Post-Transplant Lymphoproliferative Disorders: Role of Viral Infection, Genetic Lesions and Antigen Stimulation in the Pathogenesis of the Disease

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication of solid organ transplantation or, more rarely, hematopoietic stem cell transplantation. The majority of PTLD is of B-cell origin and associated with Epstein–Barr virus (EBV) infection. PTLD generally display involvement of extranodal sites, aggressive histology and aggressive clinical behavior. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely EBV, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of cMYC, BCL6, TP53, DNA hypermethylation, and aberrant somatic hypermutation of protooncogenes. The occurrence of IGV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC) B-cells and their descendants both in EBV–positive and EBV–negative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6+/MUM1+/-/CD138− profile reflect B-cells actively experiencing the GC reaction, and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma. PTLD expressing the BCL6−/MUM1+/CD138− phenotype putatively derive from B-cells that have concluded the GC reaction, and comprise the majority of polymorphic PTLD and a fraction of DLBCL immunoblastic. A third group of PTLD is reminiscent of post-GC and preterminally differentiated B-cells that show the BCL6−/MUM1+/CD138+ phenotype, and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic

Investigational drugs for the treatment of diffuse large B-cell lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most frequent lymphoma in adults. 30-40% DLBCL eventually relapse and 10% are primary refractory, posing an unmet clinical need, especially in patients not eligible for hematopoietic stem cell transplant. Knowledge of DLBCL molecular pathogenesis has identified druggable molecular pathways. Surface antigens can be targeted by novel antibodies and innovative cell therapies. Areas covered: This review illuminates those investigational drugs and cell therapies that are currently in early phase clinical trials for the treatment of DLBCL. New small molecules that modulate the pathways involved in the molecular pathogenesis of DLBCL, monospecific and bispecific monoclonal antibodies, drug-immunoconjugates, and cellular therapies are placed under the spotlight. A futuristic perspective concludes the paper. Expert opinion: A precision medicine strategy based on robust molecular predictors of outcome is desirable in the development of investigational small molecules for DLBCL. Novel monoclonal and bispecific antibodies may be offered to (i) relapsed/refractory patients ineligible for CAR-T cells because of comorbidities, and (ii) younger patients before CAR-T cell infusion to reduce a high tumor burden. A focus on the optimal sequencing of the emerging DLBCL drugs is appropriate and necessary

Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study

Tafasitamab; Diffuse large B-cell lymphoma; RelapsedTafasitamab; Limfoma difús de cèl·lules B grans; RecaigudaTafasitamab; Linfoma difuso de células B grandes; RecaídaTafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.This study was sponsored by MorphoSys AG

An update on: molecular genetics of high-risk chronic lymphocytic leukemia

ABSTRACTIntroduction: During the past few years, new genomic approaches have elucidated the molecular genetics of chronic lymphocytic leukemia (CLL) to a large extent. As a consequence, specific hi..

Liquid biopsy in hematological malignancies: current and future applications

The assessment of the cancer mutational profile is crucial for patient management, stratification, and therapeutic decisions. At present, in hematological malignancies with a solid mass, such as lymphomas, tumor genomic profiling is generally performed on the tissue biopsy, but the tumor may harbor genetic lesions that are unique to other anatomical compartments. The analysis of circulating tumor DNA (ctDNA) on the liquid biopsy is an emerging approach that allows genotyping and monitoring of the disease during therapy and follow-up. This review presents the different methods for ctDNA analysis and describes the application of liquid biopsy in different hematological malignancies. In diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), ctDNA analysis on the liquid biopsy recapitulates the mutational profile of the tissue biopsy and can identify mutations otherwise absent on the tissue biopsy. In addition, changes in the ctDNA amount after one or two courses of chemotherapy significantly predict patient outcomes. ctDNA analysis has also been tested in myeloid neoplasms with promising results. In addition to mutational analysis, liquid biopsy also carries potential future applications of ctDNA, including the analysis of ctDNA fragmentation and epigenetic patterns. On these grounds, several clinical trials aiming at incorporating ctDNA analysis for treatment tailoring are currently ongoing in hematological malignancies

Precision Medicine in Systemic Mastocytosis

Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice

Assessing prognosis of chronic lymphocytic leukemia using biomarkers and genetics

Chronic lymphocytic leukemia (CLL) is a clinically and genetically heterogenous disease. Genomic studies have deciphered the pathogenesis of CLL and has allowed the identification of prognostic and..

Targeting p53 in chronic lymphocytic leukemia.

Genomic studies have allowed to identify molecular predictors for chronic lymphocytic leukemia (CLL) treatment tailoring.The review covers the p53 biological pathway, its genetic alterations and clinical implications in CLL, and its druggable targets. The potential therapeutic options forThe key approach to improve CLL outcome is treatment tailoring in individual patients. BCR and BCL2 inhibitors have significantly improved CLL survival, howeve