Hematological Oncology最新文献

Bridging therapy (BT) is frequently used in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) undergoing chimeric antigen receptor T cell (CAR T) therapy, but the optimal BT approach remains uncertain. We evaluated BT strategies and their associations with response and survival outcomes. Accordingly, we included patients with R/R LBCL evaluated for third-line or later CD19-directed CAR T at Princess Margaret Cancer Center from 2017 to 2024 (follow-up to 01/2025). BT modalities included chemotherapy, polatuzumab-based chemotherapy, radiotherapy, corticosteroids, and none. We assessed the associations of BT modality with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) using logistic regression and Cox models. Among 219 patients, 188 underwent apheresis and 157 (84%) received CAR T. Of those apheresed, 79% received BT (radiotherapy 41%, polatuzumab-based 26%, third-line chemotherapy 16%, corticosteroids 17%, while 21% received no BT). ORR was highest with polatuzumab (50%) and radiotherapy (40%) versus chemotherapy (16%) (p = 0.009). Median ΔSUVmax in 84 patients was higher in polatuzumab and radiotherapy treated patients, compared to chemotherapy (p < 0.001). Radiotherapy encompassing all active disease had higher ORR (51%) versus non-comprehensive (12%) (p = 0.04). Two-year PFS was highest with radiotherapy (47%) and polatuzumab (37%) BT versus chemotherapy (21%). Adjusted analyses showed improved PFS with radiotherapy (adjusted hazard ratio [aHR] 0.29) and polatuzumab (aHR 0.41). OS was also improved with radiotherapy (HR 0.40). Chemotherapy BT was associated with the highest 2-year lymphoma-related mortality (74%). In conclusion, polatuzumab-based and radiotherapy BT as well as no BT were associated with improved responses and outcomes compared to chemotherapy. Although these results may have been influenced by patient selection, prospective studies integrating these approaches are needed to define optimal, individualized BT strategies.

This retrospective study evaluated 11 patients who received valemetostat, a novel selective dual inhibitor of the enhancer of zeste homologs 1 and 2, as a salvage therapy for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic cell transplantation (allo-HCT). The median age of the patients at allo-HCT was 64 (range: 43-70) years. The median interval between allo-HCT and valemetostat therapy was 210 (range: 35-682) days. The median lactate dehydrogenase and soluble interleukin-2 receptor levels were 238 (range: 184-298) U/L and 818 (range: 435-2193) U/mL, respectively. Eight patients initially received valemetostat at a reduced dose because of thrombocytopenia. The median treatment duration was 156 (range: 39-645) days, with five patients continuing treatment. The best response rate was 73%, including clinical responses (complete or partial response) in six patients and molecular responses defined by clearance of blood measurable residual disease in two patients. The reasons for treatment discontinuation were adverse events (cytomegalovirus infection, pericardial effusion, and dysgeusia) (n = 3) and progressive disease (n = 3). None of the patients developed graft-versus-host disease. The median overall survival after valemetostat therapy was 294 (range: 56-645) days. At the last follow-up, four patients were alive without disease, four were alive with disease, and three died due to progressive disease. Hence, valemetostat is a promising salvage therapy for relapsed adult T-cell leukemia/lymphoma after allo-HCT.

T-cell lymphomas (TCLs) account for a relatively small fraction of lymphoid malignancies and are characterized by highly aggressive course often refractory to current available therapies. We previously reported potent in vitro and in vivo antitumor activity of a Bispecific T-Cell Engager (UMG1/CD3ε-BTCE) directed against UMG1, a unique CD43 epitope that is abundantly expressed on T-cell acute lymphoblastic leukemia (T-ALL) and diffuse large B-cell lymphoma (DLBCL) cells, while absent in most normal tissues, except thymocytes and a small fraction of peripheral blood T lymphocytes (< 5%). Here, we investigated the in vitro efficacy of UMG1/CD3ε-BTCE against TCLs. IHC analysis of Tissue Micro Arrays (TMAs) revealed high UMG1 expression in 62.3% of TCL samples, including peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and ALK-negative anaplastic large cell lymphoma (ALCL). Notably, all T-PLL primary specimens (27/27) were positive, and 3 of 4 TCL cell lines also expressed UMG1 by flow cytometry. The asymmetric UMG1/CD3ε-BTCE induced robust redirected cytotoxicity against UMG1-expressing TCL cells. Moreover, this activity was strengthened by cell exposure to the HDAC inhibitor SAHA. We observed a dose-dependent engaged T-cell-mediated cytotoxicity and inflammatory cytokine release, resulting in lysis of UMG1-expressing cells, with no significant effect on UMG1-not expressing cells. Our findings suggest that the UMG1/CD3ε-BTCE selectively exerts potent anti-tumor activity against a relevant subset of TCLs. These findings support the development of a precision immunotherapy approach for patients with UMG1-expressing aggressive hematologic malignancies.

B-cell receptor inhibitors (BCRi) and B-cell lymphoma-2 inhibitor (BCL2i) improved outcomes of patients with chronic lymphocytic leukemia (CLL), but relapsing after two inhibitors still represent an unmet clinical need. This multicenter real-world study analyzes outcomes of a cohort treated in Italy between May 2017 and September 2023 following prior exposure to both BCRi and BCL2i. The median follow-up after venetoclax initiation was 47 months (IQR 28-56). Of 153 double-exposed patients, 104 (68%) discontinued venetoclax and 53 of them (51%) received a subsequent treatment. Venetoclax was discontinued due to progressive disease (PD) in 51/104 cases (49.0%), with nine deaths occurring rapidly after PD without the administration of any further treatment. Fifty-three patients received treatment after venetoclax: 29/53 (54.7%) received inhibitors (13 cBTKi, 11 idelalisib, 2 BCL2i, 3 non-covalent BTKi), 19/53 (35.8%) received chemoimmunotherapy (CT: 16 intensive, 3 palliative), 5/53 (9.4%) received hematopoietic stem cell transplantation (HSCT). Overall response rate was 50%; median event free survival (EFS) in the groups of inhibitors, CT and HSCT was 11, 2, and 10 months, respectively (p < 0.0001); median overall survival (OS) was 12, 5, and 10 months, respectively (p = 0.020). Disease progression during venetoclax treatment was associated with shorter subsequent EFS compared to discontinuation for other reasons, even if the finding did not reach statistical significance (median EFS 4 vs. 10 months; p = 0.11). No decrease in EFS was associated with del17p and/or TP53 mutations, the use of venetoclax monotherapy or a previous treatment with one versus multiple BCRi. Despite its limitations, this real-world study provides additional insights into double-exposed patients, who still pose a clinical challenge, demonstrating the superior efficacy of inhibitors over alternative treatment options. Enrollment in clinical trial and treatments with novel molecules, if available, may help address this unmet clinical need.

Radiotherapy (RT) constitutes an important treatment modality in multiple myeloma (MM), traditionally used for the management of symptomatic osteolytic and extramedullary lesions. Objectives of RT are symptom alleviation and prevention of complications such as neurological deficits and pathological fractures. Over the past decade, systemic therapy (ST) for MM has undergone substantial advancements, notably with the incorporation of monoclonal antibodies in frontline regimens, as well as the emergence of bispecific antibodies and chimeric antigen receptor T-cells (CAR-T) for relapsed and refractory disease. These therapeutic innovations have introduced new clinical challenges and expanded the indications for RT, including its role as bridging therapy prior to CAR-T therapy, salvage therapy following CAR-T failure, and in the management of oligoprogressive and/or extramedullary disease. The integration of novel systemic agents prompts critical questions regarding synergistic interactions, feasibility, efficacy, and tolerability of combined RT and ST approaches. Herein, we present a literature review summarizing current evidence stratified by systemic treatment modalities, and discuss the clinical implications within the contemporary therapeutic landscape of MM.

Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti-apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B-cell lymphoma (BCL)-X_L/BCL-2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi-naïve patients with myelofibrosis. JAKi-naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate-2 and high-risk myelofibrosis, and ECOG 0-2) and platelet count > 100 × 10⁹/L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 10⁹/L or > 150 × 10⁹/L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR₃₅) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS₅₀) at week 24, change in grade of BMF, anemia response, and safety. Thirty-two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow-up was 44 months (5-58). 63% (20/32) of patients achieved SVR₃₅ at week 24; median (range) time to first SVR₃₅ was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS₅₀ at week 24; median (range) time to first TSS₅₀ of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion-independent and 100% (2/2) for transfusion-dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi-naïve patients with myelofibrosis. TRIAL REGISTRATION: NCT03222609.

162 patients with relapsed secondary central nervous system lymphoma (R-SCNSL) (median age, 65 years; male, 59.9%) including central nervous system (CNS)-only (n = 120) and concomitant CNS/systemic relapse (n = 42) were retrospectively analyzed. Overall, 21.9% of patients were classified as high risk according to the CNS International Prognostic Index (CNS-IPI). Several biological and clinical features were significantly associated with leptomeningeal involvement, including double- or triple-hit (DHL/THL) status, MYC rearrangement, negative BCL6 expression by IHC, bone marrow involvement, and concomitant R-SCNSL. Multivariable analysis showed that leptomeningeal involvement independently predicted inferior OS and was associated with a 98% increase in the hazard of death compared with parenchymal relapse (HR = 1.98, 95% CI: 1.20-3.26, p = 0.008). Based on anatomical localization, R-SCNSL was classified into four subtypes: parenchymal-only involvement (parenchymal-CNS [P-CNS], 68/42%) and parenchymal involvement plus systemic relapse (parenchymal-concomitant [P-concomitant], 17/10.5%); and leptomeningeal with or without parenchymal involvement (leptomeningeal-CNS [LM-CNS], 52/32.1%) and leptomeningeal with systemic relapse (leptomeningeal-concomitant [LM-concomitant], 25/15.4%). This anatomical classification significantly impacted OS and PFS (p < 0.001). Two-year OS and PFS were 58.2% and 29.1% for P-CNS, 32.4% and 17.7% for P-concomitant, 22% and 13.9% for LM-CNS, and 7.1% and 0% for LM-concomitant, respectively. ASCT showed a trend toward improved survival among patients with a response (CR/PR) in a 4-month landmark analysis. These findings support the clinical application of the anatomical classification in the management of R-SCNSL.

Concurrent follicular and diffuse large B-cell lymphoma (FL/DLBCL) and transformed follicular lymphoma (tFL) are distinct B-cell lymphoma entities, posing challenges for understanding pathogenesis and clinical management. The clinical characteristics of 98 FL/DLBCL, 31 tFL, 403 FL1-2/3A, and 608 DLBCL patients were analyzed. DNA sequencing was performed in these cohorts, and RNA sequencing was performed on 60 FL/DLBCL, 8 tFL, 175 FL1-2/3A, and 329 DLBCL patients. FL/DLBCL was characterized by localized disease, whereas tFL was associated with elevated LDH levels. Genomic analyses revealed that FL/DLBCL harbored frequent mutations in the Wnt signaling pathway but lacked the epigenetic alterations observed in FL, while tFL retained FL-associated epigenetic mutations and acquired additional alterations in cell cycle/p53 and JAK-STAT pathways. Both FL/DLBCL and tFL exhibited increased gene mutations related to the tumor microenvironment and B-cell differentiation, most notably CD70 and CD79B. Transcriptomic profiling further demonstrated enrichment of tumor microenvironment and B-cell differentiation-related pathways, consistent with the mutational landscape. Functionally, co-culture assays showed that knockdown of CD70 in B-lymphoma cells reduced naive CD4+ and CD8+ T-cell subsets, whereas CD79B^Y197H transfected B-lymphoma cells enhanced tumor cell viability. Our findings comprehensively characterize FL/DLBCL and tFL molecularly, elucidating their distinct pathogenesis and rationalize CD70 and CD79B targeted immunotherapies.