, though registry and trial data should help refine our understanding of these risks. We hereby describe a case of COVID-19 complicating an unusual rheumatic illness, resulting in severe multi-system disease and premature death.Case report - Case descriptionA 69 year-old male presented to rheumatology and haematology with symmetrical polyarthritis, thrombocytopenia (18 x 109/L), eosinophilia (25.4 x 109/L), raised C-reactive protein (CRP, 43 mg/L), positive rheumatoid factor (>200), antinuclear antibody (ANA) and anti-Ro. Bone marrow biopsy did not demonstrate evidence of haematological malignancy. Seropositive rheumatoid arthritis and connective tissue disease overlap were diagnosed, and treatment with Prednisolone 60mg daily was initiated. Despite rituximab and intravenous immunoglobulins, thrombocytopenia deteriorated on reducing corticosteroids, however the addition of mycophenolate mofetil (MMF) allowed gradual prednisolone tapering to 3mg daily. Hydroxychloroquine was briefly added but discontinued due to headaches. MMF was discontinued after he developed fungal pneumonia followed by jaundice. Liver biopsy was consistent with drug-induced cholestasis, attributed to co-amoxiclav, and his liver function tests (LFTs) improved on ursodeoxycholic acid. Following a further deterioration in thrombocytopenia, hyperferritinaemia and new onset erythema nodosum, he had a repeat bone marrow examination. This demonstrated large areas of fibrosis and granulomatous inflammation with a dense, pleomorphic T-cell infiltrate, but no haemophagocytosis. Haematologists felt this was reactive and prednisolone dose was increased to 10mg daily.Six months later he developed cholangitis. Magnetic resonance cholangiopancreatography (MRCP) demonstrated a tight 4cm stricture of the distal common bile duct (CBD) within the head of pancreas, which was diffusely swollen without any clear focal mass. Serum amylase was mildly elevated (316 units/L). Concurrent CT thorax, abdomen and pelvis demonstrated bilateral ground-glass changes within the lungs, and a SARS-CoV-2 nasopharyngeal PCR test was positive, though he had no respiratory symptoms or oxygen requirement at that stage.Sadly, four days after the CT scan and before a planned endoscopic retrograde cholangiopancreatography (ERCP) could be performed, he became markedly hypoxic with plain chest x-ray features suggestive of COVID-19 pneumonia. Despite medical management, including doubling of his prednisolone dose, he rapidly deteriorated and died.Case report - DiscussionThis case highlights an unusual presentation of COVID-19 in a patient with a complex background of inflammatory arthritis with immune-mediated thrombocytopenia. At the time of his final illness, these conditions were managed with steroid monotherapy. Based on the COVID-19 risk matrix recommended by the British Society for Rheumatology, he was not identified as a patient requiring shielding.Cholangitis was the major problem precipitating his final admission to hospital, and at the time of admission he had no respiratory symptoms. One week prior to this admission, his father-in-law had died of COVID-19 pneumonia, though they had not been in recent direct contact. Interstitial lung changes were incidentally noted on a CT performed to identify the cause of cholangitis, which prompted the nasopharyngeal PCR that detected SARS-CoV-2. This occurred prior to widespread routine testing of hospital inpatients for SARS-CoV-2 by PCR. Unfortunately he then rapidly developed COVID-19 pneumonia and died before the underlying cause of cholangitis could be definitively identified, though an MRCP demonstrated an obstructed CBD within a diffusely swollen pancreas, where a differential diagnosis of pancreatic malignancy or autoimmune pancreatitis was suggested by the reporting radiologist. There are emerging case reports of COVID-19 resulting in significant pancreatic injuryand a further recent laboratory analysis has suggested that ACE2 receptors, which are utilised by SARS-CoV-2 to gain entry to host cells, are highly expressed on cholangiocytes at a comparable level to type II alveolar cells. Whilst the ultimate cause of cholangitis will remain unknown in this patient, this case highlights the potential for atypical presentations and extra-pulmonary manifestations of COVID-19. Case report - Key learning points COVID-19 is a multi-system illness which can cause significant extra-pulmonary as well as pulmonary pathology, with emerging reports that the biliary tract and pancreas are frequently affected.Evidence to inform accurate prediction of which patients with rheumatic diseases are at highest risk of acquiring severe COVID-19 disease remains insufficient, with current shielding guidelines based on expert consensus.This case highlights the importance of widespread testing for COVID-19 in hospital patients, as not all patients carrying the SARS-CoV-2 virus will demonstrate classical respiratory features of the disease at the point of admission.

Clinical Profile in Genetically Proven Blau Syndrome: A Case Series from South India

ABSTRACT Purpose: To report the clinical profile of genetically proven Blau syndrome in seven cases from a single center in South India. Materials & Methods: Retrospective case series Results: There were four females and three males. All cases had a history of skin and joint involvement of varying severity. Flexion contractures of the proximal interphalangeal joints were seen in all cases except Case 2. Ocular involvement was bilateral and included keratoconjunctivitis sicca (six cases), granulomatous panuveitis (three cases), granulomatous anterior uveitis (three cases), conjunctival granulomas (three cases), subepithelial corneal opacities (one case), and subretinal granuloma (one case). Other ocular findings included band-shaped keratopathy (five cases) and cataract (three cases). All cases received oral steroids and methotrexate with an addition of mycophenolate mofetil in one case. Visual prognosis was good in all cases. Conclusions: Blau syndrome is underreported in India. This is the largest case series of genetically proven Blau syndrome from South India and highlights the clinical profile of Blau syndrome seen in India.

Calcineurin Inhibitor Alone or in Combination with Mycophenolate Mofetil for Graft-Versus-Host-Disease Prophylaxis in Patients with Acute Myeloid Leukemia Undergoing Transplantation from Matched Unrelated Donors: A Study from the ALWP of the EBMT

Cyclosporine A (CsA) alone or in combination with mycophenolate mofetil (MMF) has been used as graft-versus-host-disease (GvHD) prophylaxis since the development of reduced intensity conditioning (RIC). The association of CsA+MMF, while commonly used after transplantation from a matched unrelated donor (MUD), has never been tested in a large randomized prospective trial. We retrospectively investigated the outcomes of 497 adult patients with AML in complete remission (CR) undergoing a MUD transplant between 2007-2017 using CsA+MMF or CsA alone as GvHD prophylaxis, and registered with the ALWP of the EBMT. Patients had CsA alone (n=183) or CsA+MMF (n=314) as GvHD prophylaxis. All underwent a RIC regimen with fludarabine and busulfan and received anti-thymocyte globulin. The median age at transplant was similar (59 and 60 years in the CsA and CsA+MMF group). The median follow-up was not significantly different between the two groups (33 vs 34 months in CsA and CsA+MMF, respectively). Disease status at transplant was first complete remission (CR1) for 81% in CsA group and 86% in CsA+MMF group (p=NS). Peripheral blood stem cells (PBSC) was the graft source in 93% of patients receiving CsA alone and in 96% of patients who received CsA+MMF (p=0.17). All but 2 patients engrafted. The 100 day cumulative incidence (CI) of grade II-IV and grade III-IV acute GvHD were 30% and 10%, respectively. The 2-year CI of chronic GvHD was 35% and CI of extensive cGvHD was 15%. The 2-year CI of non-relapse mortality (NRM) and relapse were 19% and 25%, respectively. Disease recurrence (n=31), GvHD (n=20) and infection (n=17) were the most common causes of death in the CsA group. Relapse (n=53), GvHD (n=28) and infection (n=28) were the most frequent causes of death in the CsA+MMF group. The 2-year GVHD-free relapse-free survival (GRFS), leukemia- free survival (LFS), and overall survival (OS) were 45%, 56% and 60%, respectively. On multivariate analysis (MVA), no statistically significant differences between the two groups with respect to relapse, NRM, LFS, OS, acute and chronic GvHD were identified. A positive cytomegalovirus serology of the donor was associated with higher NRM [HR=2.03, p In a subgroup analysis in patients in CR1 who received PBSC, no differences were detected between the two groups for relapse, NRM, LFS, OS, or aGvHD. Patients who received CsA alone tended to have a higher cGvHD (p=0.05). However, this finding was not statistically significant in MVA. We observed comparable outcomes in AML patients in CR1 who underwent MUD transplantation and RIC with CsA+MMF or CsA alone as GvHD prophylaxis. This suggests that both strategies may be considered valid approaches. Randomized trials are needed to further assess which patients could benefit from the addition of MMF in GvHD prophylaxis

Comparison of Mycophenolate Mofetil and a Calcineurin Inhibitor Versus Calcineurin Inhibitor Based Graft-Versus-Host-Disease Prophylaxis for Matched Unrelated Donor Transplant for Acute Myeloid Leukemia. a Study from the ALWP of the EBMT

Cyclosporine A (CsA) alone or in combination with mycophenolate mofetil (MMF) has been used as graft-versus-host-disease (GvHD) prophylaxis since the early development of reduced intensity conditioning (RIC). The association of CsA+MMF, while commonly used after transplantation from a matched unrelated donor (MUD), has never been tested in a large randomized prospective trial. We retrospectively investigated the outcomes of adult patients with AML in complete remission (CR) undergoing a MUD transplant using CsA+MMF or CsA alone as GvHD prophylaxis, transplanted between 2007-2017 and registered with the ALWP of the EBMT. Of the 497 patients who were evaluated, 183 received CsA alone and 314 received CsA+MMF. The median age at transplant was similar, being 59 (range, 20-75) years in the CsA group and 60 (range, 21-75) years in the CsA+MMF group. All patients underwent a RIC regimen with fludarabine and busulfan and received anti-thymocyte globulin as part of the conditioning. The median follow-up was 33 (range, 18-60) months in the CsA group and 34 (range, 18-75) months in the CsA+MMF group. Disease status at transplant was first complete remission (CR1) for 81% (n=149) in CsA group and 86% (n=268) in CsA+MMF group (p=NS). Poor risk cytogenetics was reported for 19% of patients who received GvHD prophylaxis with CsA alone and for 15% of patients receiving CsA+MMF (p=NS). Peripheral blood stem cells (PBSC) was the graft source in 93% of patients receiving CsA alone and in 96% of patients who received CsA+MMF (p=0.17). Female to male mismatch was present in 13% and 15% of patients in the CsA goup and CsA+MMF group respectively, (p=NS). All but 2 patients engrafted. The 100 day cumulative incidence (CI) of grade II-IV and grade III-IV GvHD were 30% and 10%, respectively. The 2-year CI chronic GvHD was 35% and CI of extensive cGvHD was 15%. The 2-year CI of non-relapse mortality (NRM) and relapse were 19% and 25%, respectively. Of the 81 patients who died in the CsA group, disease recurrence (n=31), GvHD (n=20) and infection (n=17) were the most common causes of death. One hundred twenty seven patients died in the CsA+MMF group; cause of death was relapse for 53, GvHD for 28 and infection for 28 of them. The 2-year GVHD-free relapse-free survival (GRFS), leukemia- free survival (LFS), and overall survival (OS) were 45%, 56% and 60%, respectively. On multivariate analysis (MVA), no statistically significant differences were found among the two GvHD prophylaxis groups with respect to relapse, NRM, LFS, OS, acute and chronic GvHD. A positive cytomegalovirus serology of the donor was associated with higher NRM [HR=2.03, p<0.001] and higher cGvHD [HR=1.44, p=0.03] and a lower OS [HR 1.66, p<0.001], LFS [HR=1.69, p=0.001] and GRFS [HR=1.75, p<0.001]. In a subgroup analysis of patients in CR1 who received PBSC, (CsA alone, n=138; CsA+MMF, n=257), no differences were detected between the two groups for relapse, NRM, LFS, OS, or aGvHD, but patients who received CsA alone tended to have a higher cGvHD (41% vs 33%, p=0.05). However, on MVA, although the risk of cGvHD was lower in the CsA+MMF group, this finding was not statistically significant [HR=0.67, p=0.08]. Adverse cytogenetics was an independent risk factor for relapse [HR=2.22, p<0.001]. In this study, we observed comparable outcomes in patients with AML in CR1 who underwent MUD transplantation and RIC with CsA+MMF or CsA alone as GvHD prophylaxis. This suggests that both strategies may be considered valid approaches. Additional randomized trials are needed to further assess which patients could benefit from the addition of MMF in GvHD prophylaxis. Disclosures Blaise: Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Socie:Alexion: Consultancy. Chevallier:Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Update on the Systemic Treatment of Pediatric Localized Scleroderma.

Juvenile localized scleroderma (jLS) is an orphan disease that can lead to cosmetic disfiguration and orthopedic problems. Two recent publications review the current recommendations regarding diagnosis, assessment, follow up and treatment of pediatric localized scleroderma cases, both of which suggest the Localized Scleroderma Cutaneous Assessment Tool as an important instrument to assess activity and damage. This review focuses on the systemic treatment of jLS. Systemic treatment includes synthetic and biologic disease-modifying antirheumatic drugs. Systemic therapy is indicated if the lesion crosses any joint, or leads to potential cosmetic disfiguration or orthopedic problems. The only controlled trial of systemic treatment has shown the efficacy of methotrexate, which is the first choice of treatment. It appears superior to phototherapy according to a recently published meta-analysis. In case of methotrexate intolerance, mycophenolate mofetil is an option. In case of methotrexate nonresponse, addition of mycophenolate mofetil, tocilizumab or abatacept seems to be effective. Future treatment options derived and extrapolated from adult trials regarding treatment of skin involvement of systemic scleroderma or fibrosis are promising, as the final pathway in the skin seems to be similar in both diseases.

Mycophenolate mofetil and tacrolimus versus tacrolimus alone for the treatment of idiopathic membranous glomerulonephritis: a randomised controlled trial

BackgroundTacrolimus (TAC) is effective in treating membranous nephropathy (MN); however relapses are frequent after treatment cessation. We conducted a randomised controlled trial to examine whether the addition of mycophenolate mofetil (MMF) to TAC would reduce relapse rate.MethodsForty patients with biopsy proven idiopathic MN and nephrotic syndrome were randomly assigned to receive either TAC monotherapy (n = 20) or TAC combined with MMF (n = 20) for 12 months. When patients had been in remission for 1 year on treatment the MMF was stopped and the TAC gradually withdrawn in both groups over 6 months. Patients also received supportive treatment with angiotensin blockade, statins, diuretics and anticoagulation as needed. Primary endpoint was relapse rate following treatment withdrawal. Secondary outcomes were remission rate, time to remission and change in renal function.Results16/20 (80%) of patients in the TAC group achieved remission compared to 19/20 (95%) in the TAC/MMF group (p = 0.34). The median time to remission in the TAC group was 54 weeks compared to 40 weeks in the TAC/MMF group (p = 0.46). There was no difference in the relapse rate between the groups: 8/16 (50%) patients in the TAC group relapsed compared to 8/19 (42%) in the TAC/MMF group (p = 0.7). The addition of MMF to TAC did not adversely affect the safety of the treatment.ConclusionsAddition of MMF to TAC does not alter the relapse rate of nephrotic syndrome in patients with MN.Trial registrationThis trial is registered with EudraCTN2008–001009-41. Trial registration date 2008-10-08.

Diagnostic Criteria and Treatment Algorithm for Susac Syndrome

Susac syndrome (SS) classically presents with the clinical triad of retinal artery occlusion, sensorineural hearing loss, and encephalopathy and the neuroimaging triad of white matter lesions, deep gray matter lesions, and leptomeningeal disease. However, patients can present with an incomplete clinical or neuroimaging triads making diagnosis difficult in certain situations. A standard treatment paradigm also is lacking in this illness. It is important for neuro-ophthalmologists to recognize clinical and radiographic findings that are pathognomonic for this syndrome and have a basic understanding of the available treatment options. Review of medical literature. A definite diagnosis of SS is made when the clinical triad or the neuroimaging triad is present. There are numerous reports of 2 other imaging findings in this condition: arteriolar wall hyperfluorescence (AWH) on fluorescein angiography in retinal arterioles remote from retinal ischemia and central callosal lesions on MRI. Both of these imaging findings are diagnostic of SS. Gass plaques in retinal arterioles are almost always seen in the acute phase of the illness but are not pathognomonic for SS. The most common medications used in this syndrome are corticosteroids and intravenous immunoglobulin. A number of other medications have been used including mycopheolate, rituximab, azathioprine, and cyclophosphamide. In the absence of the clinical triad or magnetic resonance imaging triad for SS, AWH remote from retinal vascular injury and central callosal lesions are confirmatory of the diagnosis because they have never been described in any other condition. The presence of Gass plaques in retinal arterioles should strongly suggest the diagnosis. Despite the lack of clinical trial data, patients with SS must be treated promptly and aggressively. In more fulminant cases, addition of mycophenolate mofetil or rituximab is required, followed by cyclophosphamide when disease is refractory to other medications.

Cytokine profiles of amyopathic dermatomyositis with interstitial lung diseases treated with mycophenolate

A 59‐year‐old Japanese man diagnosed with interstitial lung disease associated with amyopathic dermatomyositis with anti‐melanoma differentiation‐associated gene 5 (MDA‐5) antibodies was treated with intravenous methyl prednisolone (PSL) 1000 mg, oral PSL 1 mg/kg, and oral cyclosporin 200 mg daily. His respiratory condition worsened after treatment with two times of intravenous cyclophosphamide and another steroid pulse therapy as well as PSL and cyclosporin. Addition of mycophenolate mofetil (MMF), 1.5 g daily improved PaO2/FiO2 (PF) ratio of the patient from 294 to 360 at 4 weeks and 416 at 15 weeks after addition of MMF. We measured cytokine concentration in preserved serum taken at 11 and 7 weeks before addition of MMF and at 4, 11, and 15 weeks after MMF administration. Of the 28 cytokines evaluated, the concentrations of fibroblast growth factors‐2 (FGF‐2), chemokine (C‐X3‐C motif) ligand 1 (CX3CL1), interleukin (IL)‐1ra, IL‐17A, inducible protein 10 (IP‐10), and monocyte chemotactic protein‐1 (MCP‐1) decreased after addition of MMF. These results suggest that MMF may be beneficial to patients with interstitial lung disease by modification of the cytokine/growth factor protein expression.

Dermatomyosite œdémateuse sévère

Edematous dermatomyositis is a rare entity with localized or generalized subcutaneous edema and only 21 cases have been reported in the literature. It is considered to be a severe form of dermatomyositis which needs quick therapeutic decision. We report 2 cases with difficult therapeutic decisions. Two patients aged 23 and 80 years were admitted in hospital for DM with typical cutaneous and muscular involvement without any sign of gravity and which have been treated by steroids: methylprednisolone bolus and prednisone. They both then developed severe edema of the upper limbs as well as worsening of the cutaneous and muscular symptoms with dysphagia. The addition of mycophenolate mofetil and intravenous immunoglobulin has permitted in the case of the first patient the disappearance of the cutaneous symptoms in particular the edema with restitution of the muscular force and withdrawal of the dysphagia and swallowing symptoms. The therapeutic failure for the second patient was due to a refusal of the treatment and a probable paraneoplastic context. Subcutaneous edema localized or generalized must not be confused with periorbital erythematous edema, classically observed in DM, nor with DM with mucinosis. Potential marker of gravity, it is often associated to important muscular weakness and dysphagia. In this case, an aggressive treatment associating corticosteroids, immunosuppressive therapy and intravenous immunoglobulin is necessary.

Studying the Optimal Intravenous Busulfan Exposure in Pediatric Allogeneic Hematopoietic Cell Transplantation (alloHCT) to Improve Clinical Outcomes: A Multicenter Study

s / Biol Blood Marrow Transplant 21 (2015) S79eS107 S102 success using HLA-matched related donors; however, use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplantrelated mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant disorders using alternative donors and PT/Cy. Design: We transplanted 9 patients with non-malignant conditions (CGD1⁄43, DKC1⁄42, DBA1⁄41, HyperIgM1⁄41, XIAP1⁄41, IPEX1⁄41) using an alemtuzamab/fludarabine based reduced intensity conditioning (RIC). All patients received GVHD prophylaxis with PT/Cy, with the addition of mycophenolate mofetil and tacrolimus for HSCT with haploidentical donors and for alkylator-sensitive diagnoses (DKC). Six patients had 10/10 HLA-matched unrelated donors, and 3 had HLA-haploidentical related donors. Results: All 9 patients successfully engrafted by day 30. Ultimately, all patients have had sustained donor engraftment sufficient to eliminate manifestations of their underlying diseases. 6 of 9 patients are full donor chimeras off immunosuppression,1 patient is a stablemixed donor chimera (76% CD3+ T cells) off immunosuppression, 1 patient is a stable mixed donor chimera on a calcineurin inhibitor (CNI), and 1 patient had secondary graft failure but was ultimately retransplanted with myeloablative conditioning using the same donor, resulting in full donor chimerism and elimination of disease. One patient developed Grade 1 and one patient Grade 2 acute GVHD, both treated successfully with steroids and a CNI. Mild skin chronic GVHD developed in 1 patient, treated successfully with phototherapy. No serious infections occurred and there was no TRM. 1 patient developed veno-occlusive disease, treated successfully with defibrotide. Disease-free survival is 89% with a median follow-up of 14 months (6-30 months). The patient with secondary graft failure is now disease-free after myeloablative transplant, for an overall disease-free survival of 100% at a median of 14 months follow-up (6-60 months). Overall survival is 100%. Conclusion: We have observed successful engraftment sufficient to eliminate manifestations of disease, limited GVHD, and no TRM in 9 patients with nonmalignant disorders using alternative donors, RIC, and PT/Cy. RIC HSCT with PT/Cy shows promise for curing nonmalignant pediatric disorders, and potentially eliminates the need for CNI use after MUD BMT. Development of prospective clinical trials to confirm these observations is warranted.

Autologous Transplant/Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency

s / Biol Blood Marrow Transplant 21 (2015) S79eS107 S102 success using HLA-matched related donors; however, use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplantrelated mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant disorders using alternative donors and PT/Cy. Design: We transplanted 9 patients with non-malignant conditions (CGD1⁄43, DKC1⁄42, DBA1⁄41, HyperIgM1⁄41, XIAP1⁄41, IPEX1⁄41) using an alemtuzamab/fludarabine based reduced intensity conditioning (RIC). All patients received GVHD prophylaxis with PT/Cy, with the addition of mycophenolate mofetil and tacrolimus for HSCT with haploidentical donors and for alkylator-sensitive diagnoses (DKC). Six patients had 10/10 HLA-matched unrelated donors, and 3 had HLA-haploidentical related donors. Results: All 9 patients successfully engrafted by day 30. Ultimately, all patients have had sustained donor engraftment sufficient to eliminate manifestations of their underlying diseases. 6 of 9 patients are full donor chimeras off immunosuppression,1 patient is a stablemixed donor chimera (76% CD3+ T cells) off immunosuppression, 1 patient is a stable mixed donor chimera on a calcineurin inhibitor (CNI), and 1 patient had secondary graft failure but was ultimately retransplanted with myeloablative conditioning using the same donor, resulting in full donor chimerism and elimination of disease. One patient developed Grade 1 and one patient Grade 2 acute GVHD, both treated successfully with steroids and a CNI. Mild skin chronic GVHD developed in 1 patient, treated successfully with phototherapy. No serious infections occurred and there was no TRM. 1 patient developed veno-occlusive disease, treated successfully with defibrotide. Disease-free survival is 89% with a median follow-up of 14 months (6-30 months). The patient with secondary graft failure is now disease-free after myeloablative transplant, for an overall disease-free survival of 100% at a median of 14 months follow-up (6-60 months). Overall survival is 100%. Conclusion: We have observed successful engraftment sufficient to eliminate manifestations of disease, limited GVHD, and no TRM in 9 patients with nonmalignant disorders using alternative donors, RIC, and PT/Cy. RIC HSCT with PT/Cy shows promise for curing nonmalignant pediatric disorders, and potentially eliminates the need for CNI use after MUD BMT. Development of prospective clinical trials to confirm these observations is warranted.

Pulmonary hemosiderosis in children with bronchopulmonary dysplasia.

We describe a possible association between pulmonary hemosiderosis (PH) and a history of bronchopulmonary dysplasia (BPD). Both patients were born at 28-week gestation and presented with PH at ages 22 months and 6 years, respectively. Both initially presented with cough and tachypnea, and bronchoalveolar lavage showed evidence of hemosiderin-laden macrophages. Initial hemoglobin levels were < 4 g/dL and chest radiographs showed diffuse infiltrates that cleared dramatically within days after initiation of intravenous corticosteroids. In the first case, frank pulmonary blood was observed upon initial intubation, prompting the need for high frequency ventilation, immediate corticosteroids, and antibiotics. The mechanical ventilation wean was made possible by the addition of mycophenolate mofetil (MMF) and hydroxychloroquine. Slow tapering off of medications was accomplished over 6 years. These cases represent a possible correlation between prematurity-associated BPD and PH. We present a review of the literature regarding this possible association. In addition, MMF proved to be life-saving in one of the PH cases, as it has been in pulmonary hemorrhage related to systemic lupus erythematosus. Further studies are warranted to investigate the possible association between PH and prematurity-related BPD, as well as the use of MMF in the treatment of PH.

The outcomes of mycophenolate mofetil therapy combined with systemic corticosteroids in acute uveitis associated with Vogt‐Koyanagi‐Harada disease

AbstractPurpose: To study the effectiveness of mycophenolate mofetil (MMF) as first‐line therapy in acute uveitis associated with Vogt‐Koyanagi‐Harada (VKH) disease. The outcomes in this group were compared with those of another group of patients who were treated with corticosteroid monotherapy. Methods: 19 patients(38 eyes) diagnosed with acute uveitis associated with VKH were included prospectively. Results: The mean follow‐up period was 27.0±11.1 months. Corticosteroid‐sparing effect was achieved in all patients. Ten patients discontinued treatment without relapse of inflammation. Visual acuity of 20/20 was achieved by 37.5% of the eyes in the corticosteroid group and by 73.7% in the corticosteroid + MMF group. Recurrent inflammation of 3 times or more was reduced significantly in the corticosteroid + MMF group as compared to corticosteroid group. Development of all complications was significantly higher in the corticosteroid group (42.6%) compared to the corticosteroid + MMF group (7.9%). None of the eyes in the corticosteroid + MMF group developed “sunset glow fundus”. Conclusions: Addition of MMF as first‐line therapy to corticosteroids improves clinical outcomes in patients with acute uveitis associated with VKH disease.

Even “Moderate” Dose Cyclophosphamide for Severe Aplastic Anemia Is Associated with Significant Toxicities and Does Not Prevent Relapse and Clonal Evolution

AbstractAbstract 1259Severe aplastic anemia (SAA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. As most patients lack a histocompatible donor, the majority of patients are treated with immunosuppressive therapy (IST) with horse anti-thymocyte globulin plus cyclosporine (h-ATG/CsA). The current limitations of IST in SAA are: 1) most responses are not complete; 2) 1/3 of patients are refractory to initial h-ATG/CsA; 3) hematologic relapses occur in 30–35% of responders following initial response ATG/CsA; 4) and clonal evolution is observed in about 15% of patients at 10 years after first therapy (Scheinberg and Young 2012). Efforts to improve initial IST in treatment-naïve patients with the addition of mycophenolate mofetil and sirolimus to standard h-ATG/CsA or use of lymphocytotoxic agents such as rabbit ATG or alemtuzumab have not yielded better outcomes when compared to standard h-ATG/CsA (Scheinberg and Young 2012). Cyclophosphamide (Cy) has been proposed as an alternative IST regimen to h-ATG/CsA. A pilot and single institution phase II study suggested that high dose Cy (200 mg/kg) yielded similar results to that observed for h-ATG/CsA but with fewer relapses and clonal evolutions (Brodsky, Chen et al. 2010). However, in a randomized study at NHLBI comparing high dose Cy (200 mg/kg) and h-ATG/CsA in treatment-naïve patients excess toxicity and deaths from invasive fungal infections were observed in the Cy arm, which led to the discontinuation of this regimen (Tisdale, Dunn et al. 2000). In a recent Chinese protocol introduced by Dr. Zhang (Institute of Hematology & Blood Disease Hospital, China), lower doses of Cy (30 mg/kg/d * 4 days, 120 mg/kg total) plus CsA, were reported to achieve similar results as with high-dose Cy at 200 mg/kg with reduced toxicity (Kojima, Nakao et al. 2011). Because of the marked improvement in survival in SAA, especially among patients who did not respond to IST, likely due at least in part to improved antifungal drugs (Valdez, Scheinberg et al. 2011), we considered it reasonable to investigate “moderate” dose Cy + CsA as proposed by the Chinese as first line in SAA. The main objective was to assess the safety and efficacy of Cy at 120 mg/kg + low dose CsA, at doses aimed to achieve plasma levels of 100 – 200 mg/L, in treatment-naïve SAA, and the primary hematologic endpoint was response, defined as no longer meeting criteria for SAA, at 6 months. The study was designed to show an increase in complete response rate > 30%, in our experience a surrogate for fewer late events. Prophylactic voriconazole was administered with target levels between 1 – 5.5 ug/L, with ciprofloxacin and Bactrim. From October 2010 to April 2012, 22 patients were accrued. Toxicity from Cy + CsA was considerable and in some cases unexpected, with absolute neutrophil levels of 0/uL universal regardless of pre-therapy blood counts. Granulocyte transfusions were required in 5 participants for uncontrolled infections, and to date 5 patients have died, all from infections. Confirmed fungal infections were documented in 4 participants. In 10 patients with a pre-treatment ANC > 500/uL, 5 remained with severe neutropenia at 6 months as salvage therapies were being sought. In a companion protocol using Cy at 60 mg/kg + fludarabine at 125 mg/m2, neutropenia was also prolonged and severe in a patient leading to pulmonary murcomycosis and need for frequent granulocyte transfusions. In total 9 patients responded to “moderate” dose Cy (120 mg/kg total dose) + CsA, with 4 complete and 5 partial responders. In the relative short follow-up period, cytogenetic abnormalities have been observed in 4 patients: 1 to monosomy 7, 1 del20q, 1 trisomy 15, and 1 del7q. We conclude that Cy at 120 mg/kg + CsA, while capable of producing meaningful hematologic responses in some cases, results in significant toxicity, despite maximum prophylactic and intensive supportive care. The regimen led to very prolonged hospitalizations and frequent bacterial and fungal infections. Hematologic relapses with a higher than expected number of clonal evolution events were observed in our cohort. Due to the high toxicity of Cy (120 mg/kg) + CsA, without likelihood of benefit from decreased relapse and clonal evolution, both protocols using “moderate” dose Cy were terminated by our data and safety monitoring board. Although Cy has activity in SAA, its toxicity is not justified when far less toxic alternatives, such as h-ATG, are available. Disclosures:Off Label Use: Cyclophosphamide in aplastic anemia.

The outcomes of mycophenolate mofetil therapy combined with systemic corticosteroids in acute uveitis associated with Vogt–Koyanagi–Harada disease

To study the effectiveness of mycophenolate mofetil (MMF) as first-line therapy combined with systemic corticosteroids in acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease. The outcomes in this group were compared with those of another group of patients with VKH disease who were treated with corticosteroid monotherapy or with delayed addition of immunomodulatory therapy. This prospective study included 19 patients (38 eyes) diagnosed with acute uveitis associated with VKH disease. The mean follow-up period was 27.0 ± 11.1 months (range 16-54 months). Corticosteroid-sparing effect was achieved in all patients. The mean interval between starting treatment and tapering prednisone to 10 mg or less daily was 5.1 ± 1.2 months (range 3-7 months). Ten (53%) patients discontinued treatment without relapse of inflammation. The mean time observed of treatment was 17.3 ± 11.9 months (range 3-41.5 months). Visual acuity of 20/20 was achieved by 38% of the eyes in the corticosteroid group and by 74% in the corticosteroid + MMF group (p < 0.001). Recurrent inflammation of ≥3 times was reduced significantly (p = 0.0383) in the corticosteroid + MMF group (3%) as compared to corticosteroid group (18%). Development of all complications was significantly higher in the corticosteroid group (43%) compared with the corticosteroid + MMF group (8%) (p < 0.001). None of the eyes in the corticosteroid + MMF group developed 'sunset glow fundus'. Addition of MMF as first-line therapy to corticosteroids in patients with acute uveitis associated with VKH disease leads to significant reduction in recurrences of uveitis and development of late complications and significantly improves visual outcome.

Hot-topic debate on kidney function: Renal-sparing approaches are beneficial

1. Renal function is frequently compromised in candidates for transplantation with advanced cirrhosis. These patients frequently have chronic and irreversible kidney changes at the time of transplantation. 2. The accumulated incidence of chronic renal failure is high in liver transplant recipients. Chronic renal failure has a deleterious impact on the outcome. 3. Calcineurin inhibitor (CNI)-based immunosuppression is highly effective at preventing rejection. However, CNI nephrotoxicity has a central role in the occurrence of chronic renal failure. 4. Renal function impairment frequently occurs within the first year after transplantation. Once renal function is significantly impaired [glomerular filtration rate (GFR) < 60 mL/minute/1.73 m(2) ], any intervention is unlikely to result in a return to normal renal function. Early interventions are needed to prevent chronic and irreversible kidney injury. 5. De novo CNI minimization has been proven to be effective at reducing the rate of impaired renal function after transplantation. The reduction in the CNI doses should be offset by the addition of mycophenolate mofetil or enteric-coated mycophenolate sodium. 6. Delayed CNI minimization in patients with established renal insufficiency may result in a significant improvement in the GFR, even though the increase in the GFR after minimization is generally modest. 7. Mammalian target of rapamycin (mTOR) inhibitors are considered nonnephrotoxic immunosuppressive agents. They may be an option for improving renal function in liver transplant recipients. However, not all patients with renal dysfunction benefit from a switch to mTOR inhibitors. In addition, the benefits in terms of renal function should be balanced against specific side effects. 8. New immunosuppressive agents without intrinsic nephrotoxicity are currently under development for solid organ transplantation. These agents could help to reduce the burden of impaired renal function in transplantation in the near future.