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This document is a letter to the editor published in the journal Leukemia & Lymphoma. It discusses three cases of tumor flare, a localized inflammatory response, in patients with non-Hodgkin lymphoma who received glofitamab, a T-cell-engaging bispecific monoclonal antibody. The cases range from mild to life-threatening, and multidisciplinary evaluation is recommended when the tumor site is near a vital organ. The authors suggest that ongoing treatment with T-cell-engaging bispecific antibodies may be feasible and beneficial for patients with no other treatment options. [Extracted from the article]

The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT. This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2–8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2–18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed. Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8–32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6–84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6–78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5–59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2–48·7) patients, which were most commonly infections (five [18%; 6·1–36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed. The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT. Roche. [ABSTRACT FROM AUTHOR]

Introduction: Targeting the B-cell receptor pathway via ibrutinib, a specific inhibitor of Bruton's tyrosine kinase, has shown marked clinical efficacy in treatment of patients with chronic lymphocytic leukemia (CLL), thus becoming a preferred first line option independent of risk factors. However, acquired resistance to ibrutinib poses a major clinical problem and requires the development of novel treatment combinations to increase efficacy and counteract resistance development and clinical relapse rates. Case Presentation: In this study, we performed exome and transcriptome analyses of an ibrutinib resistant CLL patient in order to investigate genes and expression patterns associated with ibrutinib resistance. Here, we provide evidence that ibrutinib resistance can be attributed to aberrant mammalian target of rapamycin (MTOR) signaling. Conclusion: Thus, our study proposes that combined use of MTOR inhibitors with ibrutinib could be a possible option to overcome therapy resistance in ibrutinib treated patients. [ABSTRACT FROM AUTHOR]

The Hodgkin variant Richter syndrome (HvRS) is an infrequent complication occurring in 1% of lymphocytic lymphoma/chronic lymphocytic leukemia patients. We report a case of HvRS diagnosed in Sub-Saharan Africa. A 63-year-old patient was consulted for the investigation of an abdominal mass that had been evolving for 5 years prior to admission. His history revealed night sweats, 13% weight loss in 3 months and persistent pruritis. Examination revealed bilateral cervical axillary and inguinal macroadenopathies, painless abdominal distension, pruritic lesions and WHO 2 PS. The blood count showed anemia at 9.5 g/dL. Histology revealed a lymphomatous proliferation of diffuse architecture, nodular in places, with Hodgkin and Sternberg cells associated with small lymphocytes, histiocytes and eosinophilic polymorphs. Immunohistochemistry showed CD20, PAX5, BCL2, CD5, CD23 and MYC positivity; Ki67 at 10% and cyclin D1, BCL6 and CD10 negativity; CD30 positivity on Hodgkin and Sternberg cells that remained CD20 negative; difficulty interpreting CD15; EBV positivity (EBERs); and CD3 and CD5 positivity on reactive T cells. CD138 and kappa and lambda light chains were non-contributory. The extension work-up classified the patient as Ann Arbor stage III B with a Hasenclever score of 3/7. This case illustrates the difficulties in diagnosing HvRS in our countries, where the number of haematopathologists is insufficient and the technical facilities are limited. [ABSTRACT FROM AUTHOR]

AbstractRichter’s transformation (RT) is defined as the evolution of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. This complication is rare and aggressive, with poor prognosis and dismal survival. Clonal relationship with the underlying CLL/SLL, observed in ∼80% of cases, represents one of the main factors affecting prognosis. Treatment has been historically based on chemoimmunotherapy, but frequent mutations in genes involved in cell survival and proliferation—such as TP53, NOTCH1, MYC, CDKN2A—confer resistance to standard treatments. During the last years, advances in the knowledge of the biological mechanisms underlying RT allowed to identify genetic and molecular lesions that can potentially be targeted by novel selective agents. Pathway and checkpoint inhibitors, bispecific antibodies and CAR T-cell therapy are currently under investigation and represent promising treatment options. This review summarizes current biological evidence and available data on novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 μg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT. A combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a commonly used regimen for patients with Richter transformation (RT), an aggressive lymphoma with a poor prognosis. Here the authors report the results of a phase 2 clinical trial of blinatumomab (an anti-CD3/anti-CD19 bispecific T-cell-engager) after R-CHOP bridging therapy for patients with RT. [ABSTRACT FROM AUTHOR]

Richter's transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. MGA (Max gene associated), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of MGA deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of Mga in the Sf3b1/Mdr CLL model using CRISPR-Cas9 to determine the role of Mga in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified Nme1 (nucleoside diphosphate kinase) as an Mga target, which drives RT by modulating OXPHOS. Given that NME1 is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and electron transport chain complex II substantially prolongs the survival of RT mice in vivo. Our results suggest that the Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT. Editor's summary: Richter's transformation (RT) involves the progression of chronic lymphocytic leukemia (CLL) to a more aggressive lymphoma with poor outcomes. Understanding the transition into RT is key to more targeted therapeutic strategies. Iyer et al. examined the role of the MYC suppressor MGA, which is differentially expressed in RT, in an in vivo CLL model with MGA dysfunction. MGA loss resulted in increased mitochondrial function and reactive oxygen species and led to aberrant cell morphology and up-regulated MYC as commonly observed in patients. Combined inhibition of MYC and mitochondrial respiration prolonged in vivo survival in this model, highlighting potential therapeutic strategies for RT with this genetic profile. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Background: Central nervous system involvement in chronic lymphocytic leukemia rarely occurs, and there is no standard therapy for central nervous system involvement in chronic lymphocytic leukemia. This article aims to analyze the diagnosis and treatment of central nervous system involvement in chronic lymphocytic leukemia. Case presentation: It reports two cases of central nervous system involvement in chronic lymphocytic leukemia describing the clinical course, therapy, and prognosis. Case 1 is a 67-year-old Asian male patient, he experienced complications with central nervous system involvement after developing resistance to ibrutinib, bendamustine, and rituximab (BR) chemotherapies. The central nervous system lesion was controlled with high-dose methotrexate combined with pomalidomide, but Richter transformation occurred several months later. Case 2 is a 62-year-old Asian female patient, she had central nervous system involvement at initial diagnosis, and bone marrow and central nervous system lesions were controlled by ibrutinib therapy. Conclusion: Central nervous system involvement in chronic lymphocytic leukemia is rare and can be diagnosed on the basis of clinical features, cerebrospinal fluid testing, and radiographic evaluation. Ibrutinib, pomalidomide, and other drugs that can cross the blood–brain barrier may be effective for treating central nervous system involvement in chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

Introduction. In rare cases, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma may transform into Hodgkin lymphoma, with about a hundred cases reported in the literature so far. We present a case of the Hodgkin variant of Richter transformation. Case report. After a oneyear watch and wait period, a 60-year-old male with CLL developed B symptoms, generalized lymphadenopathy, and splenomegaly. Upon initial staging (Binet B/Rai 3), he was started on fludarabine, cyclophosphamide, and rituximab (FCR) regimen. After the third cycle of treatment, the rightsided axillary lymphadenopathy persisted and became painful, while the dimensions of the remaining organs affected by the disease decreased. Upon the finalization of the final sixth FCR cycle, the painful right-sided axillary lymphadenopathy persisted (though partially decreasing in size), with the development of local redness and swelling. A biopsy of the residual axillary node was performed, which revealed disease transformation into Hodgkin lymphoma. Upon multislice computed tomography-based s taging ( IV E c linical stage) and prognostic assessment (unfavorable prognosis), it was decided that the treatment be continued with doxorubicin, vinblastine, dacarbazine (AVD) regimen. The presented patient died two months after the diagnosis of Hodgkin transformation (HT) was established during the initial cycle of AVD. Conclusion. Although CLL is an indolent malignancy, in rare cases of HT, the prognosis is largely dismal. The available treatment strategies demonstrate suboptimal results, although novel immunotherapies may change the landscape of HT therapy in the near future. [ABSTRACT FROM AUTHOR]

This article discusses the clonal dynamics of Richter transformation in chronic lymphocytic leukemia (CLL). Richter's syndrome (RS) is an aggressive lymphoma that occurs in a small percentage of CLL patients. The study used whole exome sequencing to analyze samples from CLL and RS patients, revealing genomic heterogeneity and clonal evolution during RS transformation. The findings suggest that RS is characterized by the expansion of rare or undetectable clones from the CLL phase, while CLL specimens show relatively stable clonal dynamics. The study highlights the need for timely diagnosis of RS based on symptoms, imaging, and pathology. [Extracted from the article]

Although the chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically, unmet clinical needs are emerging, as CLL in many patients does not respond, becomes resistant to treatment, relapses during treatment, or transforms into Richter. In the majority of cases, transformation evolves the original leukemia clone into a diffuse large B-cell lymphoma (DLBCL). Richter transformation (RT) represents a dreadful clinical challenge with limited therapeutic opportunities and scarce preclinical tools. CLL cells are well known to highly depend on survival signals provided by the tumor microenvironment (TME). These signals enhance the frequency of immunosuppressive cells with protumor function, including regulatory CD4+ T cells and tumor-associated macrophages. T cells, on the other hand, exhibit features of exhaustion and profound functional defects. Overall immune dysfunction and immunosuppression are common features of patients with CLL. The interaction between malignant cells and TME cells can occur during different phases of CLL development and transformation. A better understanding of in vivo CLL and RT biology and the availability of adequate mouse models that faithfully recapitulate the progression of CLL and RT within their microenvironments are "conditio sine qua non" to develop successful therapeutic strategies. In this review, we describe the xenograft and genetic-engineered mouse models of CLL and RT, how they helped to elucidate the pathophysiology of the disease progression and transformation, and how they have been and might be instrumental in developing innovative therapeutic approaches to finally eradicate these malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma is a heterogeneous entity comprised of several distinct biological subtypes. Multiple molecular studies have attempted to classify this histological subtype and identify potential prognostic factors and treatment targets. Among these, the role of TP53, a gene often mutated in many human malignancies, appears particularly relevant. In this review, we summarize the current advances in molecular and genetic subtyping of diffuse large B-cell lymphoma and discuss the pathogenetic and prognostic role of the TP53 pathway alterations. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20–30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL. [ABSTRACT FROM AUTHOR]

Patients with Richter's transformation of chronic lymphocytic leukemia (CLL) to diffuse large B‐cell lymphoma (DLBCL‐RT) face a dismal prognosis. A 51‐year‐old female patient diagnosed with CLL with deletion (17p) in 2009. CLL treatment included chemoimmunotherapy and targeted substances. DLBCL‐RT was diagnosed in November 2016. After receiving an allogeneic hematopoietic stem cell transplantation, she relapsed in September 2019 and tisagenlecleucel was infused in December 2019. Cytokine release syndrome grade 2 was treated with two doses of tocilizumab and the patient was started on 140 mg ibrutinib in February 2020. Our patient remains in remission up to 4 years after CAR T‐cell treatment. [ABSTRACT FROM AUTHOR]

In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0–2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax–rituximab, venetoclax–obinutuzumab, or venetoclax–obinutuzumab–ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1–2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1–3) and intravenous cyclophosphamide (250 mg/m2, days 1–3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax–rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2–6: 1000 mg on day 1). In the venetoclax–obinutuzumab–ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax–rituximab and the venetoclax–obinutuzumab group and between 12 and 36 cycles in the venetoclax–obinutuzumab–ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov , NCT02950051 , recruitment is complete, and all patients are off study treatment. Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax–rituximab group n=237; venetoclax–obinutuzumab group n=229; and venetoclax–obinutuzumab–ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6–57·9]), patients in the venetoclax–obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32–0·69], p<0·0001) and the venetoclax–rituximab group (0·57 [0·38–0·84], p=0·0011). The venetoclax–obinutuzumab–ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19–0·47]; p<0·0001) and the venetoclax–rituximab group (0·38 [0·24–0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax–obinutuzumab–ibrutinib and venetoclax–obinutuzumab groups (0·63 [0·39–1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax–rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9–91·1; 37 [16%] events) in the venetoclax–obinutuzumab–ibrutinib group, 81·8% (75·8–87·8; 55 [24%] events) in the venetoclax–obinutuzumab group, 70·1% (63·0–77·3; 84 [35%] events) in the venetoclax–rituximab group, and 62·0% (54·4–69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax–rituximab group, 127 [56%] of 228 in the venetoclax–obinutuzumab group, and 112 [48%] of 231 in the venetoclax–obinutuzumab–ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax–rituximab and venetoclax–obinutuzumab groups, and four (2%) in the venetoclax–obinutuzumab–ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). With more than 4 years of follow-up, venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax–rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. AbbVie, Janssen, and F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

A 12-year-old spayed female Dalmatian presented with acute vomiting and anorexia. The clinicopathological and imaging abnormalities included icterus, biliary obstruction, and multiple diffuse splenic hypoechogenic nodules. Cholecystectomy was performed to remove the obstruction, followed by liver biopsy and splenectomy. Histopathological and immunohistology evaluation of the spleen, liver, and gallbladder revealed splenic marginal zone lymphoma (MZL) with gallbladder and hepatic infiltration of neoplastic CD20/CD79α-positive cells. Moreover, we observed clonal rearrangements of the immunoglobulin heavy-chain (IgH) gene in all three tissues. The dog was in good condition without chemotherapy. However, there was progressive elevation of liver enzymes, which could be attributed to neoplastic hepatic infiltration. Chlorambucil and prednisolone were administered until day 108, when the liver enzyme levels normalized. On day 156, the dog developed diffuse large B-cell lymphoma (DLBCL) of the peripheral lymph nodes. Sequence analysis of the clonally rearranged IgH gene revealed that all neoplastic cells in the spleen, gallbladder, and liver at initial presentation, as well as lymph nodes on day 156, possessed the same sequence identity of the amplified IgH fragments. This demonstrated that all neoplastic cells were derived from the same B-lymphocyte clone. The DLBCL was considered to have transformed from the splenic MZL, with gallbladder involvement. In cases of splenic MZL, it is important to consider gallbladder involvement and transformation to DLBCL. Moreover, gallbladder lymphoma should be included in the differential diagnosis of dogs with gallbladder abnormalities. Further studies are warranted to investigate the prognosis of splenic MZL. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) typically presents as an indolent disease with a benign disposition in most patients. In select patients, CLL can progress into a more aggressive disease via its original morphology, following a Richter transformation to an alternative non‐Hodgkin's lymphoma, or with the concomitant development of multiple myeloma. In an extremely rare subset of individuals with CLL, an extramedullary plasmacytoma may coexist. This case report seeks to describe the diagnosis and treatment of a patient with concurrent CLL and a plasmacytoma. [ABSTRACT FROM AUTHOR]

Background: Richter transformation refers to the progression of an initially slowgrowing small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) into an aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma. Case presentation: The patient presented with a rapid onset of localized cervical swelling, accompanied by monoclonal B-cell lymphocytosis displaying a CLL immunophenotype. The histopathological analysis identified a Burkitt lymphoma (BL) located in the submandibular gland and adjacent lymph node. The patient's bone marrow displayed a minor infiltration of monoclonal B-cells with a CLL immunophenotype (< 10%). Molecular analysis demonstrated the presence of the same monoclonal rearrangement in the framework region (FR3 region) of the immunoglobulin heavy chain (IGH) locus. High-throughput sequencing of the immunoglobulin heavy and light chains also confirmed the presence of the same rearrangement in SLL/CLL and in the Burkitt lymphoma sample, but also highlighted the presence of a second rearrangement in the Burkitt lymphoma cells, not shared with the SLL/CLL cells in the bone marrow. The patient was treated with DA-EPOCH-R, which lead to a complete metabolic response. Conclusion: This report provides an exceptionally rare description of a CLL-type monoclonal B-cell lymphocytosis transforming into a very aggressive Burkitt lymphoma in a treatment naïve patient. [ABSTRACT FROM AUTHOR]

Simple Summary: Richter transformation (RT) is characterized by the transformation of CCL in the aggressive lymphoma variant with a significant worsening in prognosis. Initial reports about a substantial impact of 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) in predicting RT are available in the literature. Using data from 15 published studies, including 1593 CLL patients, we demonstrated that 2-[18F]FDG uptake expressed as the maximum standardized uptake value (SUVmax) has a high negative predictive value. Richter transformation is a rare phenomenon characterized by the transformation of cell chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma variant. The early identification of CLLs with a high risk of RT is fundamental. In this field, 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) has been shown to be a non-invasive and promising tool, but apparently, unclear data seem to be present in the literature. This systematic review and bivariate meta-analysis aimed to investigate the diagnostic performance of 2-[18F]FDG PET/CT and its parameters in predicting RT. Between 2006 and 2024, 15 studies were published on this topic, including 1593 CLL patients. Among semiquantitative variables, SUVmax was the most investigated, and the best threshold derived for detecting RT was five. With this cut-off value, a pooled sensitivity of 86.8% (95% CI: 78.5–93.3), a pooled specificity of 48.1% (95% CI: 27–69.9), a pooled negative predictive value of 90.5% (95% CI: 88.4–92.4), a pooled negative likelihood ratio of 0.35 (95% CI: 0.17–0.70), a pooled positive likelihood ratio of 1.8 (95% CI: 1.3–2.4), and a pooled diagnostic odds ratio of 6.7 (3.5–12.5) were obtained. With a higher cut-off (SUVmax = 10), the specificity increased while the sensitivity reduced. The other metabolic features, like metabolic tumor volume, total lesion glycolysis, and radiomic features, were only marginally investigated with controversial evidence. [ABSTRACT FROM AUTHOR]

Richter's transformation (RT) is defined as the development of an aggressive lymphoma in 2-10% of patients with chronic lymphocytic leukemia (CLL). Despite significant advances in the last decade, there is currently no established standard of care for RT, making its management a significant challenge. Questions regarding patients' treatment management in the era of novel agents and targeted therapies have yet to be answered. Nevertheless, several retrospective studies and clinical trials have emphasized the use of novel targeted agents to address this problem. In this review, we provide a summary of potential therapeutic options for RT. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma variant of Richter's transformation (HvRT) is a rare complication for patients with chronic lymphocytic leukemia (CLL), with an overall poor prognosis. We present the first known case series of patients with HvRT treated with the combination of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A + AVD). In our series of 4 patients, two patients treated with A + AVD for HvRT had durable remissions of 40 and 42 months, while two patients had disease progression and ultimately died. Continued investigation into the optimal management for patients with HvRT is still needed. [ABSTRACT FROM AUTHOR]

Richter transformation (RT) is defined as developing an aggressive lymphoma in 2–10% of patients suffering from chronic lymphocytic leukemia (CLL). So far, no complex analysis of RT demographics and treatment outcomes has been performed in Poland. Thus, the retrospective analysis of 124 patients with RT from Polish hematology centers was designed. Ninety-nine patients with diffuse large B-cell lymphoma (DLBCL-RT) were identified. The median overall survival (OS) for DLBCL-RT was 17.3 months, while for Hodgkin lymphoma (HL-RT)-21.3 months. In multivariate analysis, the independent factors of worse OS for DLBCL-RT were: prior CLL therapy, ECOG stage ≥2, and elevated serum LDH activity. Patients who proceeded to hematopoietic stem cell transplantation (HSCT) achieved better results. The median OS in allogeneic HSCT recipients was not reached, while in autologous HSCT median OS was 51.3 months. In conclusion, our study represents the largest dataset of patients diagnosed with RT in Poland and confirms its dismal prognosis. [ABSTRACT FROM AUTHOR]

Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton's kinase (BTK) have become the main strategies to restrain CLL activity. These agents are generally well tolerated, but the discontinuation of these therapies happens due to resistance, adverse effects, and Richter's transformation. A growing population of patients who have previously used both BTK inhibitors and BCL2 suffer from the constriction of the following regimens. This review explores the resistance mechanisms for both ibrutinib and venetoclax. Moreover, we present innovative approaches evaluated for treating double-refractory CLL. [ABSTRACT FROM AUTHOR]

Background and Objectives: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in developed countries, which can evolve into aggressive lymphoma variants, a process called Richter transformation (RT). The aim of this retrospective study was to analyze the role of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]-FDG PET/CT) and its semiquantitative and radiomics features in detecting RT and evaluate the impact on overall survival (OS). Materials and Methods: One hundred and thirty-seven patients with histologically proven CLL were retrospectively recruited. PET/CT images were qualitatively and semiquantitatively examined by estimating the main metabolic parameters (the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), lesion-to-blood-pool SUV ratio (L-BP SUV R), lesion-to-liver SUV ratio (L-L SUV R), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and radiomics first- and second- order variables of the lesion with highest uptake. The role of these parameters in predicting RT and OS was analyzed. Results: One hundred and thirty (95%) PET/CT scans were positive, showing an increased tracer uptake at the site of disease, whereas the remaining 7 (5%) scans were negative. SUVbw, SUVlbm, SUVbsa, L-L SUV ratio, and L-BP SUV ratio were significantly higher in the RT group (p < 0.001 in all cases). Radiomics first- and second-order features were not significantly associated with RT. After a median follow-up of 44 months, 56 patients died; OS was significantly shorter in patients with RT than patients without RT (28 vs. 34 months; p = 0.002). Binet-stage, RT, and L-BP SUV R were shown to be independent prognostic features. Conclusions: Semiquantitative PET/CT parameters such as SUVbw, SUVlbm, SUVbsa, L-L SUV ratio and L-BP SUV ratio may be useful in discriminating patients with a high risk of developing RT, whereas Binet-stage, RT, and L-BP SUV R are also significant in predicting OS. [ABSTRACT FROM AUTHOR]

Background: Primary extranodal lymphomas (pENL) are lymphomas with minimal nodal involvement and dominant extranodal disease. We aimed to study the prevalence and clinicopathological characteristics of pENL presenting at our center over 5 years from January 2015 to January 2020. Methods: This is a cross-sectional study of pENL patients in which relevant clinical and laboratory data was collected including demography, site, stage, international prognostic index-revised, imaging findings, hematological, and biochemical parameters and comorbidities including underlying immunodeficiency. The paraffin blocks were subjected to routine hematoxylin and eosin stain and immunohistochemistry with standard lymphoma panel. Results: Of 341 lymphomas, 73 (21.4%) were pENL with commonest site being gastrointestinal tract (31.5%) followed by head and neck (23.2%) and soft tissues (9.6%). Diffuse large B-cell lymphoma (DLBCL) (39.7%) was the commonest histological type (germinal center type--48%, nongerminal center--52%) followed by marginal zone lymphomas (MZL) (23.3%) and primary CNS lymphoma (8.2%). Primary breast lymphoma, primary bone marrow lymphoma, and follicular lymphoma constituted 4.1, 5.4, and 4.1% of pENL, respectively. There was a case of high grade B cell lymphoma of ileum with features intermediate between DLBCL and Burkitt. Other unusual pENL were anaplastic DLBCL of tonsils, DLBCLs of bone marrow with M band, MZL of base of tongue, Richter's transformation of tonsillar small lymphocytic lymphoma, and follicular lymphoma presenting as pericardial mass. Of 12 cases of T-non-Hodgkin lymphoma, commonest were mycosis fungoides (4/12) followed by mediastinal T-lymphoblastic lymphoma (2/12) and peripheral T-cell lymphoma (2/12). Conclusion: pENL has unique clinical presentation depending on the location with site-specific distribution of histological subtypes. [ABSTRACT FROM AUTHOR]

Although chronic lymphocytic leukemia (CLL) predominantly affects the elderly, limited data exists about the outcomes of over 80‐year‐old patients, usually underrepresented in clinical trials. We conducted a multicenter study enrolling 79 consecutive CLL patients ≥80 years at the time of frontline therapy, all treated with ibrutinib. Nearly 48% of cases exhibited unmutated IGHV genes, 32% 17p deletion, and 39.2% TP53 mutations; 63.3% displayed a cumulative illness rating scale (CIRS) > 6. The overall response rate on ibrutinib, computed in 74/79 patients (5 patients excluded for early withdrawal), was 89.9%. After a median follow‐up of 28.9 months, the median progression‐free survival (PFS) and overall survival (OS) were 42.5 and 51.8 months, respectively. CIRS>6 and temporary discontinuation of ibrutinib lasting for 7–30 days were the only parameters associated with a significantly shorter PFS and were both relevant in predicting a shorter PFS compared to patients with CIRS≤6 and therapy discontinuation ≤7 days. The most common grade≥3 adverse events were infections (25.5%), neutropenia (10.1%), and anemia (2.5%). Eighteen patients (22.8%) experienced a cardiovascular event, including grade‐2 atrial fibrillation (n = 9; 11%), grade‐2 hypertension (n = 5; 6%), heart failure (n = 3; 3%), and acute coronary syndrome (n = 1; 1%). Mild bleeding events were observed in 27 patients (34.2%). Ibrutinib was permanently discontinued in 26 patients due to progressive disease (n = 11, including 5 Richter's syndromes), secondary malignancies (n = 6), infections (n = 3), cardiac failure (n = 3), severe bleeding (n = 2), and sudden death (n = 1). In conclusion, our analyses confirmed the overall effectiveness and favorable safety profile of the ibrutinib‐single agent therapeutic approach in CLL patients ≥80 years. [ABSTRACT FROM AUTHOR]

Background: Richter's syndrome (RS) defines the transformation of chronic lymphocytic leukemia into high-grade lymphoma, which usually involves lymph nodes and bone marrow. Extranodal involvement of the heart is an extremely rare condition. Patients with heart involvement tended to have a low response to chemotherapy and relative poor prognosis. The transformation process of RS is often insidious and nonspecific making it challenging to diagnose. Case presentation: A 64-year-old woman wih a history of chronic lymphocytic leukemia (CLL) presented with intermittent chest pain and was diagnosed with non-ST-elevation myocardial infarction (NSTEMI). However, the contrast enhanced echocardiography revealed a large irregular mass, measuring about 75.4 mm × 37.5 mm, located on the lateral and posterior wall of the right ventricle. Biopsy of the cardiac mass and the results revealed diffuse large B-cell lymphoma. Conclusions: We present a case of a 64-year-old woman with aggressive diffuse large B-cell lymphoma involving the heart. This case could provide some insights in the diagnosis of cardiac lymphoma. [ABSTRACT FROM AUTHOR]

Introduction and aims: Richter syndrome (RS) represents the clonal evolution of chronic lymphocytic leukemia with histological transformation into a high-grade B cell lymphoma (diffuse large B cell lymphoma - DLBCL) or Hodgkin lymphoma. Considering that RS is an uncommon condition with poor prognosis, few high-quality evidence is available. To overcome this unmet need, this meta-analysis aimed to pool efficacy of early clinical trials in Richter syndrome (DLBCL subtype). Methods: MEDLINE, Scopus and Web of Science were searched up to May of 2023 to identify clinical trials decoying efficacy. The pooled complete response, objective response and intension-to-treat failure rates were calculated by pharmacological categories (classical chemotherapy, immunochemotherapy, immunotherapy, Bruton-tyrosine kinase inhibitors, targeted approaches, cell-based therapies and combinatorial regimens) using the Der-Simonian and Laird random-effects model. The Freeman-Tukey double arcsine method was used to estimate variance and confidence intervals. Heterogeneity was assessed using the I² method. Results: Overall, from 1242 studies identified, 30 were included, pooling data from 509 patients. The higher efficacy rates when, cell-based therapies were excluded, were achieved by immunochemotherapeutic regimens followed by combinatorial regimens, with complete response rates of 21.54% (IC95%14.93-28.87) and 23.77% (IC95% 8.70-42.19), respectively. Bispecific antibodies (alone or coupled with a chemotherapy debulking strategy) overtook Bruton tyrosine kinase inhibitors response rates. The latter, although achieving objective response rates above average, presented scarce complete response rates. Checkpoint inhibitors alone usually do not lead to complete responses, but their effectiveness may improve when combined with other agents, unveiling the importance of immune microenvironmental modulation. Conclusion: This is the first meta-analysis of early clinical trials assessing the impact of different therapeutics in RS. By analyzing the pooled efficacy estimates, our work suggests the role of a tailor-made bridging therapy for young patients with RS eligible for allogeneic hematopoietic stem cell transplantation (alloSCT), formally the only curative strategy. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a clonal mature B‐cell neoplasm with a typically indolent clinical course. Though most clinicians follow these neoplasms through observation alone, an aggressive transformation to prolymphocytic leukemia, diffuse large‐B‐cell lymphoma (Richter transformation) or classical Hodgkin lymphoma requires immediate attention. We present a case of extreme leukocytosis (>1 million/μL) in a previously diagnosed CLL patient. Due to symptomatic leukostasis, she was started on cytoreductive therapies including leukocytapheresis. After three rounds of leukocytapheresis (LCP) and concurrent chemotherapy, her white blood cell count decreased from a maximum 1262 × 103/μL to 574 × 103/μL. To our knowledge, CLL with symptomatic leukostasis that required therapeutic LCP is rarely reported in literature. We propose that therapeutic LCP is of value in such rare, yet dangerous settings like our case. [ABSTRACT FROM AUTHOR]

Key Clinical Message: When chronic lymphocytic leukemia progressed to Richter syndrome, the coexistence of small and large lymphocytes was observed as a bone marrow finding. We consider this finding to be a clue for the progression of chronic lymphocytic leukemia to Richter syndrome. [ABSTRACT FROM AUTHOR]

This letter, published in the Annals of Hematology, presents a case of a patient with small lymphocytic lymphoma (SLL) infiltrating the gastrointestinal tract and mimicking inflammatory bowel disease (IBD). The patient initially presented with symptoms such as fatigue, diarrhea, abdominal cramps, and weight loss, which were initially thought to be related to IBD. However, further examination revealed widespread GI infiltration by SLL cells. The patient was successfully treated with acalabrutinib, a next-generation Bruton's tyrosine kinase inhibitor (BTKi), and experienced significant improvement in symptoms and remission of the lymphoma. This case highlights the efficacy of acalabrutinib in treating SLL and the importance of considering GI lymphomas in the differential diagnosis of IBD. [Extracted from the article]

Background: Richter transformation (RT) is the development of aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This rare disease is characterised by dismal prognosis. In recent years, there has been a deeper understanding of RT molecular pathogenesis, and disruptions of apoptosis (TP53) and proliferation (CDKN2A, MYC, NOTCH1) has been described as typical aberrations in RT. Results: A single-institution cohort of 33 RT patients were investigated by karyotyping, fluorescence in situ hybridization and single nucleotide polymorphism/copy number (CN) arrays. Most of RTs were typically manifested by diffuse large B-cell lymphoma, not otherwise specified, among the remaining cases one was classified as high-grade B-cell lymphoma with 11q aberrations. The most frequent alterations (40–60% of cases) were represented by MYC rearrangement/gain, deletions of TP53 and CDKN2A, IGH rearrangement and 13q14 deletion. Several other frequent lesions included losses of 14q24.1-q32.33, 7q31.33-q36.3, and gain of 5q35.2. Analysis of 13 CLL/SLL-RT pairs showed that RT arised from the CLL/SLL by acquiring of 10 ~ 12 cytogenetic or CN lesions/case, but without acquisition of loss of heterozygosity regions. Our result affirmed the higher genetic complexity in RT than CLL/SLL and confirmed the linear features of RT clonal evolution as predominant. Conclusions: Cytogenomic profile was concordant with the literature data, however the role of IGH rearrangement, 14q deletion and 5q35.2 gain need to be explored. We anticipate that further characterization of RT lesions will probably facilitate better understanding of the RT clonal evolution. [ABSTRACT FROM AUTHOR]

Objective: Richter syndrome (RS) occurs in approximately 2–10% of chronic lymphocytic leukemia (CLL) patients, more often during the disease course than at diagnosis, with a diffuse large B-cell Lymphoma (DLBCL) histology in 95% of cases. Despite great advances in the treatment of CLL in recent years, RS also develops in patients treated with novel agents, as summarized in our case report and review. Methods: We summarized 3 patients with RS treated with immunochemotherapy combined with BTK inhibitor (BTKi) or BCL2 inhibitor (BCL2i) and reviewed the literature. Results: Three RS patients were summarized. Patient 1 was transformed into DLBCL during dose reductions in ibrutinib and achieved bone marrow (BM) minimal residual disease (MRD)-negative complete response (CR) after rituximab etoposide, dexamethasone, doxorubicin, cyclophosphamide, and vincristine (R-EDOCH) combined with BTKi treatment and sustained progression-free survival (PFS) for more than 2 years. Patient 2, who transformed at the time of diagnosis, progressed after being treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), followed by PD1 antibody combined with cytosine, arabinoside, cisplatin and dexamethasone (DHAP) treatment and PD1 antibody combined with ifosfamide, carboplatin, and etoposide (ICE) treatment. Patient 2 achieved CR after treatment with rituximab, gemcitabine, and oxaliplatin (R-GemOx) combined with BTKi. Patient 3, who transformed at the time of diagnosis with CARD11, TP53, and ATM mutations, progressed after being treated with R-EDOCH combined with BTKi and achieved MRD-negative CR after treatment with R-GemOx and venetoclax, which has continued for 3 months. We summarized new protocols utilizing targeted therapy, such as BTKi acalabrutinib, and checkpoint inhibition, and the potential role of precision medicine in future trials of RS treatment. The efficacy of these protocols as single agents or in combination with immunochemotherapy is currently being evaluated. Conclusion: In our study, immunochemotherapy combined with BTKi or BCL2i achieved favorable efficacy in the treatment of RS. The treatments should be optimized by the combination of both chemotherapies and targeted therapy to develop a specific individual approach for each patient, according to previous treatment and biological characteristics. [ABSTRACT FROM AUTHOR]

MALAT1 long non-coding RNA has oncogenic roles but has been poorly studied in indolent B-cell neoplasms. Here, MALAT1 expression was analyzed using RNA-seq, microarrays or qRT-PCR in primary samples from clinico-biological subtypes of chronic lymphocytic leukemia (CLL, n = 266), paired Richter transformation (RT, n = 6) and follicular lymphoma (FL, n = 61). In peripheral blood (PB) CLL samples, high MALAT1 expression was associated with a significantly shorter time to treatment independently from other known prognostic factors. Coding genes expressed in association with MALAT1 in CLL were predominantly related to oncogenic pathways stimulated in the lymph node (LN) microenvironment. In RT paired samples, MALAT1 levels were lower, concordant with their acquired increased independency of external signals. Moreover, MALAT1 levels in paired PB/LN CLLs were similar, suggesting that the prognostic value of MALAT1 expression in PB is mirroring expression differences already present in LN. Similarly, high MALAT1 expression in FL predicted for a shorter progression-free survival, in association with expression pathways promoting FL pathogenesis. In summary, MALAT1 expression is related to pathophysiology and more aggressive clinical behavior of indolent B-cell neoplasms. Particularly in CLL, its levels could be a surrogate marker of the microenvironment stimulation and may contribute to refine the clinical management of these patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: The treatment paradigm of chronic lymphocytic leukemia (CLL) has dramatically changed with the advent of novel targeted agents over the past decade. Richter transformation (RT), or the development of an aggressive lymphoma from a background of CLL, is a well-recognized complication of CLL and carries significantly poor clinical outcomes. Here, we provide an update on current diagnostics, prognostication, and contemporary treatment of RT. Recent Findings: Several genetic, biologic, and laboratory markers have been proposed as candidate risk factors for the development of RT. Although a diagnosis of RT is typically suspected based on clinical and laboratory findings, tissue biopsy is essential for histopathologic confirmation of diagnosis. The standard of care for RT treatment at this time remains chemoimmunotherapy with the goal of proceeding to allogeneic stem cell transplantation in eligible patients. Several newer treatment modalities are being studied for use in the management of RT, including small molecules, immunotherapy, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy. Summary: The management of patients with RT remains a challenge. Ongoing trials show enormous promise for newer classes of therapy in RT, with the hope being that these agents can synergize, and perhaps supersede, the current standard of care in the near future. [ABSTRACT FROM AUTHOR]

As shown in Figure 2F, pseudotime trajectories indicated that the evolutionary trajectory of T cells was from state 5 to state 1, but in the RS sample, T cells were enriched at the end of state 4, which indicated that T cells of RS sample deviated from the normal path. Richter's syndrome (RS) is an uncommon clinicopathological condition in which chronic lymphocytic leukaemia (CLL) evolves into aggressive lymphoma, the mechanism of which still remains difficult to elucidate. The IGHV 3-48*03 gene was used by both CLL cells and RS tumour cells, and establishing RS and CLL was clonally related. (H) CellphoneDB analysis showing the number of ligand-receptor interactions between (Left) B-cell clusters of CLL sample and (Right) B-cell clusters of RS sample with T-cell subgroups. [Extracted from the article]

This document provides information on a small-molecule inhibitor called BMF-219, which has shown promise in inhibiting cancer cell signaling. It introduces a Phase I study called COVALENT-101, which aims to evaluate the safety and efficacy of BMF-219 in patients with various types of leukemia and lymphoma. The study found that intermittent dosing of duvelisib was effective in controlling the disease and had manageable side effects. Another study explored the impact of comorbidities on treatment outcomes in chronic lymphocytic leukemia (CLL) patients, finding that comorbidities were associated with poorer response and survival. The document also discusses the potential benefits of combining CAR T cell therapy with bispecific antibodies (BsAb) in CLL and other B-cell non-Hodgkin lymphomas (B-NHL), as well as the use of PI3Kδ inhibitors to improve T cell function in CLL patients. These studies provide valuable insights into treatment options and prognostic factors for CLL patients. [Extracted from the article]

This document is an editorial published in Frontiers in Immunology, discussing the importance of mouse models in studying B cell malignancies. The editorial highlights the need for a deeper understanding of the origin, progression, and treatment of these diseases in order to develop more effective therapies. It emphasizes that mouse models provide valuable insights into the genetic factors and immune system interactions involved in B cell malignancies, as well as serving as tools for testing new therapies and understanding disease mechanisms. The editorial also mentions the inclusion of three reviews and one perspective in this volume, which provide a comprehensive overview of mouse models of leukemia and lymphomas. Overall, the articles in this volume contribute to our understanding of B cell lymphoma and leukemia and underscore the essential role of genetically modified mice in this research. [Extracted from the article]

This letter, published in the Annals of Hematology, discusses a case of leukemic non-nodal mantle cell lymphoma (LNN-MCL) in a woman in her 70s. LNN-MCL is characterized by abnormal B-cells in the blood and bone marrow, without significant lymphadenopathy. Typically, LNN-MCL is associated with the overexpression of cyclin D1 protein, but in this case, the patient had a rearrangement of the CCND3 gene instead. The authors highlight the challenges in diagnosing cyclin D1-negative LNN-MCL, as it can be mistaken for other types of lymphoma. The case also revealed mutations in TP53 and ARID1A genes, indicating disease progression. This is the first reported case of MCL involving a cavernous hemangioma. [Extracted from the article]

Introduction and aimsRichter syndrome (RS) represents the clonal evolution of chronic lymphocytic leukemia with histological transformation into a high-grade B cell lymphoma (diffuse large B cell lymphoma - DLBCL) or Hodgkin lymphoma. Considering that RS is an uncommon condition with poor prognosis, few high-quality evidence is available. To overcome this unmet need, this meta-analysis aimed to pool efficacy of early clinical trials in Richter syndrome (DLBCL subtype).MethodsMEDLINE, Scopus and Web of Science were searched up to May of 2023 to identify clinical trials decoying efficacy. The pooled complete response, objective response and intension-to-treat failure rates were calculated by pharmacological categories (classical chemotherapy, immunochemotherapy, immunotherapy, Bruton-tyrosine kinase inhibitors, targeted approaches, cell-based therapies and combinatorial regimens) using the Der-Simonian and Laird random-effects model. The Freeman-Tukey double arcsine method was used to estimate variance and confidence intervals. Heterogeneity was assessed using the I2 method.ResultsOverall, from 1242 studies identified, 30 were included, pooling data from 509 patients. The higher efficacy rates when, cell-based therapies were excluded, were achieved by immunochemotherapeutic regimens followed by combinatorial regimens, with complete response rates of 21.54% (IC95%14.93-28.87) and 23.77% (IC95% 8.70-42.19), respectively. Bispecific antibodies (alone or coupled with a chemotherapy debulking strategy) overtook Bruton tyrosine kinase inhibitors response rates. The latter, although achieving objective response rates above average, presented scarce complete response rates. Checkpoint inhibitors alone usually do not lead to complete responses, but their effectiveness may improve when combined with other agents, unveiling the importance of immune microenvironmental modulation.ConclusionThis is the first meta-analysis of early clinical trials assessing the impact of different therapeutics in RS. By analyzing the pooled efficacy estimates, our work suggests the role of a tailor-made bridging therapy for young patients with RS eligible for allogeneic hematopoietic stem cell transplantation (alloSCT), formally the only curative strategy.

Chronic lymphocytic leukemia can evolve to an aggressive lymphoma—in most of the cases diffuse large B cells lymphoma, rarely Hodgkin lymphoma—and this complication is defined Richter syndrome (RS). Immunogenotypic features that characterize RS include unmutated IgHV status with high prevalence of IgHV4‐39/D6‐13/J5 sequence; deletion of chromosome 17p or 11q; activation of oncogenes as NOTCH1 and c‐MYC; inactivation of onco‐suppressors as TP53 and CDKN2A; high expression of CD38 in lymph‐nodes. The prognosis of this condition is very poor: patients experience a rapid clinical deterioration with frequent therapeutic failure since the current options include suboptimal strategies as standard chemo‐immunotherapy followed by hematopoietic stem cells transplantation or enrollment in clinical trials which investigate the efficacy of target drugs. Understanding the biology of such a heterogeneous condition is crucial to personalize the treatment and improve patient's survival. [ABSTRACT FROM AUTHOR]

Reassuringly, we observed a shift in practice with an increasing number of patients receiving CLL concordant treatment in recent years of our study, although some patients continued to receive iNHL therapies in lieu of a BTK or BCL2 inhibitor. Of the 72 total lines of therapy administered as outlined in Table 2, 36 (50%) were congruent with iNHL treatment protocols, including 32/60 (53%) first-line therapies, 4/9 (44%) second-line therapies and 0/3 (0%) third-line therapies. Of note, patients initiating first-line treatment in 2019-2022 were more likely to receive CLL concordant treatment compared to patients treated in 2015-2018 (64% vs. 28%) (Table S1). [Extracted from the article]

The case report presents a patient with chronic lymphocytic leukaemia that was diagnosed in 2006 in Rotterdam, the Netherlands. In September 2010, the patient was admitted to the Department of Haematology in Poland due to progression of the underlying disease. The clinical problem during treatment was the suspicion of Richter's transformation into another, more aggressive non-Hodgkin lymphoma. The diagnosis was based on the peripheral blood immunophenotype. The patient was diagnosed with an immunoglobulin deficiency. Unfortunately, repeated examinations did not confirm the transformation hypothesis, despite the increasing symptoms. The patient was treated with various therapeutic regimens until May 2021, when an increased number of NK cells was diagnosed in the peripheral blood. NK-cell lymphoproliferative disease was finally diagnosed de novo. Nevertheless, it was found that the patient had active Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) infection. The suspected NK-cell lymphoma/leukaemia was most likely a complication of the active EBV infection and severe immunodeficiency state. [ABSTRACT FROM AUTHOR]

Objectives Session 3 of the 2021 Workshop of the Society for Hematopathology/European Association for Haematopathology examined progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B-cell prolymphocytic leukemia (B-PLL). Methods Thirty-one cases were reviewed by the panel. Additional studies such as immunohistochemistry and molecular genetic testing, including whole-exome sequencing and expression profiling, were performed in select cases. Results Session 3 included 27 CLL/SLL cases and miscellaneous associated proliferations, 3 cases of B-PLL, and 1 case of small B-cell lymphoma. The criteria for -accelerated CLL/SLL are established for lymph nodes, but extranodal disease can be diagnostically challenging. Richter transformation (RT) is a broad term and includes true transformation from original CLL/SLL clone(s) and clonally unrelated neoplasms. The morphologic, immunophenotypic, and genetic spectrum is diverse with classical and highly unusual examples. T-cell proliferations can also be encountered in CLL/SLL. B-cell prolymphocytic leukemia is a rare, diagnostically challenging disease due to its overlaps with other lymphoid neoplasms. Conclusions The workshop highlighted complexity of progression and transformation in CLL/SLL and B-PLL, as well as diagnostic caveats accompanying heterogeneous presentations of RT and other manifestations of disease progression. Molecular genetic studies are pivotal for diagnosis and determination of clonal relationship, and to predict response to treatment and identify resistance to targeted therapy. [ABSTRACT FROM AUTHOR]

Introduction. The presence of aneuploidy in patients diagnosed with chronic lymphocytic leukemia (CLL), except trisomy 12, is considered quite uncommon. Hyperdiploidy or near-tetraploidy (occurring in 1-3% of all CLL patients) usually confer a poor prognosis. Case report. We report a patient in a progressive phase of CLL with near-triploid karyotype. The prognosis of the disease was more precisely determined by applying the cytogenetic analysis of the karyotype and was complemented with molecular methods and pathohistological examination. The complex karyotype was accompanied by the TP53, C-MYC, and IGH gene disruptions, the most probable cause of rapid evolution into Richter's syndrome. Conclusion. The use of comprehensive contemporary diagnostic techniques is highly recommended in patients who are in the progressive phase of CLL, primarily for the adequate choice of management strategy. The presented case confirms that aneuploidy in CLL patients indicates poor prognosis, which is in accordance with previous publications reporting on cases of CLL patients with aneuploidy. [ABSTRACT FROM AUTHOR]

Fifteen (14%) patients experienced either new onset Afib (47%; Table 2) or exacerbation of known Afib (53%) while on therapy with acalabrutinib (Supplemental Table 1). Strengths include providing a real-world review of key adverse events during acalabrutinib treatment, reporting of patients with significant comorbidities and the inclusion of patients who received prior treatment with ibrutinib. No patient discontinued therapy because of HTN, however acalabrutinib was dose-reduced in one patient. New onset Afib developed in one patient (2%) and recurrent Afib was observed in four patients (8%) during acalabrutinib therapy. [Extracted from the article]

Keywords: B cell; carcinoma; chronic; leukaemia; lymphocytic; neoplasm metastasis; skin neoplasms; squamous cell EN B cell carcinoma chronic leukaemia lymphocytic neoplasm metastasis skin neoplasms squamous cell 291 295 5 05/12/23 20230501 NES 230501 INTRODUCTION Chronic lymphocytic leukaemia patients have a greater than a twofold increased risk of developing a second malignancy,[1] and of these second cancers, non-melanoma skin cancers are the most frequent.[[1]] Basal cell carcinomas account for approximately 80% of non-melanoma skin cancers in the general population.[2] However, in patients with chronic lymphocytic leukaemia, there is a reversal of this basal cell carcinoma: cutaneous squamous cell carcinoma ratio, consistent with reports in other immunocompromised states.[1] Given the increased risk of non-melanoma skin cancer in chronic lymphocytic leukaemia patients, combined dermatology and haematology clinics have been established to better manage these patients.[3] We aim to determine the features of metastatic squamous cell carcinoma in chronic lymphocytic leukaemia from six patients at a combined dermatology-haematology clinic in Australia. Of patients who had cutaneous squamous cell carcinoma, six subsequently developed metastatic cutaneous squamous cell carcinoma; thus, the overall rate of metastatic squamous cell carcinoma in the chronic lymphocytic leukaemia cohort was 1.2% (6/517) and 10.3% (6/58) of the chronic lymphocytic leukaemia cases with cutaneous squamous cell carcinoma. Metastatic squamous cell carcinoma was defined as metastasis to locoregional areas, including lymph nodes and in-transit (local cutaneous) metastases, metastatic cutaneous squamous cell carcinomas of unknown origin and distant metastases. [Extracted from the article]

Thirty-seven patients were alive at the last follow-up, 13 had died (two dementia-related causes, one pneumonia, one warfarin-related bleeding, one ovarian cancer, eight because of unknown causes); no patient died due to CLL progression. Of the five patients initially categorized as in partial SR, three have subsequently converted to SR, one remains in partial SR and in one patient who achieved a partial SR after 19 years from diagnosis the lymphocyte count started to increase five years later. Of the four patients in stage B/II at diagnosis, two converted to A/0 and one to A/I. In the five patients with a partial SR, the median lymphocyte count at regression was 6.3 × 10 SP 9 sp /L, with a median lymphocyte decrease of 75.1% (69-89%), and at the last follow-up a median lymphocyte count of 5.6 × 10 SP 9 sp /L (5.3-11.8) (Figure 1). [Extracted from the article]

Simple Summary: Though rare, Richter Transformation (RT) is a serious complication of chronic lymphocytic leukemia. RT carries a high mortality rate and represents an unmet clinical need. With an improved understanding of its molecular biology, there is hope that novel targeted therapies and immunotherapies will lead to improved outcomes in this disease. This review outlines what is known about RT as well as where the field is headed. An illustrative case is also included to facilitate the reader's understanding of the material presented. Richter Transformation (RT) refers to the development of an aggressive lymphoma in the setting of chronic lymphocytic leukemia (CLL). While many variants of RT are recognized, diffuse large B-cell lymphoma (RT-DLBCL) is the most common (80%), followed by Hodgkin's lymphoma (RT-HL, 19%). Diagnosis is based upon histologic evaluation of clinically suspicious lymph nodes. Positron emission tomography (PET) may be used to select the node of interest for biopsy. Although clonality testing is not a prerequisite of RT diagnosis, it has significant implications for survival. Clonally related DLBCL carries the worst prognosis with a median overall survival (OS) of less than one year in the era of combination chemotherapies with or without anti-CD20 antibodies. Prognosis has improved with the use of stem cell transplant and newer agents such as targeted therapy and newer forms of immunotherapy. Consideration of a clinical trial is encouraged. This review describes our current understanding of RT and focuses on treatment of RT-DLBCL, including clinical trials in progress and new therapies in development. We also report an illustrative example of a patient with clonally related DLBCL who survived two years after diagnosis without the use of combination chemotherapy. [ABSTRACT FROM AUTHOR]

Keywords: chronic lymphocytic leukemia; clonal haematopoiesis; composite lymphoma; mantle cell lymphoma EN chronic lymphocytic leukemia clonal haematopoiesis composite lymphoma mantle cell lymphoma 660 664 5 02/21/23 20230301 NES 230301 Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in the Western world, accounting for 25% of adult leukaemias. To further determine which lymphoma population displaying these cytogenetic changes, we sort-purified CLL cells and MCL cells from peripheral blood by flow cytometry (Figure 2A) and performed FISH using relevant probes. Previous studies have demonstrated that CLL and MCL in composite lymphoma cases are clonally unrelated.[[3]] For example, in the largest CLL/MCL case series, using micro-dissected tissues, Hoeller et al.[3] reported that all their seven cases of composite CLL/MCL lymphomas lacked a clonal relatedness. In addition to our findings, somatic mutations that are frequently observed in clonal haematopoiesis have also been detected in CLL and angioimmunoblastic T-cell lymphoma.[[12], [15]] However, it is unclear how these pro-myeloid mutations contribute to lymphomagenesis and at which developmental stage the mutated precursor cells transform to lymphoma initiating cells. [Extracted from the article]