MYD88 wild‐type Waldenstrom Macroglobulinaemia: differential diagnosis,risk of histological transformation,and overall survival

MYD88 mutations are present in 95% of Waldenstrom Macroglobulinaemia (WM) patients, and support diagnostic discrimination from other IgM‐secreting B‐cell malignancies. Diagnostic discrimination can be difficult among suspected wild‐type MYD88 (MYD88^WT) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD88^WT WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD88^WT WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10‐year survival was 73% (95% confidence interval [CI] 52–86%) for MYD88^WT versus 90% (95% CI 82–95%) for mutated (MYD88^MUT) WM patients (Log‐rank P < 0·001). Multivariate analysis only showed MYD88 mutation status (P < 0·001) as a significant determinant for overall survival. Diffuse large B‐cell lymphoma (DLBCL) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD88^WT and MYD88^MUT patients, respectively (Odds ratio 23·3; 95% CI 4·2–233·8; P < 0·001). Overall survival was shorter among MYD88^WT patients with an associated DLBCL event (Log‐rank P = 0·08). The findings show that among suspected MYD88^WT WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD88^WT disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD88^MUT disease.     

How we manage Bing–Neel syndrome

Bing–Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.     

Transformed Waldenström macroglobulinaemia: clinical presentation and outcome. A multi‐institutional retrospective study of 77 cases from the French Innovative Leukemia Organization (FILO)

Histological transformation (HT) to diffuse large B‐cell lymphoma (DLBCL) is a rare and poorly reported complication of Waldenström macroglobulinaemia (WM). We performed a retrospective study of 77 WM patients with biopsy‐proven transformation to DLBCL. The median time from WM diagnosis to HT was 4·6 years and 16 patients (21%) had never been treated for WM. At HT, extranodal sites were observed in 91% of patients with a rather high incidence of central nervous system, cutaneous or testicular involvement. Fluorodeoxyglucose‐positron emission tomography was performed in half of the patients and the median maximum standardized uptake value was 15 for transformed disease. More than 80% of cases with available data for assessment by the Hans’ algorithm harboured a non‐germinal centre B‐cell phenotype. First‐line treatment for transformation consisted of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)‐like regimen in 85% of patients. The overall response rate after first‐line treatment was 61% and the median overall survival was only 16 months for the entire cohort. Time to transformation above 5 years (P = 0·0004) and elevated LDH (P = 0·02) were associated with worse outcome. Based on these findings, HT should be considered and lead to a biopsy in WM patients presenting with extranodal involvement, elevated LDH and constitutional symptoms. The optimal therapeutic approaches remain to be defined.     

Increased post‐induction intensification improves outcome in children and adolescents with a markedly elevated white blood cell count (≥200 × 109/l) with T cell acute lymphoblastic leukaemia but not B cell disease: a report from the Children's Oncology Group

Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC ≥200 × 10⁹/l) comprise a unique subset of high‐risk patients with acute lymphoblastic leukaemia (ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group‐1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post‐induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC <200 × 10⁹/l (5‐year event‐free survival 62% vs. 73%, P = 0·0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B‐ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B‐ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival.     

R‐CHOP versus dose‐adjusted R‐EPOCH in frontline management of primary mediastinal B‐cell lymphoma: a multi‐centre analysis

Primary mediastinal (thymic) large B‐cell lymphoma (PMBCL) is an uncommon subtype of non‐Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose‐adjusted (DA) R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R‐CHOP versus DA‐R‐EPOCH. 132 patients were identified from 11 contributing centres (56 R‐CHOP and 76 DA‐R‐EPOCH). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, complete response (CR) rate, and rates of treatment‐related complications. Demographic characteristics were similar in both groups. DA‐R‐EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA‐R‐EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA‐R‐EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment‐related toxicities. At 2 years, 89% of R‐CHOP patients and 91% of DA‐R‐EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R‐CHOP to DA‐R‐EPOCH for PMBCL.     

Peginterferon‐alfa mono‐therapy in the treatment of acute hepatitis C in HIV‐infection

The ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal treatment outcome in HIV co‐infected individuals. Cohort study of 105 HIV‐infected patients with AHC infection from five centres in two European countries was carried out. Choice of treatment with pegIFN‐alfa alone (group 1; n = 36) or pegIFN‐alfa and ribavirin (RBV) (group 2; n = 69) was at the discretion of the investigator. Outcome was evaluated as RVR and SVR. Fisher's exact and Mann Whitney U tests were used for statistical analysis. All patients were male, median age was 39 years, main route of transmission MSM (91%). In 69% of patients, clinical signs of acute hepatic infection were missing, dominant HCV genotypes were 1 (64%) and 4 (16%) and mean baseline HCV‐RNA was 3.559.085 IU/mL. 60% received HAART and CD4 cell count was 469/mm³. Overall SVR rate was 64.8% (68/105). SVR was reached in 69% of treated patients in group 1 and in 63% of treated patients in group 2 (P = 0.67) while RVR was seen in 61% and 49%, respectively (P = 0.35). Interestingly, by univariate analysis, SVR rates in group 1 were significantly higher in patients initiating therapy within 4 weeks of AHC diagnosis compared to patients initiating therapy within 5–36 weeks after diagnosis (P = 0.03). PegIFN‐alfa alone or in combination with ribavirin results in similar response rates in HIV‐infected patients with AHC. In particular, when treatment is initiated within 4 weeks of diagnosis, pegIFN mono‐therapy might be sufficient to allow for an optimal treatment response.     

Renal disease related to Waldenström macroglobulinaemia: incidence,pathology and clinical outcomes

The incidence and prognostic impact of nephropathy related to Waldenström macroglobulinaemia (WM) is currently unknown. We performed a retrospective study to assess biopsy‐confirmed WM‐related nephropathy in a cohort of 1391 WM patients seen at a single academic institution. A total of 44 cases were identified, the estimated cumulative incidence was 5·1% at 15 years. There was a wide variation in kidney pathology, some directly related to the WM: amyloidosis (n = 11, 25%), monoclonal‐IgM deposition disease/cryoglobulinaemia (n = 10, 23%), lymphoplasmacytic lymphoma infiltration (n = 8, 18%), light‐chain deposition disease (n = 4, 9%) and light‐chain cast nephropathy (n = 4, 9%), and some probably related to the WM: thrombotic microangiopathy (TMA) (n = 3, 7%), minimal change disease (n = 2, 5%), membranous nephropathy (n = 1, 2%) and crystal‐storing tubulopathy (n = 1, 2%). The median overall survival in patients with biopsy‐confirmed WM‐related nephropathy was 11·5 years, shorter than for the rest of the cohort (16 years, P = 0·03). Survival was better in patients with stable or improved renal function after treatment (P = 0·05). Based on these findings, monitoring for renal disease in WM patients should be considered and a kidney biopsy pursued in those presenting with otherwise unexplained renal failure and/or nephrotic syndrome.     

Dexamethasone,rituximab and cyclophosphamide for relapsed and/or refractory and treatment‐naïve patients with Waldenstrom macroglobulinemia

The management of Waldenström macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide (DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88^WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88^L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate (ORR) was 87%. The median progression‐free survival (PFS) and time‐to‐next‐therapy (TTNT) were 32 (95% confidence interval [CI]: 15–51) and 50 (95% CI: 35–60) months, respectively. In the previously untreated cohort (n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23–not reached [NR]) and NR (95% CI: 37–NR), respectively. Twenty‐five (86%) of 29 genotyped patients harbored MYD88^L265P. The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well‐tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed‐duration option, with preliminary data suggesting efficacy independent of the patients’ MYD88 status.     

Multiple myeloma: routes to diagnosis,clinical characteristics and survival – findings from a UK population‐based study

Prompt cancer diagnosis may align UK survival with European averages. We examined the impact of route to diagnosis on survival for multiple myeloma patients diagnosed 2012–2013 using data from our population‐based patient cohort that links to national death notifications and collects details on treatment and response (n = 441). Emergency presentation was associated with advanced disease and poorer outcomes, and was the commonest route to diagnosis (28·1%) followed by General Practitioner urgent (19·0%) and two‐week wait (17·2%) referrals. CRAB (elevated C alcium, R enal failure, A naemia, B one lesions) distribution varied by route (P < 0·001), with patients with emergency presentations most likely to have ≥2 features and significantly worse survival (log‐rank test χ² = 13·8, P = 0·0002).     

Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: an analysis of the Surveillance,Epidemiology and End Results database

Waldenström macroglobulinaemia (WM) is a rare and incurable lymphoma. Given that the survival of WM patients can be prolonged, our objective was to describe trends in overall survival (OS) and analyse competing risks of death in patients with WM. The analysis included 5784 patients diagnosed with WM between 1991 and 2010 from the Surveillance, Epidemiology and End Results (SEER) database. Multivariate hazard models for OS and cumulative incidence of death were fitted according to epoch of diagnosis (1991–2000 vs. 2001–10) while adjusting for age, sex, race, histology, site of involvement and registry. Median OS for the 1991–2000 and the 2001–10 cohorts was 6 and 8 years, respectively (P < 0·001). In the multivariate analysis, better OS [hazard ratio (HR) 0·73, 95% confidence interval (CI) 0·67–0·79; P < 0·001] was seen in the 2001–10 cohort. Survival benefits were identified, for the 2001–10 cohort, in almost every stratum analysed, with the exception of patients aged <50 years and blacks. In the multivariate competing‐risk analysis, the 2001–10 cohort experienced lower rates of WM‐related (HR 0·57, 95% CI 0·49–0·66; P < 0·001) and non‐WM‐related deaths (HR 0·72, 95% CI 0·66–0·79; P < 0·001). In conclusion, there have been significant improvements in OS, WM‐related and non‐WM‐related mortality in patients with WM diagnosed in the last decade.     

Prognostic value of complete remission status at end‐of‐treatment FDG‐PET in R‐CHOP‐treated diffuse large B‐cell lymphoma: systematic review and meta‐analysis

This study systematically reviewed and meta‐analysed the prognostic value of complete remission status at end‐of‐treatment ¹⁸F‐fluoro‐2‐deoxy‐d ‐glucose positron emission tomography (FDG‐PET) in diffuse large B‐cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP). The systematic PubMed/MEDLINE search yielded seven suitable studies comprising a total of 737 R‐CHOP‐treated DLBCL patients who were in complete remission at end‐of‐treatment FDG‐PET. Overall, the methodological quality of included studies was reasonable. The disease relapse rate among all patients with complete remission status according to end‐of‐treatment FDG‐PET ranged from 7·0% to 20·0%, with a weighted summary proportion of 13·7%. Five of seven studies reported progression‐free survival (PFS) of these patients at various specific time points, i.e., 2‐year PFS (n = 1), estimated 3‐year PFS (n = 3) and 5‐year PFS (n = 1), which was 83%, 85–86·4% and 75%, respectively. Three of seven studies reported overall survival (OS) of these patients at various specific time points, i.e., estimated 3‐year OS (n = 2) and estimated 5‐year OS (n = 1), which were 90%, 93·6% and 83%, respectively. In conclusion, a non‐negligible proportion of R‐CHOP‐treated DLBCL patients who achieve complete remission according to end‐of‐treatment FDG‐PET experiences disease relapse during follow‐up.     

Issue Information ‐ Editorial Board

We analysed the long‐term outcome of 35 children and adolescents (<20 years at diagnosis) with chronic myeloid leukaemia (CML) in chronic phase: 20 patients had received interferon‐alpha and/or tyrosine kinase inhibitors (TKIs), and 15 underwent a haematopoietic stem cell transplant. The 10‐year survival probabilities were similar in transplanted and non‐transplanted patients (73·3% vs. 72·1%, respectively), whereas the survival probability was significantly lower in patients diagnosed before 1999 compared to those diagnosed afterwards (62·1% vs. 100%, P = 0·0384). The availability of TKIs and the standardized molecular monitoring have significantly improved treatment, management and outcome in children and adolescents with CML.     

Autologous stem cell‐based therapy for sickle cell leg ulcer: a pilot study

Recurrent chronic leg ulcers are among the most severe vasculopathic complications of sickle cell disease (SCD). Their treatment remains a challenge. Stem cell therapy with bone marrow mononuclear cells (BMMC) is a promising new therapeutic option for other forms of chronic ulcers. This prospective pilot study was performed to evaluate safety and feasibility of BMMC implantation in patients with SCD and chronic leg ulcers (SCLU). Ulcer closure, recurrence and local pain were evaluated. BMMC were successfully administered to 23 SCLU patients and no serious adverse events occurred. During the 6‐month follow‐up period, 91·3% of patients had improved ulcer pain compared with baseline and 29·2% of the treated ulcers achieved total healing. The frequency of progenitor stem cells (CD34CD45^low and fibroblast colony‐forming units) in BMMC was found to be significantly reduced in SCLU patients and compared to SCD patients without ulcers (P < 0·004 and P < 0·01, respectively). No relationship was observed between treatment outcome and the number of implanted BM progenitor stem cells. In conclusion, BMMC implantation is a feasible and safe procedure, showing favourable outcomes for the treatment of SCLU, and encouraging further controlled clinical trials.     

High‐dose CD20‐targeted radioimmunotherapy‐based autologous transplantation improves outcomes for persistent mantle cell lymphoma

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high‐dose anti‐CD20 radioimmunotherapy (RIT)‐based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high‐dose RIT‐based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT‐based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT‐based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation‐based strategies in a risk‐adapted approach to ASCT for persistent MCL.     

CXCR4 WHIM‐like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88L265P‐directed survival signalling in Waldenström macroglobulinaemia cells

CXCR4^WHIM frameshift and nonsense mutations follow MYD88^L265P as the most common somatic variants in Waldenström Macroglobulinaemia (WM), and impact clinical presentation and ibrutinib response. While the nonsense (CXCR4^S338X) mutation has been investigated, little is known about CXCR4 frameshift (CXCR4^FS) mutations. We engineered WM cells to express CXCR4^FS mutations present in patients, and compared their CXCL12 (SDF‐1a) induced signalling and ibrutinib sensitivity to CXCR4^{wild‐type (WT)} and CXCR4^S338X cells. Following CXCL12 stimulation, CXCR4^FS and CXCR4^S338X WM cells showed impaired CXCR4 receptor internalization, and enhanced AKT1 (also termed AKT) and MAPK1 (also termed ERK) activation versus CXCR^WT cells (P < 0·05), though MAPK1 activation was more prolonged in CXCR4^S338X cells (P < 0·05). CXCR4^FS and CXCR4^S338X cells, but not CXCR4^WT cells, were rescued from ibrutinib‐triggered apoptosis by CXCL12 that was reversed by AKT1, MAPK1 or CXCR4 antagonists. Treatment with an inhibitor that blocks MYD88^L265P signalling triggered similar levels of apoptosis that was not abrogated by CXCL12 treatment in CXCR4^WT and CXCR4^WHIM cells. These studies show a functional role for CXCR4^FS mutations in WM, and provide a framework for the investigation of CXCR4 antagonists with ibrutinib in CXCR4^WHIM‐mutated WM patients. Direct inhibition of MYD88^L265P signalling overcomes CXCL12 triggered survival effects in CXCR4^WHIM‐mutated cells supporting a primary role for this survival pathway in WM.     

Circulating myeloid‐derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up‐front with a risk‐adapted strategy

In the attempt to find a peripheral blood biological marker that could mirror the dysregulated microenvironment of Hodgkin Lymphoma (HL), we analysed the amount of myeloid‐derived suppressor cells (MDSC), including the three main sub‐types (monocytic, granulocytic and CD34 + fraction). The absolute MDSC count was investigated in 60 consecutive newly diagnosed HL patients and correlated with clinical variables at diagnosis and outcome. Patients received standard‐of‐care chemotherapy with the exception of interim fluorodeoxyglucose positron emission tomography (PET‐2)‐positive patients, who were switched early to a salvage regimen. All MDSC subsets were increased in HL patients compared to normal subjects (P < 0·0001) and were higher in non‐responders. However, a strong prognostic significance was limited to immature (CD34⁺) MDSC. A cut‐off level of 0·0045 × 10⁹/l for CD34⁺MDSC resulted in 89% (95% confidence interval [CI] 52–99%) sensitivity and 92% (95% CI 81–98%) specificity. The positive predictive value to predict progression‐free survival was 0·90 for PET‐2 and 0·98 for CD34⁺MDSC count; the negative predictive value was 0·57 for PET‐2 and 0·73 for CD34⁺MDSC. PFS was significantly shorter in patients with more than 0·0045 × 10⁹ CD34⁺MDSC cells/l at diagnosis and/or PET‐2 positivity (P < 0·0001). In conclusion, all circulating MDSC subsets are increased in HL; CD34⁺MDSC predict short PFS, similarly to PET‐2 but with the advantage of being available at diagnosis.     

Combined intravitreal methotrexate and immunochemotherapy followed by reduced‐dose whole‐brain radiotherapy for newly diagnosed B‐cell primary intraocular lymphoma

Primary intraocular lymphoma (IOL) has a propensity for central nervous system (CNS) relapse within 2 years of initial diagnosis, affecting clinical outcome. To reduce CNS relapse, we performed the combination treatment protocols of intravitreal methotrexate injections, methotrexate‐based systemic induction chemotherapy and consolidation high‐dose cytarabine and reduced‐dose whole brain radiation therapy (rdWBRT, 23·4 Gy) for B‐cell primary IOL with or without newly diagnosed CNS involvement. All patients underwent longitudinal brain magnetic resonance imaging (MRI) and cognitive assessment for evaluation of treatment‐induced leucoencephalopathy. Seventeen patients initiated and 16 completed the protocol treatment. CNS relapse occurred in 2 patients and intraocular relapse in 3. Four‐year progression‐free survival (PFS) was 74·9% and 4‐year overall survival (OS) was 86·3%, with a median follow‐up period of 48·9 months. Of 11 patients without CNS involvement, 1 had CNS relapse and 3 intraocular relapse, and 4‐year PFS and OS was 72·7% and 88·9%, respectively. Although white matter abnormalities shown by MRI were significantly increased at 4 years after rdWBRT, only one patient developed mild cognitive impairment. The combination of intravitreal chemotherapy, prophylactic systemic chemotherapy and rdWBRT for primary IOL showed a potential to reduce CNS relapse rate and improved 4‐year PFS and OS without increase of cognitive dysfunction.     

Pre‐ and post‐transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre‐HSCT and during the first and third trimesters after HSCT (post‐HSCT1 and post‐HSCT3). The overall event‐free survival (EFS) was 50%. The cumulative incidence of relapse and non‐relapse mortality was 41% and 9%. Any degree of detectable pre‐HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10⁻³ and ≥1 × 10⁻³, respectively, versus 73% in MRD‐negative patients (P < 0·001). This effect was maintained in different disease remissions, but low‐level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post‐HSCT1 and post‐HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre‐emptive immuno‐therapy.     

Long‐term outcome of hypertensive patients with heart failure with mid‐range ejection fraction: The significance of blood pressure control

Heart failure (HF) with mid‐range ejection fraction (HFmrEF) is a newly suggested entity in HF. Since it has been inadequately addressed, there is an urgent need to determine the profile of HFmrEF patients and the optimal approach to their management. The present study aimed to assess the long‐term clinical outcomes of hypertensive patients with HFmrEF and the impact of blood pressure (BP) on their mortality and cardiovascular outcome. We performed a retrospective observational study that included 121 hypertensive patients with HFmrEF and 149 hypertensives with heart failure and preserved ejection fraction (HFpEF). The median follow‐up was 84 months (22‐122). Our analysis did not reveal any statistically significant difference between the two groups in total mortality (P = 0.34) or cardiovascular mortality (P = 0.54). The total mean survival time was 102.9 months (100.5‐110.1), while the mean survival time was 105.3 months (80.4‐90.2) in HFpEF and 97.6 months (92.7‐102.6) in HFmrEF. An office systolic BP > 139 mm Hg and diastolic BP > 89 mm Hg were significantly associated with both all‐cause mortality (P = 0.02 and P = 0.013, respectively) and cardiovascular mortality (P = 0.02 for both). In HFpEF patients, no significant association was found between outcome and office BP. HFpEF and HFmrEF have similar long‐term outcomes. Suboptimal BP levels are a significant risk factor for an adverse outcome in HFmrEF. Our results emphasize the importance of good BP control in order to achieve better outcomes in hypertensives with impaired EF and HF symptomatology.     

Long‐term entecavir or tenofovir disoproxil fumarate therapy in treatment‐naïve chronic hepatitis B patients in the real‐world setting

The aim of this study was to determine the long‐term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment‐naïve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End‐Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long‐term follow‐up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.