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.     

Hodgkin lymphoma patients in first remission: routine positron emission tomography/computerized tomography imaging is not superior to clinical follow‐up for patients with no residual mass

There is no consensus regarding optimal follow‐up mode for Hodgkin lymphoma (HL) patients that achieve complete remission following chemotherapy or combined chemo‐ and radiation therapy. Several studies demonstrated high sensitivity of positron emission tomography/computerized tomography (PET/CT) in detecting disease progression; however, these techniques are currently not recommended for routine follow‐up. This retrospective study conducted in two Israeli (N = 291) and one New Zealand academic centres (N = 77), compared a group of HL patients, followed‐up with routine imaging every 6 months during the first 2 years after achieving remission, once in the third year, with additional dedicated studies performed due to symptoms or physical findings (Group I) to a group of patients without residual masses who underwent clinically‐based surveillance with dedicated imaging upon relapse suspicion (Group II). Five‐year overall survival (OS) was 94% and median time to relapse was 8·6 months for both modes. Relapse rates in Groups I and II were 13% and 9%, respectively. During the first 3 years of follow‐up, 47·5 and 4·7 studies were performed per detected relapse in Groups I and II, respectively. The current study demonstrated no benefit in either progression‐free survival (PFS) or OS in HL patients followed by routine imaging versus clinical follow‐up. The cost was 10 times higher for routine imaging.     

No survival benefit associated with routine surveillance imaging for Hodgkin lymphoma in first remission: a Danish‐Swedish population‐based observational study

The use of routine imaging for patients with classical Hodgkin lymphoma (HL) in complete remission (CR) is controversial. In a population‐based study, we examined the post‐remission survival of Danish and Swedish HL patients for whom follow‐up practices were different. Follow‐up in Denmark included routine imaging, usually for a minimum of 2 years, whereas clinical follow‐up without routine imaging was standard in Sweden. A total of 317 Danish and 454 Swedish comparable HL patients aged 18–65 years, diagnosed in the period 2007–2012 and having achieved CR following ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)/BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) therapy, were included in the study. The cumulative progression rates in the first 2 years were 4% (95% confidence interval [CI] 1–7) for patients with stage I–II disease vs. 12% (95% CI 6–18) for patients with stage III–IV disease. An imaging‐based follow‐up practice was not associated with a better post‐remission survival in general (P = 0·2) or in stage‐specific subgroups (P = 0·5 for I–II and P = 0·4 for III–IV). Age ≥45 years was the only independent adverse prognostic factor for survival. In conclusion, relapse of HL patients with CR is infrequent and systematic use of routine imaging in these patients does not improve post‐remission survival. The present study supports clinical follow‐up without routine imaging, as encouraged by the recent Lugano classification.     

Circulating Citrullinated Vimentin Fragments Reflect Disease Burden in Ankylosing Spondylitis and Have Prognostic Capacity for Radiographic Progression

Objective

Ankylosing spondylitis (AS) has been considered a seronegative rheumatic disease based on absent or low levels of antibodies against citrullinated proteins. The present study was undertaken to evaluate whether a citrullinated and matrix metalloproteinase–degraded fragment of vimentin (VICM) could be a prognostic biomarker in AS.

Methods

VICM was measured in serum samples from healthy controls (n = 35), control patients with rheumatoid arthritis (RA) (n = 47), and patients with AS (n = 201). The optimal cutoff for diagnostic sensitivity and specificity was determined by receiver operating characteristic curve analysis. Baseline and 2‐year spine radiographs were available from 118 AS patients, and were scored using the modified Stoke AS Spine Score (mSASSS). We assessed correlations with patient demographic characteristics (age, disease duration), disease activity (Bath AS Disease Activity Index [BASDAI], C‐reactive protein level), and disease severity (mSASSS) using Spearman's rho. The independent association of VICM with 2‐year radiographic progression, defined as a change of >0 in the mSASSS or the development of a new syndesmophyte, was analyzed by multivariate regression.

Results

Levels of degraded VICM were significantly higher in both RA patients and AS patients than in healthy controls (both P < 0.001). AS patients with the highest levels of VICM had the largest burden of disease (P < 0.01), i.e., highest mSASSS score and BASDAI. VICM levels were significantly and independently associated with radiographic progression after 2 years (β = 0.69, P = 0.0005). Patients with both a high VICM level and a high baseline mSASSS had the highest risk of radiographic progression (odds ratio 13 for mSASSS change, 32 for new syndesmophytes), with progression occurring in 67% of these patients.

Conclusion

The present findings show that serum VICM may be of prognostic value in AS. The data also suggest that citrullination may be relevant in AS pathogenesis.

     

Long‐term follow‐up of dose‐adjusted EPOCH plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group

This prospective multi‐institutional phase II study was designed to assess the efficacy and safety of dose‐adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphomas. Eighty‐one patients diagnosed with diffuse large B‐cell lymphoma (DLBCL, n = 68), primary mediastinal DLBCL (n = 6) and follicular lymphoma Grade 3b (n = 7), with an age‐adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21–77). Sixty‐five patients (80·2%) achieved complete response. After a median follow‐up time of 64 months, 10‐year event‐free survival and overall survival (OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10‐year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B‐cell tumours and germinal centre B‐cell without BCL2 rearranged tumours. Results achieved with DA‐EPOCH‐R showed a good long‐term outcome and a tolerable toxicity profile in high‐risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high‐risk DLBCL patients.     

Phase II study of HCVIDD/MA in patients with newly diagnosed peripheral T‐cell lymphoma

A phase II study was performed to evaluate the efficacy of hyper‐fractionated cyclophosphamide, vincristine, pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarabine (HCVIDD/MA) in patients with newly diagnosed peripheral T‐cell lymphoma (PTCL), excluding ALK‐positive anaplastic large cell lymphoma. Fifty‐three patients were enrolled. Treatment was planned for up to 8 cycles but only 9% of patients received more than 6 cycles due primarily to disease progression (n = 13) or prolonged thrombocytopenia (n = 12). The overall response rate was 66% with a complete response rate of 57%. Median progression‐free survival (PFS) was 7·5 months. With a median follow‐up of 7·6 years, 5‐year PFS and overall survival (OS) were 21% and 48%, respectively. The patients with extranodal Natural Killer‐cell lymphoma had a shorter PFS (median, 2·4 months) than other subtypes. Grade 3/4 anaemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79% of patients, respectively. Of note, 23% of patients discontinued therapy due to prolonged thrombocytopenia. In conclusion, HCVIDD/MA for the first‐line treatment of PTCL patients is associated with significant myelosuppression leading to poor treatment adherence, and the response and survival outcomes with this regimen are similar to standard CHOP. This study was registered at www.clinicaltrials.gov as #NCT00290433.     

Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid‐refractory,grade III–IV acute graft‐versus‐host disease

Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with steroid‐refractory, acute graft‐versus‐host disease (aGvHD) but comprehensive data on paediatric patients are limited. We retrospectively analysed a cohort of 37 children (aged 3 months‐17 years) treated with MSCs for steroid‐refractory grade III–IV aGvHD. All patients but three received multiple MSC infusions. Complete response (CR) was observed in 24 children (65%), while 13 children had either partial (n = 8) or no response (n = 5). Cumulative incidence of transplantation‐related mortality (TRM) in patients who did or did not achieve CR was 17% and 69%, respectively (P = 0·001). After a median follow‐up of 2·9 years, overall survival (OS) was 37%; it was 65% vs. 0% in patients who did or did not achieve CR, respectively (P = 0·001). The median time from starting steroids for GvHD treatment to first MSC infusion was 13 d (range 5–85). Children treated between 5 and 12 d after steroid initiation showed a trend for better OS (56%) and lower TRM (17%) as compared with patients receiving MSCs 13–85 d after steroids (25% and 53%, respectively; P = 0·22 and 0·06, respectively). Multiple MSC infusions are safe and effective for children with steroid‐refractory aGvHD, especially when employed early in the disease course.     

Long‐term follow‐up of clinical trial patients treated for chronic HCV infection with daclatasvir‐based regimens

Background & Aims

Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long‐term efficacy and safety of daclatasvir‐based regimens administered during clinical studies.

Methods

Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow‐up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non‐responders or responders who relapsed, and characterization of liver disease progression.

Results

Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir‐based regimens (follow‐up cut‐off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype‐1a (42%) or ‐1b (45%) infection, and 18% had cirrhosis. Median follow‐up from parent study follow‐up Week 12 was 111 (range, 11‐246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow‐up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon‐free or interferon‐containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non‐responders, emergent non‐structural protein‐5A (NS5A) and ‐3 (NS3) substitutions were replaced by wild‐type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively.

Conclusions

SVR12 was durable in 99% of recipients of daclatasvir‐based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non‐responders.     

Prognostic significance of programmed cell death‐1‐positive cells in follicular lymphoma patients may alter in the rituximab era

Programmed cell death‐1 (PD‐1) is involved in one of the inhibitory pathways of the B7‐cluster of differentiation (CD) 28 family; this pathway is known to be involved in the attenuation of T‐cell responses and promotion of T‐cell tolerance. PD‐1 is known to negatively regulate T‐cell receptor‐mediated proliferation and cytokine production, lead to alternation in the tumor microenvironment. Although several studies have shown that high levels of PD‐1‐positive cells in follicular lymphoma (FL) patients influence their prognosis, those studies included patients treated without rituximab, and the prognostic impact of PD‐1 positivity in the rituximab era (R‐era) has not yet been elucidated. We retrospectively studied 82 patients with FL uniformly treated with standard R‐CHOP therapy at six institutions between 2001 and 2009 (median follow‐up for survivors: 55 months). We also collected and examined biopsy specimens for diagnosis with respect to PD‐1 positivity. The PD‐1 positivity was significantly higher in male patients and patients with high beta‐2 microglobulin (B2M ≥ 3.0) (P = 0.03 and 0.003, respectively). Three‐year progression free survival (PFS) and overall survival (OS) were 60% and 86%, respectively. By univariate analysis, elevated LDH (P = 0.07) worsened PFS. Male gender (P = 0.03), high FLIPI score (P = 0.05), and high B2M levels (P = 0.08) worsened OS. Multivariate analysis detected no significant prognostic factors, including PD‐1 positivity. However, in male subgroup, high levels of PD‐1‐positive cells were found to be a prognostic factor for PFS. Addition of rituximab might have altered the prognostic impact of PD‐1‐positive cells.     

Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT‐2 follow‐up and post‐hoc analyses on progression‐free survival and tumour growth

The randomized phase III ELOQUENT‐2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3‐year follow‐up data. Endpoints included progression‐free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post‐hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M‐protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1‐, 2‐ and 3‐year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M‐protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.     

Human leucocyte antigen‐B27 subtypes in Korean patients with ankylosing spondylitis: higher B*2705 in the patient group

Aim: To investigate the distribution of human leucocyte antigen (HLA) class I antigens and B27 subtypings in a group of B27(+) ankylosing spondylitis (AS) patients and a group of B27(+) control individuals, and to compare differences in their clinical features using subtyping. Methods: At otal of 143 B27(+) AS samples and 32 B27(+) control samples were collected consecutively from two rheumatology centres in South Korea. All patients were diagnosed according to the modified New York criteria for AS. Medical records of the patients were retrospectively reviewed for demographic information, Bath disease activity index (BASDAI) scores, laboratory parameters at diagnosis and extra‐articular manifestations. Polymerase chain reaction‐sequence‐specific primer typing for the B27 subtypes was performed using the Dynal HLA‐B27 high resolution kit. Results: Whereas subtypes in Korean AS patients include B*2704 (n = 11, 7.7%) B*2705 (n = 130, 90.9%), and B*2710 (n = 2, 1.4%), those of the control groups include B*2704 (n = 11, 34.4%), B*2705 (n = 19, 59.4%), B*2710 (n = 1, 3.1%), and B*2715 (n = 1, 3.1%). The proportion of B*2705 subtypes were significantly higher in the AS group than the control group (P < 0.01). There were no differences in clinical features (peripheral arthritis, uveitis, BASDAI scores) or laboratory parameters between the two groups. Conclusion: In Korean AS patients, not in the control group, the HLA‐B*2705 subtype was higher than other subtypes, in contrast to AS patients from Japan and China. B27 subtypes in AS patients were not associated with clinical features or laboratory parameters.     

High ten‐year remission rates following rituximab,fludarabine, mitoxantrone and dexamethasone (R‐FND) with interferon maintenance in indolent lymphoma: Results of a randomized Study

We report a single‐centre, randomized study evaluating the efficacy and safety of concurrent fludarabine, mitoxantrone, dexamethasone (FND ) and rituximab versus sequential FND followed by rituximab in 158 patients with advanced stage, previously untreated indolent lymphoma, enrolled between 1997 and 2002. Patients were randomized to 6–8 cycles of FND followed by 6 monthly doses of rituximab or 6 doses of rituximab given concurrently with FND . All patients who achieved at least a partial response received 12 months of interferon (IFN ) maintenance. Median ages were 54 and 55 years. The two groups were comparable with the exception of a higher percentage of females (65% vs. 43%) and baseline anaemia (23% vs. 11%) in the FND followed by rituximab group. Complete response/unconfirmed complete response rates were 89% and 93%. The most frequent grade ≥ 3 toxicity was neutropenia (86% vs. 96%). Neutropenic fever occurred in 21% and 16%. Late toxicity included myelodysplastic syndrome (n  = 3) and acute myeloid leukaemia (n  = 5). With 12·5 years of follow‐up, no significant differences based on treatment schedule were observed. 10‐year overall survival estimates were 76% and 73%. 10‐year progression‐free survival estimates were 52% and 51%. FND with concurrent or sequential rituximab, and IFN maintenance in indolent lymphoma demonstrated high response rates and robust survival.     

The survival outcome of patients with relapsed/refractory peripheral T‐cell lymphoma‐not otherwise specified and angioimmunoblastic T‐cell lymphoma

Survival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL ‐NOS ) and angioimmunoblastic T‐cell lymphoma (AITL ) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL ‐NOS (n  = 180) or AITL (n  = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS ) and overall survival (OS ) were calculated from the time of first disease progression (FFS 1, OS 1), from second disease progression (FFS 2, OS 2) and from third progression (FFS 3, OS 3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL ‐NOS , 105 AITL ) experienced progression/relapse. In patients with PTCL ‐NOS , the median durations of FFS 1, FFS 2 and FFS 3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL , they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS 1 and OS 1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.     

Prospective phase II study of rituximab with alternating cycles of hyper‐CVAD and high‐dose methotrexate with cytarabine for young patients with high‐risk diffuse large B‐cell lymphoma

We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R‐HCVAD) alternating with rituximab, high‐dose methotrexate, and cytarabine (R‐MA) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) in diffuse large B‐cell lymphoma (DLBCL). This study randomized patients aged ≤60 years with DLBCL and an age‐adjusted international prognostic index ≥2 to R‐HCVAD/R‐MA or R‐CHOP based on a Bayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate (CRR) was higher with R‐HCVAD/R‐MA than R‐CHOP (P = 0·03); thus, R‐CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R‐HCVAD/R‐MA and R‐CHOP arms respectively; CRR were 82% and 60% respectively (P = 0·13); 3‐year progression‐free survival (PFS) rates were 75·7% and 77·8% respectively (P = 0·53). In the R‐HCVAD/R‐MA arm, 3‐year PFS rates in patients aged 46–60 years and ≤45 years were 70·3% and 87·1% respectively (P = 0·13), and the treatment‐associated early mortality rate in patients >45 years was 12%. In conclusion, R‐HCVAD/R‐MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R‐HCVAD/R‐MA is associated with unacceptable mortality rates.     

Favourable outcomes of poor prognosis diffuse large B‐cell lymphoma patients treated with dose‐dense Rituximab,high‐dose Methotrexate and six cycles of CHOP‐14 compared to first‐line autologous transplantation

The optimal therapeutic approach for young diffuse large B‐cell lymphoma (DLBCL) patients with high‐intermediate and high‐risk age‐adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10‐year single‐centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R‐CHOP‐21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first‐line high‐dose chemotherapy with autologous stem‐cell support (HDCT‐ASCT), resulting in 2‐year progression‐free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP‐14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose‐dense rituximab and high‐dose methotrexate resulting in promising overall response‐ (93·3%) and complete remission (90%) rates and sustained survival (2‐year PFS and OS: 93·3%). In an intention‐to‐treat analysis, 2‐year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox‐regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83–35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28–26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor‐prognosis DLBCL patients appears superior after early therapy intensification.     

Fibrosis evolution in chronic hepatitis B e antigen‐negative patients across a 10‐year interval

The degree of liver fibrosis in chronic hepatitis B (CHB) infection influences outcome and management. Existing data describing the long‐term dynamic changes of liver fibrosis are limited. This study aimed to evaluate the evolution of liver fibrosis in CHB across a 10‐year period. CHB patients with liver stiffness measurement (LSM) by transient elastography 10 years ago were recruited for follow‐up LSM. Fibrosis stages were classified according to EASL‐ALEH guidelines. Fibrosis progression/regression was arbitrarily defined as ≥1 fibrosis stage change from baseline. A total of 459 hepatitis B e antigen (HBeAg)‐negative patients (224 untreated, 235 treated with nucleos(t)ide analogues [NAs]) were recruited. The mean age at baseline LSM was 41.7 ± 9.0 years (56.2% male). Over 10 years, the proportion of patients with advanced fibrosis/cirrhosis significantly reduced from 16.3% to 5.7% (P < 0.001). Fibrosis progression and regression were observed in 8.7% and 37.5%, respectively. No treatment with NAs (OR 2.259, 95% confidence interval [CI]: 1.032‐4.945), metabolic syndrome (OR 4.379, 95% CI: 1.128‐16.999) and hepatic steatosis (OR 7.799, 95% CI: 2.271‐26.776) was associated with fibrosis progression. Liver stiffness decline demonstrated positive correlation with the time after HBsAg seroclearance (r = ?0.50, P < 0.001). Median liver stiffness was higher both at baseline (14.0 vs 6 kPa, P < 0.001) and 10 years (9.1 vs 4.9 kPa, P < 0.001) in patients with cirrhosis‐related complications/hepatocellular carcinoma compared with those without. In conclusion, CHB‐related liver fibrosis changed dynamically across 10 years. Metabolic syndrome and hepatic steatosis were associated with fibrosis progression, while antiviral therapy was associated with fibrosis regression. Patients with HBsAg seroclearance demonstrated time‐dependent decline in liver stiffness.     

Long‐term follow‐up of patients treated with entecavir and peginterferon add‐on therapy for HBeAg‐positive chronic hepatitis B infection: ARES long‐term follow‐up

Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log₁₀ HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates.     

Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long‐term follow‐up study

We analysed the long‐term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu‐mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high‐dose melphalan conditioning for autograft followed by low‐dose total body irradiation conditioning for allogeneic HCT (auto‐allo regimen). Donors included human‐leucocyte‐antigen‐matched siblings (n = 55) or matched unrelated donors (n = 5). With a median follow‐up of 9·8 years, 7‐year overall survival (OS) and progression‐free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft‐versus‐host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post‐transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, five had normal karyotypes, and five were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.     

Next‐generation sequencing‐based detection of circulating tumour DNA After allogeneic stem cell transplantation for lymphoma

Next‐generation sequencing (NGS)‐based circulating tumour DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. We evaluated whether the presence of ctDNA was associated with outcome after allogeneic haematopoietic stem cell transplantation (HSCT) in lymphoma patients. We studied 88 patients drawn from a phase 3 clinical trial of reduced‐intensity conditioning HSCT in lymphoma. Conventional restaging and collection of peripheral blood samples occurred at pre‐specified time points before and after HSCT and were assayed for ctDNA by sequencing of the immunoglobulin or T‐cell receptor genes. Tumour clonotypes were identified in 87% of patients with adequate tumour samples. Sixteen of 19 (84%) patients with disease progression after HSCT had detectable ctDNA prior to progression at a median of 3·7 months prior to relapse/progression. Patients with detectable ctDNA 3 months after HSCT had inferior progression‐free survival (PFS) (2‐year PFS 58% vs. 84% in ctDNA‐negative patients, P = 0·033). In multivariate models, detectable ctDNA was associated with increased risk of progression/death (Hazard ratio 3·9, P = 0·003) and increased risk of relapse/progression (Hazard ratio 10·8, P = 0·0006). Detectable ctDNA is associated with an increased risk of relapse/progression, but further validation studies are necessary to confirm these findings and determine the clinical utility of NGS‐based minimal residual disease monitoring in lymphoma patients after HSCT.