Ethnicity and socio-economic status affects the incidence and survival of hepatosplenic T-cell lymphoma.

To address the lack of contemporary population-based epidemiological studies of hepatosplenic T-cell lymphoma (HSTCL), we undertook a population-based study of ICD-O-3-coded HSTCL in England. We used the National Cancer Registration Dataset and linked datasets on hospital admissions, Systemic Anti-Cancer Therapy, socio-demographics, comorbidities and death, identifying cases from 1 January 2013 to 31 December 2019 with survival data up to 5 January 2021. Crude and directly age-standardised incidence rates per million persons per year were calculated. Crude and adjusted incidence rate ratios compared incidence between groups using Poisson regression. A Cox proportional hazards model estimated mortality risks adjusted for age, sex, ethnicity, deprivation and allogenic stem cell transplant (allo-SCT; time varying). We identified 44 patients, mean age 42 years. Median survival was 11 months, and 1 and 5 year survivals were 48% (95% CI 29%-43%) and 22% (95% CI 12%-42%) respectively. The age-standardised incidence was 0.1 per million/year. Incidence was higher in areas with greater deprivation (0.15 per million/year), and more cases than expected were in non-White patients (39%). Non-Whites had a twofold increased risk of death (adjusted hazard ratio 2.21 [95% CI 1.03-4.78]) even after adjusting for deprivation, younger age and allo-SCT. In conclusion, ethnicity and socio-economic status affect both the incidence and survival of HSTCL.

Outcomes in grade 3B follicular lymphoma: an international study led by the Australasian Lymphoma Alliance.

Grade (G) 3B follicular lymphoma (FL) is a rare FL subtype which exists on a histological continuum between 'lowgrade' (Grade 1, 2 and 3A FL) and diffuse large B-cell lymphoma (DLBCL) appearing to share features with each. Clinical characteristics and outcomes are poorly understood due to lack of adequate representation in prospective trials and large-scale analyses. We analyzed 157 G3BFL cases from 18 international centers, and two comparator groups; G3AFL (n=302) and DLBCL (n=548). Composite histology with DLBCL or low-grade FL occurred in approximately half of the G3BFL cases. With a median of 5 years follow-up, the overall survival and progression-free survival of G3BFL patients was better than that of DLBCL patients (P<0.001 and P<0.001, respectively); however, G3BFL patients were younger (P<0.001) with better performance status (P<0.001), less extranodal disease (P<0.001) and more frequently had normal lactate dehydrogenase (P<0.001) at baseline. The overall and progression-free survival of patients with G3BFL and G3AFL were similar (P=0.83 and P=0.80, respectively). After frontline immunochemotherapy, 24% of G3BFL relapsed; relapse rates were 63% in the DLBCL cohort and 19% in the low-grade FL cohort. Eight percent of relapses occurred beyond 5 years. In this G3BFL cohort, the revised International Prognostic Index successfully delineated risk groups, but the Follicular Lymphoma International Prognostic Index did not. We conclude that patients with immunochemotherapy-treated G3BFL have similar survival outcomes to those with G3AFL, yet a favorable baseline profile and distinctly superior prognosis compared to patients with DLBCL.

Population-based cohort study of the efficacy of brentuximab vedotin in relapsed systemic anaplastic large-cell lymphoma using Public Health England data.

Systemic anaplastic large-cell lymphoma (sALCL) is a rare T-cell lymphoma associated with poor prognosis after relapse. The immunoconjugate brentuximab vedotin (BV) first became available for relapsed sALCL in England in 2013, following the results of a pivotal phase II study. We present a population-based study describing outcomes of relapsed sALCL in England after BV, using Public Health England data. We obtained information on all relapsed/refractory (r/r) sALCL patients ≥18 years treated with BV monotherapy in England between 1 January 2014 and 31 December 2019. The final cohort comprised 127 patients with a median age of 60 years (range 19-89). Eighteen (14·2%) had received stem cell transplant in first remission. Median two-year overall survival (OS) was 46·6%. The vast majority of deaths (59) occurred within 18 months, with very few events after this. Receipt of BV as second line compared to third or fourth line was associated with significantly improved survival (two-year OS 50·3% vs 29·7%, P = 0·03). There was no difference in OS for different subgroups, including anaplastic lymphoma kinase status, age, gender, or receipt of stem cell transplantation in first response. We report excellent survival following treatment with BV in a real-world setting, comparable with previous clinical trial data.

Incidence and survival of haemophagocytic lymphohistiocytosis: A population-based cohort study from England.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare hyper-inflammatory condition with poor outcomes. OBJECTIVES: Few population-based estimates of the incidence and survival in adults exist. We aimed to provide these data for England. METHODS: We used population-based linked data from primary care, secondary care, cancer registries and mortality databases in England to identify people diagnosed with HLH between 1 January 2000 and 31 December 2016. We calculated annual incidence rates by age and sex, modelled change in incidence over time with Poisson regression, calculated overall 1-year survival using Kaplan-Meier methods and estimated adjusted hazard ratios (HRs) of death using a Cox proportional hazards model. RESULTS: We identified 214 patients with HLH. The reported age and sex-adjusted incidence increased twofold over the period, from around one to around two per million. Incidence was highest in those below 1 year (14.6 per million) and ≥75 years (2.2 per million), and lowest in those aged 15-44 years (0.8 per million). One-year survival varied by age and sex from 77% (95% confidence interval [CI] 63%-86%) in those <15 years to 30% (95% CI 14%-49%) in those ≥75. In patients with haematological cancer, the adjusted HR for death was 2.60 (95% CI 1.45-4.66) compared to patients with no malignant or rheumatological disease. CONCLUSION: The incidence of HLH diagnosis in England has increased between 2000 and 2016 and occurs in all ages with varying underlying diseases. One-year survival varies substantially, being particularly poor in those aged over 75 years and those with haematological malignancy.

Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125). The median age at diagnosis was significantly older in the second era compared to the first (69 and 65 years respectively, P = 0·003). The 3-, 6- and 12-month overall survival (OS) rates in the second era were significantly higher compared to the first, at 85%, 77%, 62% versus 56%, 49%, 38% respectively (log-rank test P < 0·0001). On multivariate analysis, high-dose methotrexate (HD-MTX)-based induction protocols employed in the second era were associated with improved OS compared to those used in the first [hazard ratio (HR) 0·40, 95% confidence interval (CI) 0·28-0·57]. Within the second era, superior OS rates were seen with the use of intensive HD-MTX protocols (including consolidation with high-dose chemotherapy and autologous stem cell transplantation) compared to non-intensive HD-MTX schedules (HR 0·47, 95% CI 0·22-0·99). Initiating chemotherapy within 14 days of biopsy and use of rituximab were independently associated with improved OS and progression-free survival during the second era. These data suggest that prompt treatment initiation and use of intensive HD-MTX- and rituximab-based protocols have resulted in improved survival outcomes for patients.

A validation study of the identification of haemophagocytic lymphohistiocytosis in England using population-based health data.

We assessed the validity of coded healthcare data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. Out of 74 patients, 73 were coded D76.1 or D76.2 (positive predictive value 89·0% [95% Confidence Interval {CI} 80·2-94·9%]) with confirmed/probable HLH. For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97·8% [95% CI 88·2-99·9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case-finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. Five hundred and forty-one were coded D76.1 or D76.2 of whom 524 (96·9%) had HLH in the free-text cause of death. Of 157 coded D76.3, 66 (42·0%) had HLH in free text. D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic healthcare data in England can enable population-wide registration and analysis of HLH for future research.

The UK NCRI study of chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced stage follicular lymphoma: molecular response strongly predicts prolonged overall survival.

We present a long-term follow-up of the UK chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced, symptomatic follicular lymphoma (FL). This trial was the first to prospectively assess molecular response and the impact on outcomes for 400 patients. The median progression-free survival (PFS) and overall survival (OS) for CMD were 3·6 and 14·6 years vs. 3·0 and 15·7 years for FMD, respectively. Estimates for Restricted Mean Survival Time (RMST) suggested no difference in PFS or OS. For the whole cohort there was a highly significant difference in survival by POD24, with a median OS from a risk-defining event of 3·9 years compared to 13·7 years for all others (RMST P < 0·001). Molecular remission was achieved in 25/46 patients (54·3%) in the CMD arm and 20/41 (48·8%) in the FMD arm (P = 0·6). Molecular negativity resulted in median PFS of 5·6 years vs. 2·3 years for molecularly positive (log-rank P < 0·001) and median OS not reached versus 12·5 years (log-rank P < 0·01). No cases of progression occurred in minimal residual disease (MRD) negative patients after six years of follow-up. Although there was no difference in outcomes between arms, this is the first prospective study to report MRD negativity resulting in significantly improved OS.

Impact of Pretransplantation (18)F-Fluorodeoxyglucose-Positron Emission Tomography on Survival Outcomes after T Cell-Depleted Allogeneic Transplantation for Hodgkin Lymphoma.

Pretransplant (18)F-fluorodeoxyglucose (FDG) positron emission tomography status is an important prognostic factor for outcomes after autologous stem cell transplantation (SCT) in Hodgkin lymphoma (HL), but its impact on outcomes after allogeneic SCT remains unclear. We retrospectively evaluated outcomes after T cell-depleted allogeneic SCT of 116 patients with nonprogressive HL according to pretransplant Deauville scores. Endpoints were overall survival (OS), progression-free survival (PFS), relapse rate (RR), and nonrelapse-related mortality (NRM). OS, PFS, and RR did not differ significantly between the Deauville 1 to 2 and Deauville 3 to 5 cohorts (OS: 77.5% versus 67.3%, P = .49; PFS: 59.4% versus 55.7%, P = .43; RR: 20.9% versus 22.6%, P = .28 at 4 years). Differences in PFS remained statistically nonsignificant when comparisons were made between Deauville 1 to 3 and Deauville 4 to 5 cohorts (60.9% versus 51.4%, P = .10), and RR remained very similar (21.5% versus 23.8%, P = .42). Multivariate analyses demonstrated trends toward significance for an effect of Deauville score on PFS (hazard ratio 1.82 for Deauville 4 to 5, P = .06) and for number of lines of prior therapy on OS (hazard ratio 2.34 for >5 lines, P = .10). The latter effect appeared to be driven by higher NRM rather than increased RR. Our findings suggest that Deauville score before allogeneic SCT in patients with nonprogressive HL has a relatively modest impact on survival outcomes in comparison with the impact in autologous SCT and that predictive values for the individual patient remain low, indicating that residual FDG-avid disease should not preclude allogeneic SCT. Furthermore, our findings bring into question the importance of attainment of metabolic complete response in this setting if it is at the expense of increasing NRM risk.

Delineating outcomes of patients with diffuse large b cell lymphoma using the national comprehensive cancer network-international prognostic index and positron emission tomography-defined remission status; a population-based analysis.

The recently devised National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) appears superior to the revised IPI (R-IPI) in delineating outcome in diffuse large B-cell lymphoma. We examined the outcome of a population-based cohort of 223 consecutive patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOP-like immuno-chemotherapy between January 2005 and December 2011 by both the NCCN-IPI and R-IPI, and further stratified outcome by the achievement of both computerized tomography (CT) and positron emission tomography (PET)-CT complete remission (CR), with the latter reassessed using blinded central review by an independent nuclear medicine and radiology specialist. The NCCN-IPI was superior to the R-IPI in identifying patients at very high risk of systemic and/or central nervous system relapse. Notably, both the NCCN-IPI and the R-IPI remained strongly predictive of relapse irrespective of CT or PET-defined remission status following R-CHOP. Patients with high-risk NCCN-IPI scores (≥6) have a dismal outcome following R-CHOP therapy regardless of PET-defined response to R-CHOP. Moreover, such patients appear refractory to salvage chemotherapy and thus require alternative therapeutic approaches, although age and performance status may, for many patients, preclude the safe delivery of a primary intensified regimen. By contrast, patients with NCCN-IPI 1-5 who achieve PET-CR following R-CHOP have excellent outcomes and may merit reduced follow up frequency.

Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia.

Histone deacetylase inhibitor (HDACI)-induced thrombocytopenia (TCP) is a major dose-limiting toxicity of this new class of drugs. Using preclinical models to study the molecular and biologic events that underpin this effect of HDACI, we found that C57BL/6 mice treated with both the HDAC1/2-selective HDACI romidepsin and the pan-HDACI panobinostat developed significant TCP. HDACI-induced TCP was not due to myelosuppression or reduced platelet lifespan, but to decreased platelet release from megakaryocytes. Cultured primary murine megakaryocytes showed reductions in proplatelet extensions after HDACI exposure and a dose-dependent increase in the phosphorylation of myosin light chain 2 (MLC2). Phosphorylation of MLC to phospho-MLC (pMLC) and subsequent proplatelet formation in megakaryocytes is regulated by the Rho-GTPase proteins Rac1, CDC42, and RhoA. Primary mouse megakaryocytes and the human megakaryoblastic cell line Meg-01 showed reductions in Rac1, CDC42, and RhoA protein levels after treatment with HDACIs. We were able to overcome HDACI-induced TCP by administering the mouse-specific thrombopoietin (TPO) mimetic AMP-4, which improved platelet numbers to levels similar to untreated controls. Our report provides the first detailed account of the molecular and biologic processes involved in HDACI-mediated TCP. Moreover, our preclinical studies provide evidence that dose-limiting TCP induced by HDACIs may be circumvented using a TPO mimetic.

Real-world clinical effectiveness and safety of CT-P10 in patients with diffuse large B-cell lymphoma: An observational study in Europe.

The rituximab biosimilar CT-P10 is approved for the treatment of non-Hodgkin lymphoma. Previous studies have demonstrated clinical similarity between CT-P10 and reference rituximab. However, real-world data relating to treatment in patients with DLBCL with rituximab biosimilars are limited. This study collected real-world data relating to the effectiveness and safety of CT-P10 treatment from the medical records of 389 patients with DLBCL (24 centers, five European countries). For the primary outcome (clinical effectiveness), overall survival (OS), progression-free survival (PFS), and best response (BR) were assessed. The percentage (95% confidence interval [95% CI]) of patients alive at 12-, 18-, and 30 months postindex (initiation of CT-P10) was 86% (82.4%-89.4%), 81% (76.9%-84.9%), and 76% (71.2%-80.1%), respectively. The PFS rate (percent, [95% CI]) at 12-, 18-, and 30 months postindex was 78% (74.2%-82.5%), 72% (67.9%-76.9%), and 67% (61.9%-71.7%), respectively. Median OS/PFS was not reached. For 82% (n = 312) of patients, the BR to CT-P10 was a complete response. Adverse events were consistent with known effects of chemotherapy. This international, multicenter study provides real-world data on the safety and effectiveness profile of CT-P10 for DLBCL treatment and supports the adoption of CT-P10 for the treatment of DLBCL.

High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma.

PURPOSE: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Temporal Trends in the Incidence of Hemophagocytic Lymphohistiocytosis: A Nationwide Cohort Study From England 2003-2018.

Hemophagocytic lymphohistiocytosis (HLH) is rare, results in high mortality, and is increasingly being diagnosed. We aimed to quantify the incidence of diagnosed HLH and examine temporal trends in relation to age and associated diseases. Using national linked electronic health data from hospital admissions and death certification cases of HLH that were diagnosed in England between January 1, 2003, and December 31, 2018. We calculated incidence rates of diagnosed HLH per million population by calendar year, age group, sex, and associated comorbidity (hematological malignancy, inflammatory rheumatological or bowel diseases [IBD]). We modeled trends in incidence and the interactions between calendar year, age, and associated comorbidity using Poisson regression. There were 1674 people with HLH diagnosed in England between 2003 and 2018. The incidence rate quadrupled (incidence rate ratio [IRR] 2018 compared to 2003: 3.88, 95% confidence interval [CI] 2.91 to 5.28), increasing 11% annually (adjusted IRR 1.11, 95% CI 1.09 to 1.12). There was a transition across age groups with greater increases in those aged 5-14 years of HLH associated with rheumatological disease/IBD compared with hematological malignancy, with similar increases in HLH associated with both comorbidities for those 15-54, and greater increases in HLH associated with hematological malignancies for those 55 years and older. The incidence of HLH in England has quadrupled between 2003 and 2018. Substantial variation in the incidence occurred with inflammatory rheumatological diseases/IBD-associated HLH increasing more among the younger age groups, whereas in older age groups, the largest increase was seen with hematological malignancy-associated HLH.

Systemic ALCL Treated in Routine Clinical Practice: Outcomes Following First-Line Chemotherapy from a Multicentre Cohort.

INTRODUCTION: Brentuximab vedotin (BV)-CHP is the new standard regimen for first-line treatment of systemic anaplastic large cell lymphoma (sALCL). We undertook a retrospective analysis of consecutive patients diagnosed with sALCL, treated in routine practice, to serve as a benchmark analysis for comparison BV-CHP efficacy in routine practice. METHODS: Patients aged 16 years or older with sALCL treated in seven UK and Australian centres and from 14 additional centres from the UK Haematological Malignancy Research Network database (n = 214). Treatment allocation was clinician choice and included best supportive care (BSC). Main outcomes were time to treatment failure (TTF) and overall survival (OS). Multivariable analysis for predictors of both TTF and OS was also undertaken. RESULTS: The median age 52 years (range 16-93), 18% ECOG ≥ 3 and 40% of cases were ALK positive. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) was employed in 152 (71%) of patients and CHOEP (CHOP + etoposide) in 4% of patients. For CHOP-treated patients overall response rate (ORR) was 65% and complete response (CR) 47%. Only 9% of patients underwent autologous stem cell transplant (ASCT). With 57 months median follow-up, 4-year TTF and OS were 41.2% (95% CI 33.1-49.1) and 58.9% (95% CI 50.3-66.5) respectively. Multivariable analysis showed ALK+ status was independently associated with superior TTF (HR 0.36, 95% CI 0.21-0.63) but not OS (0.44, 95% CI 0.18-1.07). DISCUSSION: We present a retrospective analysis with mature follow-up of one of the largest multicentre populations of sALCL available, comparable to similar large retrospective studies. ALK status remains a strong predictor of outcomes. CONCLUSION: These data serve as a robust benchmark for BV-CHP as the new standard of care for sALCL. Similar real-world evidence with BV-CHP will be desirable to confirm the findings of ECHELON-2.

Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors.

The deacetylase inhibitors are a structurally diverse class of targeted antineoplastic agents that have demonstrated in vitro and in vivo preclinical activity in a wide range of malignancies. Based on this preclinical activity, several deacetylase inhibitors have undergone rapid clinical development in recent years. Among these, the deacetylase inhibitor panobinostat is one of the most widely studied, with extensive pharmacokinetic, pharmacodynamic and dose-finding data available across a wide variety of hematologic and solid tumors. Furthermore, panobinostat has demonstrated favorable clinical activity against various hematologic malignancies, most notably lymphomas and myeloid malignancies in Phase I and II studies. In this article, we discuss the preclinical data on panobinostat and emerging data from Phase I and II studies in cancer patients.