A population-based study of transformed marginal zone lymphoma: identifying outcome-related characteristics

Histological transformation of marginal zone lymphoma (tMZL) into diffuse large B-cell lymphoma is associated with poor outcomes. Clinical characteristics associated with transformation risk and outcome after transformation are largely unknown due to scarcity of data. In this population-based study, competing risk analyses were performed to elucidate clinical characteristics associated with developing transformation among 1793 MZL patients using the Netherlands Cancer Registry. Cox regression analyses were performed to elucidate clinical characteristics associated with risk of relapse and mortality after transformation. Transformation occurred in 75 (4%) out of 1793 MZL patients. Elevated LDH and nodal MZL subtype at MZL diagnosis were associated with an increased risk, and radiotherapy with a reduced risk of developing tMZL. Most tMZL patients received R-(mini)CHOP (n = 53, 71%). Age >60 years and (immuno)chemotherapy before transformation were associated with an increased risk of relapse and mortality after transformation. Two-year progression-free survival (PFS) and overall survival (OS) were 66% (95% CI 52-77%) and 75% (95% CI 62-85%) for R-(mini)CHOP-treated tMZL patients, as compared to a PFS and OS both of 41% (95% CI 19-63%) for patients treated otherwise. Our study offers comprehensive insights into characteristics associated with transformation and survival after transformation, thereby optimizing guidelines and patient counseling.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

R-miniCHOP versus R-CHOP in elderly patients with diffuse large B-cell lymphoma: a propensity matched population-based study

For elderly frail patients with diffuse large B-cell lymphoma (DLBCL), an attenuated chemo-immunotherapy strategy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-miniCHOP) was introduced as a treatment option as from 2014 onward in the Netherlands. Although R-miniCHOP is more tolerable, reduction of chemotherapy could negatively affect survival compared to R-CHOP. The aim of this analysis was to assess survival of patients treated with R-miniCHOP compared to R-CHOP. DLBCL patients ≥65 years, newly diagnosed in 2014–2020, who received ≥1 cycle of R-miniCHOP or R-CHOP were identified in the Netherlands Cancer Registry, with survival follow-up through 2022. Patients were propensity-score-matched for baseline characteristics. Main endpoints were progression-free survival (PFS), overall survival (OS), and relative survival (RS). The use of R-miniCHOP in DLBCL increased from 2% in 2014 to 15% in 2020. In total, 384 patients treated with R-miniCHOP and 384 patients treated with R-CHOP were included for comparison (median age; 81 years, stage 3–4; 68%). The median number of R-(mini)CHOP cycles was 6 (range, 1–8). The 2-year PFS, OS and RS were inferior for patients treated with R-miniCHOP compared to R-CHOP (PFS 51% vs. 68%, p p p Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Impact of rituximab biosimilars on overall survival in diffuse large B-cell lymphoma: a Dutch population-based study

In 2017, the European Medicines Agency approved rituximab biosimilars (R-biosimilars) for treatment of diffuse large B-cell lymphoma (DLBCL). Thereafter, the Netherlands was one of the first countries to implement R-biosimilars, given lower costs compared with rituximab originator (R-originator). This study's objective was to investigate whether overall survival (OS) of patients with DLBCL receiving R-biosimilars is similar to patients treated with R-originator. DLBCL patients >18 years, diagnosed between 2014 and 2018, who received at least 1 cycle of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) were identified in the Netherlands Cancer Registry. Patients were categorized into R-originator or R-biosimilars groups based on data from a central repository of the Dutch medicinal drug market. The primary end point was 3-year OS, defined as the time between diagnosis and all-cause death. By the end of 2018, 91% of purchased rituximab were biosimilars. In total, 4429 patients were identified with 876 in the R-biosimilars group and 3553 in the R-originator group. Patients in the R-biosimilars group less frequently received >6 cycles of R-CHOP compared with patients treated with R-originator (24% vs 30%, P = .003). The 3-year OS did not differ between patients treated with R-originator or R-biosimilars (73% vs 73%, P = .855). This was confirmed with a multivariable Cox regression analysis accounting for sex, age, International Prognostic Index score, and number of R-CHOP cycles. In conclusion, the 3-year OS is similar for patients treated with CHOP in combination with R-originator or R-biosimilars and, therefore, favors the use of R-biosimilars in DLBCL treatment management.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Cell-of-origin classification using the Hans and Lymph2Cx algorithms in primary cutaneous large B-cell lymphomas

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma with a diffuse population of large cells (PCFCL-LC) are both primary cutaneous B-cell lymphomas with large-cell morphology (CLBCL) but with different clinical characteristics and behavior. In systemic diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), gene-expression profiling (GEP) revealed two molecular subgroups based on their cell-of-origin (COO) with prognostic significance: the germinal center B-cell-like (GCB) subtype and the activated B-celllike (ABC) subtype. This study investigated whether COO classification is a useful tool for classification of CLBCL. For this retrospective study, 51 patients with PCDLBCL-LT and 15 patients with PCFCL-LC were analyzed for their COO according to the immunohistochemistry-based Hans algorithm and the NanoString GEP-based Lymph2Cx algorithm. In PCFCL-LC, all cases (100%) classified as GCB by both Hans and Lymph2Cx. In contrast, COO classification in PCDLBCL-LT was heterogeneous. Using Hans, 75% of the PCDLBCL-LT patients classified as non-GCB and 25% as GCB, while Lymph2Cx classified only 18% as ABC, 43% as unclassified/intermediate, and 39% as GCB. These COO subgroups did not differ in the expression of BCL2 and IgM, mutations in MYD88 and/or CD79B, loss of CDKN2A, or survival. In conclusion, PCFCL-LC uniformly classified as GCB, while PCDLBCL-LT classified along the COO spectrum of DLBCL-NOS using the Hans and Lymph2Cx algorithms. In contrast to DLBCL-NOS, the clinical relevance of COO classification in CLBCL using these algorithms has limitations and cannot be used as an alternative for the current multiparameter approach in differentiation of PCDLBCL-LT and PCFCL-LC.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

A non-randomized risk-adjusted comparison of lenalidomide plus R-CHOP versus R-CHOP for MYC-rearranged DLBCL patients

Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYCR DLBCL patients.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

The Dutch CAR-T tumorboard experience: population-based real-world data on patients with relapsed or refractory large B-Cell lymphoma referred for CD19-directed CAR T-Cell therapy in The Netherlands

Simple Summary CAR T-cell therapy has emerged as the new standard of care for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), but real-world outcomes differ across countries. Additionally, real-world data on health-related quality of life (HR-QoL) are scarce but important, as they reflect the direct experience of patients. In the Netherlands, patients can be referred to the CAR-T tumorboard, a national CAR-T expert panel, who decide whether CAR-T is a feasible treatment option. This multicenter study reports on the favorable outcomes, including the HR-QoL, of axicabtagene ciloleucel (axi-cel) for patients with R/R LBCL after & GE;2 lines of systemic therapy in the Netherlands. On the other hand, we show that a substantial proportion of patients are still in need of alternative treatments, including improved CAR-T strategies, as they are unfit for or do not respond to axi-cel. Comparing real-world outcomes between cohorts could help to select best practices and further optimize CAR-T treatment.Abstract The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after & GE;2 lines of systemic therapy referred for axi-cel treatment between May 2020-May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Novel approaches in prognosis and personalized treatment of cancer

The routine use of‘personalized cancer medicinein clinical settings has become justifiable for three reasons:(a)Rapid development of targeted therapies directed to various tumor types.(b)Therapeutic efficacy,benefiting from molecular and biological understanding of specific tumor types.(c)Improved proteomic and genomic biomarkers stratifying patients to particular strategies.The major ambition of current clinical research is to increase and optimize‘personalized cancer medicine’.This thesis demonstrates progress on‘personalized cancer medicine’based on four conclusions:(i)Two novel tissue biomarkers,FIH and E2F1,demonstrated independent prognostication for overall survival(OS) of renal cell cancer(RCC) patients,potentially influencing tumor staging and consequent clinical management.(ii)The Memorial Sloan Kettering Cancer Center(MSKCC) risk model is widely usedto allocate patients withmetastatic renal cell cancer(mRCC)into three prognostic risk groups(favourable,intermediate or poor) and correspondingly to differentlytargeted therapies.With a proteomics-based approach a novel biomarker Serum Amyloid Alpha(SAA) was identified in blood of mRCC patients.SAA demonstrated to be a robust and independent predictor for progression-free survival and OS in mRCC patients with equal prognostic accuracy,compared to the MSKCC risk model in two independent patient cohorts.When incorporated in the MSKCC model SAA improved the predictive accuracy of this model and thereforepatients risk categorization.Consequently,SAA -either alone or as part of the MSKCC model-may be used as an objective prognosticbiomarkerformRCC patients and improve the a-priori selection of appropriate risk-directed therapy for every individual,therebycontributingto more tailor-made therapeuticapproaches in clinical practice.(iii)Circulating mitochondrialDNA in plasma of cancer patients quantified by a newly developed and straightforward quantitativePCRshowed prognostic accuracyforOS in several cancer typesand might have significant importance as pan-tumorbiomarker.(iv)The authority of single-gene analysis,confined,as the mutational status throughout the entire pathway,might be responsible for therapy outcome.Another important limitation is that the genetic constitution of the metastasis is unknown.Therefore response to therapy is unpredictable.By employing the novel technology ‘Next Generation Sequencing’ this study comprehensively compared the genetic constitution of a composed ‘Cancer mini-Genome’ in 21 patients with primary CRC and their subsequent hepatic metastases.A ‘Cancer Mini-Genome’ was invented consisting of exons of 1,264 genes, including all relevant oncogenic and therapeutic pathways.Novel and known variations in the up/downstream genes ofEGFR/PI3K/VEGF/mTOR/TGFbeta-pathways were elucidated. On average 83(SD69) potentially function-impairing variations were gained in the metastasis and 70(SD48) variations were lost,showing that the genetic constitution of primary tumor and its subsequent hepatic metastasis are significantly dissimilar.These differencesare of such magnitude that an impact on treatment outcome is realistic andimplicates that for genetic pathway-analysis and subsequent adjustment of targeted therapy a biopsy of the metastasis is preferred to archived primary tumor tissue.This requires a different mindset for oncologists,because biopsies from metastases are not commonly taken at the start of treatment.Conclusively,genetic pathway-analysis of metastases might refine the selection of patients for targeted therapies,justifying additional modifications and optimization of currently treatment algorithm

MYD88 in the driver's seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications

More than 50 subtypes of B-cell non-Hodgkin lymphoma (B-NHL) are recognized in the most recent World Health Organization classification of 2016. The current treatment paradigm, however, is largely based on 'one-size-fits-all' immune-chemotherapy. Unfortunately, this therapeutic strategy is inadequate for a significant number of patients. As such, there is an indisputable need for novel, preferably targeted, therapies based on a biologically driven classification and risk stratification. Sequencing studies identified mutations in the MYD88 gene as an important oncogenic driver in B-cell lymphomas. MYD88 mutations constitutively activate NF-kappa B and its associated signaling pathways, thereby promoting B-cell proliferation and survival. High frequencies of the hotspot MYD88(L265P) mutation are observed in extranodal diffuse large B-cell lymphoma and Waldenstrom macroglobulinemia, thereby demonstrating this mutation's potential as a disease marker. In addition, the presence of mutant MYD88 predicts survival outcome in B-NHL subtypes and it provides a therapeutic target. Early clinical trials targeting MYD88 have shown encouraging results in relapsed/refractory B-NHL. Patients with these disorders can benefit from analysis for the MYD88 hotspot mutation in liquid biopsies, as a minimally invasive method to demonstrate treatment response or resistance. Given these clear clinical implications and the crucial role of MYD88 in lymphomagenesis, we expect that analysis of this gene will increasingly be used in routine clinical practice, not only as a diagnostic classifier, but also as a prognostic and therapeutic biomarker directing precision medicine. This review focuses on the pivotal mechanistic role of mutated MYD88 and its clinical implications in B-NHL.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

High Incidence and Clinical Significance of MYC Rearrangements in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Dermatology-oncolog

Outcomes of rare patients with a primary cutaneous CD30(+) lymphoproliferative disorder developing extracutaneous disease

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