Atypical Chronic Myeloid Leukemia, BCR-ABL1 negative (aCML) is a rare hematological entity, included in the group of myelodysplastic (MDS)/myeloproliferative (MPN) overlap syndromes. It is ...characterized by an aggressive course, a high rate of acute myeloid leukemia (AML) transformation, and a dismal outcome. The clinical presentation includes splenomegaly and leukocytosis with neutrophilia and left-shifted granulocytosis accompanied by granulocytic dysplasia and sometimes multilineage dysplasia. In past years, the disease incidence was likely underestimated, as diagnosis was only based on morphological features. Recently, the improving knowledge in the molecular biology of MDS/MPN neoplasms has made it possible to distinguish aCML from other overlapping syndromes, basing on next generation sequencing. Among the most commonly mutated genes, several involve the Jak-STAT, MAPK, and ROCK signaling pathways, which could be actionable with targeted therapies that are already used in clinical practice, opening the way to tailored treatment in aCML. However, currently, there are few data available for small samples, and allogeneic transplant remains the only curative option for eligible patients.
Summary
The prognostic role of TP53 disruption has been established in diffuse large B‐cell lymphoma (DLBCL). Aim of this analysis was to correlate TP53 mutations by Sanger sequencing, cell of origin ...(COO) profile by Lymph2Cx panel on the NanoString platform and MYC, BCL2 and BCL6 overexpression or re‐arrangements by immunohistochemistry (IHC) and fluorescent in‐situ hybridization (FISH), with outcome in DLBCL patients enrolled into the FIL‐DLCL04 trial (NCT00499018). One hundred and twenty‐five DLBCL patients with tumour block available were analyzed. TP53 was mutated in 11/125 (9%) cases; 60/125 patients received high‐dose chemoimmunotherapy up‐front, as for the randomization arm; COO was reported in 88 patients: 48 germinal centre B‐cell like, 25 activated B‐cell like and 17 unclassified; 26 patients were double expressors in IHC and 11 double hit in FISH. After a median follow‐up of 72 months, five‐year failure‐free survival (FFS) for TP53 mutated versus wild‐type was 24% and 72%, and five‐year overall survival (OS) was 34% and 83%, respectively. Adjusted hazard ratio (HR) was 2·28 95% confidence interval (CI) 0·89–5·86, p = 0·086 and 4·05 (95% CI 1·37–11·97, p = 0·011) for FFS and OS, respectively. In this series of young DLBCL patients, TP53 gene mutation identified a poor prognosis subgroup, regardless of treatment and other biological markers.
Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by ...autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field.
Introduction: High Grade B-cell Lymphomas (HGBL) have been defined as a new separate entity in 2016 revised WHO classification of lymphoid neoplasms. The previously well-known Double- and Triple-Hit ...Lymphomas (DHL/THL) are included in this umbrella category under the name of HGBL with MYC and BCL2 and/or BCL6 rearrangements (HGBL, R). A comprehensive diagnosis of HGBL is laborious, the diagnostic analyses required are expensive and time-consuming; moreover, a uniform consensus on which patients should be investigated has not been reached yet. Furthermore, there is no agreement on a standard therapeutic approach for this entity.
Areas covered: In this article, the biological and clinical peculiarities of HGBL will be reviewed and all tools for a comprehensive diagnosis as well as the current therapeutic landscape will be investigated.
Expert opinion: HGBL, R remains a challenging disease in terms of diagnosis and further research should be performed in order to define clear guidelines determining which cases have to be investigated thoroughly with FISH and other probes. Unsatisfying results have been shown in patients with HGBL, R treated with intensified chemoimmunotherapy strategies, therefore, larger prospective clinical trials should be conducted. Investigation into novel drugs that could lead to improvement of the current therapeutic approach should also be addressed.
Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common histotype in non Hodgkin lymphoma, with a peak incidence in the sixth decade. The standard treatment for elderly FIT DLBCL ...patients is Rituximab-CHOP; in unfit and frail patients, chemotherapy at reduced intensity should be considered.
Areas covered: In this article, we will review use of standard therapies and new drugs investigated such as immonomudulating agents (IMiDs), Bruton Tyrosine Kinase (BTK), in fit, unfit, frail and very elderly DLCBL patients.
Expert commentary: R-CHOP21 in fit DLBCL patients is still the standard of care, while in elderly unfit patients a reduction of doses of cytotoxic drugs or schemes that avoid antracycline should be considered. The Comprensive Geriatric Assesment based in age, comorbidities and functional abilities of daily living is an important tool in elderly, in order to discriminate between fit, unfit or frail patients. Novel drugs represent valid therapeutic options in relapsed/refractory setting so continued participation in clinical trials should be encouraged.
Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential ...regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
•SMZL comprises 4 distinct genetically defined molecular clusters and 2 distinct phenotypically defined immune-microenvironment classes.•The molecular-based nosology of SMZL can improve disease classification and discovery of novel biomarkers and therapeutic vulnerabilities.
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Elderly patients represent a consistent portion of new diagnoses of B cell Non-Hodgkin Lymphoma (B-NHL). The treatment approach in this setting can be challenging for clinicians due to treatment ...toxicities and patients' comorbidities to deal with. Immunochemotherapy still represents the main option in the front-line setting for diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), with different options to choose depending on patient characteristics. In the last decade, a number of new drugs and combinations have been investigated, demonstrating efficacy and safety even in the older population and extending the spectrum of treatment choices for this setting.
This article reviews the majority data in literature on immunochemotherapy regimens and chemo-free approaches available for DLBCL, FL, and MCL in the elderly, both in front-line and relapse/refractory setting, the incoming drugs and how to identify the best option for each patient.
The therapeutic approach for elderly B-NHL is challenging and a tailored approach guided by a geriatric assessment is mandatory, in order to optimize efficacy and minimize treatment-related toxicities. The more extended use of biological drugs may potentially lead to prolonged survival with reduction of toxicities and improved quality of life.
Introduction: Diffuse Large B-cell Lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), with an incidence in Europe of 3.8/100.000/year. A multi-drugs chemoimmunotherapy ...regimen, containing rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP) administrated every 21 days, is the standard therapy for DLBCL patients. The discovery of several biological features of DLBCL has encouraged the introduction of novel drugs in the treatment.
Areas covered: In this article, the use of standard therapies will be reviewed and will be investigated adoption of novel drugs such as Bortezomib, Bruton's tyrosine kinase, IMiDs, Venetoclax, mTOR inhibitors and other biological agents.
Expert commentary: A better knowledge of the biology of DLBCL is mandatory to tailor treatment and to ameliorate the poor prognosis of DLBCL. The addition of novel drugs to standard RCHOP should represent a modern approach in the treatment of DLBCL. Ibrutinib and lenalidomide showed important results in DLBCL and the integration of these drugs in first line treatment is under investigation. Despite encouraging results using novel drugs in the setting of relapsed/refractory DLBCL, the rate of failures still remains at 40%; for these reason, continued participation in clinical trials should be encouraged.
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