IGH (Immunoglobulin Heavy Locus)

These fusions often result in enhancer hijacking, upregulation of partner proto-oncogenes and contribute to leukemogenesis. This review highlights the mechanisms underlying IGH gene fusions, the critical role they play in ALL pathogenesis, and current detection technologies.

Median overall survival (OS) was 2.2 years once DR developed despite frequent initial responses to non-covalent BTKis or cellular therapy in the cohort. Patients with DE CLL demonstrated favorable survival (median OS not reached) and durable response to subsequent therapy.

Here, we report the two different outcomes regarding EBV-driven lymphoproliferative complications, the family with three members affected that developed the malignant lymphoproliferative complications before XMEN diagnosis, and the patient with early diagnose of MAGT1 deficiency due to EBV viremia. As a recommendation, XMEN disease should be ruled out in males with impaired clearance of EBV-infection and EBV-driven lymphoproliferative complications.

Ongoing frontiers involve optimal management of TP53 mutated MCL and those relapsing with CNS involvement. Novel therapeutic approaches including the development of non-covalent BTK inhibitors and bispecific antibody therapy carry significant promise to further improve outcomes across all subtypes of this disease.

In addition, patients with a prolymphocyte percentage >1% were more likely to progress after BTKi treatment (P=0.038) . Peripheral blood prolymphocyte percentage was associated with various clinical and biological parameters and prognosis among patients with treatment-naive CLL.

Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B-CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.

We demonstrate that although clonal relatedness of the underlying CLL confers a poorer survival, this is not demonstrated in any study to be independent of other well-described clinical and genomic variables known to influence outcome in RT-DLBCL. Further independent validation of this prognostic factor is required to help guide universal adoption into clinical practice.

P2, N=81, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2025 --> Mar 2026

After five cycles of R-MPV (rituximab, methotrexate, procarbazine, vincristine) therapy and three cycles of R-ESHAP (rituximab, etoposide, cytarabine, cisplatin, methylprednisolone) therapy, the patient received autologous hematopoietic stem cell transplantation using R-MEAM (rituximab, ranimustine, etoposide, cytarabine, melphalan) regimen after bridging therapy with ibrutinib. He did not relapse within 3 years of transplantation. To the best of our knowledge, this is the first case report of DLBCL and MCL coexistence.

We identified the lymphocyte count, the absence of TP53 mutations and del(17p), a mutated IGHV and the proportion of smudge cells as significant influences on the appearance of "shark fin" cells. Our findings indicate an impact of biological and genetic properties of the leukemic cells on the formation of "shark fins".

This study identified specific protein markers of clots that could differentiate stroke mechanisms in patients undergoing EVT. Therefore, our results could offer valuable insights into elucidating the mechanisms of ischemic stroke, which could provide information on more effective secondary prevention strategies.

This study evaluated the efficacy and safety of camrelizumab combined with platinum-based chemotherapy (taxanes [T] or fluorouracil agents [F] plus platinum [P] drugs) as the first-line treatment in advanced esophageal squamous cell carcinoma (ESCC), using immune repertoire sequencing (IRS) to explore treatment response mechanism. Similarly, for BCR, we detected differences in the clonotype abundance of CDR3 polypeptide segments and identified several differential V genes. Camrelizumab combined with platinum-based chemotherapy is effective and well-tolerated as the first-line treatment for ESCC, and IRS may reveal mechanism influencing treatment response.

P3, N=529, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jan 2026

Treatment options for CLL continue to evolve. Current treatment selection is based on clinical and patient-specific considerations. Emerging novel therapies to overcome treatment resistance and strategies to optimize supportive care generate opportunities for pharmacists to advance practice and improve patient safety.

BCP-ALL also presented shorter CDR3 regions, higher GC content, and lower productivity. Interestingly, productive clonotypes tended to be absent after induction therapy.

MRD monitoring via NGS of Ig for both IGH and IGK is a promising noninvasive tool for prognosis prediction and early relapse prediction of DLBCL patients.

Next-generation sequencing revealed a cryptic insertion of IGK enhancer sequences into the CCND1-major translocation cluster, accounting for CCND1 expression in MCL cells recognized by immunohistochemistry. Composite lymphoma is rare, but a correct diagnosis is required because effective treatments for each component are now available.

There were no significant differences between venetoclax-containing regimens and chemoimmunotherapy in all grade 3 or 4 adverse events, neutropenia, thrombocytopenia, infections, pneumonia, sepsis, infusion-related reactions, or tumor lysis syndrome. Venetoclax-containing regimens were associated with a decreased risk of anemia, leukopenia, febrile neutropenia, and pyrexia, but an increased risk of diarrhea and hypertension. Our results demonstrate the superiority of venetoclax-containing regimens in CLL patients, particularly in those with unmutated IGHV and del(17p) and/or TP53 mutations.

The AUC of metabolomics prediction model was 0.977 and the AUC of proteomics was 0.875 while the AUC of the integrative-omics prediction model was 0.955. Metabolic and protein biomarkers in peripheral blood both have high efficacy and reliability in the prediction of immunotherapy sensitivity in unresectable stage III and IV non-small cell lung cancer, but validation in larger population-based cohorts is still needed.

Acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.).

ADCs in patients with CLL exhibited fourfold more stereotyped IGHV-IGHD-IGH rearrangements than found in CD5+ B cells from healthy individuals, and IGHV use, somatic mutations, and Ig isotype distribution was similar between pADCs and CRCs. Thus, finding multiple expanded clones within the CD5+ B cells is the rule in patients with CLL, indicating that leukemogenesis is a multiclonal process that likely involves competition among B cells with special BCR features.

Ibrutinib was generally well tolerated in our cohort, as only 14.8% of our patients discontinued treatment due to adverse effects. Our study suggests that ibrutinib is a valid therapeutic option for TN or R/R CLL patients, with a high ORR and a good safety profile.

P=N/A, N=6000, Recruiting, AstraZeneca | Trial completion date: Mar 2028 --> Dec 2027 | Trial primary completion date: Mar 2028 --> Dec 2027

Our results have shown mutations in essential genes and their association with IGHV status. Overall, specific gene mutations, IGHV status, and chromosomal alterations can provide information on prognosis.

After applying Nrf2 knockdown technology by transferring short interfering RNA in HLEB3 cells, SSP demonstrated its protective role by activating Nrf2 and inhibiting ERS-mediated apoptosis. These findings indicate that SSP may protect against ARC by regulating Nrf2/ERS-mediated apoptosis, providing potential evidence for its use in preventing or delaying ARC.

Consistent with downmodulation of PM BCR, BALF0/1 overexpression reduced viability of a diffuse large B cell lymphoma cell line whose survival is dependent upon BCR signaling. Collectively, our results suggest that EBV BALF0/1 downmodulates immunoglobulin upon lytic reactivation to block BCR signaling and support virion release, but await the development of suitable models to test its roles in EBV reactivation in vivo.

We designed a novel 5'UTR, 5UTR05, which exhibited comparable protein expression levels to the reference mRNA-1273 5'UTR that has been found to exhibit high expression in the COVID-19 vaccine development...Collectively, these findings provide valuable insights for UTR optimization strategies aimed at augmenting exogenous mRNA therapeutic translation. Continuing exploration of synergistic UTR combinations offers promise to advance customized mRNA constructs with optimized expression profiles tailored for diverse applications.

P1/2, N=11, Terminated, Takeda | Completed --> Terminated; Phase 1 enrollment was terminated due to dose-limiting toxicities, thus the study was terminated by Sponsor.

In very frail patients, supportive treatment should be considered. In relapse/refractory patients, prior treatment, the biological risk of CLL, the duration of response (if prior finite treatment), or the reason for stopping BTKi (if prior continuous treatment) should be considered.

Our findings highlight the critical role of CD8+CD226+RUNX2hi T cells in CLL and suggest that their reduction is associated with disease progression and poor clinical outcomes. This study also underscores the potential of targeting IL-6 and MIP-1β to preserve polyfunctional CD8+CD226+ T cells as a promising immunotherapy strategy.

Responses to non-covalent BTKI (ncBTKI) are impacted by the mechanism of resistance to previous covalent BTKi. Finally, responses to chimeric antigen receptor T cell therapy (CAR-T) appear independent of TP53 status, but dependent on overall T- cell fitness.

P=N/A, N=215, Not yet recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

P3, N=300, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

The first-line treatment of HCL has recently changed and immunochemotherapy combining cladribine plus rituximab has become the gold standard. In relapsed or refractory forms, other treatments should be discussed in a multidisciplinary consultation meeting and combine BRAF inhibitors with anti-CD20 antibodies, BTK inhibitors or Bcl-2 inhibitors. The choices should be discussed according to the patient's profile but also their biological profile.

The non-stochastic distribution of the IGKV/LV gene expression in the individual stereotyped subsets was confirmed. Taking into account the complementary role of the light chains in antigen recognition by the clonotypic BCRs, it was suggested that the subsets with the heterogeneous IGK/LV expression might be reclassified and divided into separate subgroups based on the IGHV and IGK/LV association.

The validation cohort of 343 Rai 0 patients confirmed these findings, with UM light chain genes predicting a 7-year treatment free probability of 42.0% versus 73.7% for M genes (p < 0.0001). These results indicate that the mutational status of the light chain genes is an independent predictor of shorter TTFT in early-stage CLL patients.

The two CLL clones have distinct transcriptomes: Numerous genes were differentially expressed, with genes typical for unmutated or mutated CLL showing the expected representation in the two clones. Using PCR, cloning and Sanger sequencing of the IGHV rearrangements we detected both CLL clones over a period of three years without clinical progression of the CLL and thus giving insights into the disease biology of multi-clonal CLL.

MRD-guided duration of treatment may improve further outcomes, but longer clinical follow-up is needed before this approach is incorporated in clinical guidelines. The review gives an update on the impact of biological markers on outcomes with novel agents.

These imaging findings initially suggested a diagnosis of pulmonary malignancy. However, pathological examination and IgH gene rearrangement analysis of the resected tissue ultimately confirmed the diagnosis of PNLH.

Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

Despite remarkable advances, these markers also retain a differential prognostic and predictive impact in the context of targeted therapies, mandating risk-stratification in frontline management. Furthermore, BTK- and BCL2-targeting agents differ in their adverse event profiles, requiring adjustment of treatment choice based on patient characteristics such as coexisting conditions, comedications, and delivery-of-care aspects.

P3, N=488, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Mar 2025