Su Han Lum

Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/μl vs 910/μl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.

An emerging opportunistic infection: fatal astrovirus (VA1/HMO-C) encephalitis in a pediatric stem cell transplant recipient.

Neuroinvasive astrovirus (VA1‐HMO‐C) is an emerging life‐threatening infection in immunocompromised hosts. We describe an 8‐month‐old child who died of VA1/HMO‐C encephalitis following bone marrow transplantation. The diagnosis was only made post‐mortem using RNA deep sequencing of the brain. Repeat analysis of the post‐mortem brain tissue using polymerase chain reaction specific primers for VA1/HMO‐C was positive. Astrovirus VA1/HMO‐C should be included in the evaluation of patients with similar encephalitis.

Long term survival and cardiopulmonary outcome in children with Hurler syndrome after haematopoietic stem cell transplantation

Premature death in untreated children with Hurler syndrome (HS) in the first decade of life is largely due to life-threatening cardiopulmonary complications. We examined the long-term survival and cardiopulmonary outcome in 54 children undergoing haematopoietic stem cell transplantation (HSCT) at the Royal Manchester Children’s Hospital from 1985 to 2008. The median age at first HSCT was 15.1 months. Eighteen had graft failure and nine died after first HSCT. Of 18 patients with graft failure, 17 underwent second HSCT and the remaining one was lost to follow-up (LOF). Twelve were alive-and-engrafted after second HSCT. The overall survival at one year and 20-years was the same at 73.7%. Six children were followed up at the referral centers and excluded from cardiopulmonary endpoint review. Of the 33 evaluable children for the cardiopulmonary endpoints, nine (27.3%) had normal cardiac assessment. Of the four children on angiotensin-converting-enzyme inhibitors, two had mild cardiomyopathy and two had aortic valvular replacement. Twenty (60%) had mild/moderate mitral and/or aortic insufficiencies. Two had overnight hypoxia needing nocturnal non-invasive support. Enzyme level and donor chimerism are important predictors of long-term cardiac outcome.

Molecular monitoring of adenovirus reactivation in faeces after haematopoietic stem-cell transplantation to predict systemic infection: a retrospective cohort study

BACKGROUND Faecal shedding of adenovirus following allogeneic haematopoietic stem-cell transplantation (HSCT) is an early sign of loss of immune control over adenovirus, but there is no consensus on the role of monitoring of faecal adenoviral load by serial testing. We investigated whether serial faecal PCR monitoring could predict the risk of adenoviraemia and survival outcomes after HSCT. METHODS We did a retrospective cohort study at the Royal Manchester Childrens Hospital, Manchester, UK, of patients who had received their first allogeneic HSCT between Feb 1, 2003, and Sept 1, 2016, and adenovirus infection recorded in their medical records. We excluded patients who had received second or third transplants or autologous HSCT transplants. We obtained characteristics of patients and transplants, including mortality and adenoviral reactivation, from medical records and the hospital database. All patients had blood samples tested weekly for adenovirus by PCR until immunosuppression was stopped and CD3 T-cell count recovered to greater than 0·3 × 109/L. Faecal PCR was done before transplantation in all patients, and after transplantation in patients who had diarrhoea, at the onset of symptoms and weekly thereafter until diarrhoea resolved. We analysed all samples available before and after HSCT. We did subgroup analyses for patients undergoing HSCT for cancer versus non-malignant conditions. We also assessed whether 5 log10 copies per g faeces was a suitable predictive threshold for adenoviraemia. FINDINGS We included 341 patients who had undergone a first allogeneic HSCT (median age 4·6 years, IQR 1·5-8·0, range 0-20·0). After HSCT, PCR was done in 4116 faecal samples from 293 (86%) patients who had diarrhoea and in 10 649 blood samples from 341 patients. Follow-up ended on July 14, 2017. 173 (59%) of 293 patients had adenovirus in faecal samples and 63 (18%) of 341 had adenovirus in blood samples. Maximum faecal viral load before adenoviraemia correlated significantly with maximum blood viral load (r=0·51, 95% CI 0·38-0·61, p<0·0001). Faecal adenoviral viral load greater than 5 log10 copies per g faeces was predictive of adenoviraemia (odds ratio 10·2, 95% CI 4·9-21·6, p<0·0001) with sensitivity 75·9% and specificity 74·8%. These values were increased further in patients with cancer, to 86·4% and 87·5%, respectively. Among the 28 patients who had positive faecal and blood samples and who had undergone serial faecal PCR monitoring after HSCT, the median time between reaching the faecal viral load threshold and onset of adenoviraemia was 8·0 days (IQR 2·3-21·8, 95% CI 4·0-16·0). Non-relapse mortality was not associated with adenovirus reactivation in faeces alone (9·2%, 95% CI 5·4-14·3 in patients without reactivation vs 7·8%, 3·8-13·7 in those with positive faeces only), but was significantly increased in patients who developed adenoviraemia (27·0%, 95% CI 16·7-38·4, p<0·0001). INTERPRETATION We identified a threshold faecal viral load that can predict the risk of adenoviraemia. Our findings support proliferation of adenovirus in the gastrointestinal tract before viraemia develops. Faecal PCR is suitable for early detection of children and young adults at risk of adenoviraemia, and its use might help reduce non-relapse mortality in allogeneic HSCT recipients. FUNDING None.

Hematopoietic stem cell transplant for the mucopolysaccharidoses

ABSTRACT Introduction: The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases arising from a deficiency in the enzymes that breakdown glycosaminoglycans. They are characterised biochemically by substrate accumulation and clinically by multi-organ dysfunction and premature death. Critically, an exogenous enzyme may correct the cellular enzyme deficiency. Hematopoietic stem cell transplant (HSCT) has been used in the treatment of MPS for over 30 years. Areas covered: This paper focuses on the principle of HSCT in MPS and presents current evidence of HSCT in MPS. Factors affecting the transplant and disease outcome, as well as strategies to improve outcomes in MPS I are highlighted. Expert opinion: Transplant outcomes have hugely improved over recent decades so that most patients are expected to survive and be engrafted with donor-derived, enzyme-competent leucocytes following a transplant. The influence of an engraftment on the clinical course of the patient depends critically on the age at transplant and the enzyme dose delivered by the graft. Early therapy is best since transplant is better at preventing disease progression than reversing established disease. Some MPS are more transplant-responsive than others, and some organs respond better than others. The clinical outcome of these refractory organs and diseases may be improved beyond what is possible with wild-type donors by enhancing enzyme delivery using gene-modified, autologous cells.

G363(P) The utility of whole- blood and lineage- specific chimerism in predicting graft failure after stem cell transplantation for non- malignant disease

Background and aims Allogeneic haematopoietic stem cell transplantation (HSCT) is widely used to treat non-malignant conditions. Mixed chimerism (MC) is an increasingly observed phenomenon in such cases. This study’s purpose was to explore predictors of MC and graft failure, variations in outcome between patients with complete chimerism (CC) and MC, and the utility of lineage-specific chimerism in predicting graft outcomes. Methods Our patient sample included 284 HSCTs performed in children with non-malignant conditions between July 2000 and March 2017 at our centre. The following variables were considered in each patient: gender, age at transplant, date of transplant, disease, conditioning regimen, T-cell depletion, donor and stem cell source, alive/deceased status, chimerism status. Variables were assessed using univariate and multivariate logistic regression analysis. The relationship between myeloid chimerism, T-cell chimerism and transplant outcomes was also investigated in those patients with lineage-specific analysis. Results In total, 186 patients exhibited CC while 98 patients exhibited MC. Mean age at transplant and conditioning were identified as significant predictors of MC. Year of transplant and chimerism status were identified as significant predictors of graft failure. In 29 out of 49 patients with high-level MC, graft failure was developed. Early myeloid complete donor chimerism was identified as a useful predictor of long- term engraftment and a rising donor T-cell chimerism. Subsequently, an algorithm was created for the clinical management of chimerism in non-malignant disease. Conclusions High-level MC is a better predictor of graft failure than low-level MC. Myeloid chimerism can be used as a reliable indicator of the transplant outcome. T-cell chimerism monitoring can be important in patients with T-cell immunodeficiencies. The algorithm suggested is used to inform and predict graft outcomes as well as the need for specific interventions in patients with a non-malignant disease, whilst utilising lineage- specific (myeloid and T-cell) chimerism.

Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4-Mutated CD4+ Lymphocytopenia

Idiopathic CD4+ lymphocytopenia and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma) are rare diseases in children. We report the first case of a child with STK4‐mutated CD4+ lymphocytopenia who developed Epstein–Barr virus associated MALT lymphoma arising in the salivary gland. The child achieved complete remission with rituximab, and her immunodeficiency was cured by haematopoietic stem cell transplantation. The child remained well 24 months post transplantation.