Thrombopoietin receptor agonists (TPO-RAs) have become central second-line treatments for children with persistent or chronic immune thrombocytopenia (ITP). Their efficacy has encouraged broad use, but difficult-to-treat patients who respond suboptimally may be exposed to repeated agent switching, prolonged treatment, or doses exceeding approved limits. This commentary uses a focused narrative approach to address whether the risk of treatment-associated marrow fibrosis should be interpreted primarily as a consequence of treatment duration or as a risk marker linked to supraphysiological treatment intensity in non-responders. A recent Haematologica report by Ma and colleagues identified clinically significant bone marrow myelofibrosis in a highly selected cohort of children with chronic ITP undergoing marrow re-evaluation after suboptimal response or loss of efficacy during TPO-RA therapy. The most relevant message is not simply that fibrosis can occur, but that it was independently associated with treatment intensification, particularly overdose and frequent switching. The biological plausibility of this association is supported by the known capacity of sustained megakaryocytic stimulation to promote local pro-fibrotic signaling and reticulin deposition. This commentary places this safety concern in the context of pediatric ITP epidemiology, current regulatory indications, expert approaches to refractory disease, and practical surveillance considerations. TPO-RAs should not be viewed as routine treatment for newly diagnosed pediatric ITP; their principal role remains in selected children with persistent or chronic disease who require second-line therapy. Failure to respond at the maximum approved dose should prompt diagnostic and therapeutic reassessment rather than automatic treatment escalation. The emerging lesson is that response-adapted therapy must also be risk-adapted therapy.
The cyclin-dependent kinase 6 (CDK6) is a central regulator of cell cycle progression and an important contributor to the development of acute leukemia, particularly in poor prognosis subtypes. Preclinical studies have demonstrated activity of CDK6-targeting drugs in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), but clinical trials with CDK4/6 inhibitors as monotherapy were disappointing. In contrast, clinical efficacy was observed for the combination of the dual CDK4/6 inhibitor, palbociclib, with chemotherapy in pediatric acute leukemia and lymphoma patients. We sought to evaluate the potential of CDK6 inhibition to sensitize AML cells to both standard-of-care and novel targeted therapies. We found the CDK2- targeting drug, tegtociclib, to be particularly effective in potentiating the inhibitory effects of CDK4/6 inhibitors against acute leukemia cells. While similar strategies have been considered for solid tumors where CDK4/6 targeted agents may work as monotherapy, we have discovered a unique and novel approach to introduce this class of drugs to acute leukemias. Our results also demonstrate that synergy between these agents, as has been previously shown in breast cancer, is also observed in acute leukemia and correlates with suppression of the Rb/E2F axis and inhibition of cell cycle progression. The universality between the underlying mechanisms of synergy for CDK2 inhibitors combined with CDK4/6 inhibitors in breast cancer and AML warrants further evaluation in other malignancies characterized by dependencies on these CDK subtypes.
CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces durable remissions in only 30-40% of patients with relapsed or refractory (R/R) B-cell non- Hodgkin lymphoma (B-NHL), highlighting a major need to improve outcomes. In dose-escalation studies, higher CAR T-cell doses improved tumor control but caused prohibitive toxicities. Having established the maximum tolerated JCAR014 dose in patients with B-NHL at 2 x 106 CAR+ cells/kg, we hypothesized that a second infusion at day 14 ("dose-dense") at the same dose and without repeat lymphodepletion, would be safe and enhance antitumor efficacy. We report outcomes from the pilot dose-dense cohort of a phase 1/2 trial (ClinicalTrials.gov identifier: NCT01865617) with 8-year follow-up. Two CAR T-cell products, each containing 2 x 106 CAR+ cells/kg, were manufactured for all 20 treated patients; 17 received both infusions. Any-grade cytokine release syndrome (CRS) and neurotoxicity (NT) occurred in 10 (59%) and 3 (18%) of dose-dense patients, respectively, and-except for one grade 2 CRS-events followed the first infusion only. Despite no additional lymphodepletion, CAR T-cell re-expansion after the second infusion occurred in 16 (94%) patients. By Lugano criteria, overall and complete response rates were 47% (8/17) and 41% (7/17), respectively. Among responders, the 8-year durationof- response rate was 63% (95% CI: 37-100), comparing favorably with the 26% (95% CI: 14-48) observed in patients treated with a single infusion. In conclusion, early redosing on day 14 was feasible, safe and led to durable responses in patients with R/R B-NHL.
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Many patients with chronic myeloid leukemia (CML) treated with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) experience persistent adverse events (AEs) that negatively impact daily living and the ability to remain on treatment. Asciminib, an allosteric inhibitor of BCR::ABL1, was designed to enhance efficacy and reduce off-target effects vs ATPcompetitive TKIs. The phase 3 randomized ASC4FIRST trial established the overall favorable safety profile of asciminib in patients with newly diagnosed CML in chronic phase (CP). This exploratory post hoc analysis of ASC4FIRST focused specifically on the tolerability of asciminib vs imatinib and asciminib vs second-generation [2G] TKIs. Analyses were conducted within each stratum to account for differences between strata; patients prerandomized to the imatinib stratum were older and had higher cardiovascular risk than those in the 2G stratum. Within both strata, patients receiving asciminib experienced fewer difficult-to-tolerate AEs (such as gastrointestinal toxicity, rash, and pleural effusion) and fewer AEs leading to dose modifications and discontinuations due to nonhematologic and hematologic AEs vs the investigator-selected (IS) TKI comparator, with a shorter median duration of dose modification. Additionally, median onset of AEs leading to dose modification occurred later in patients receiving asciminib vs ISTKIs. The safety and tolerability of asciminib observed in the ASC4FIRST trial demonstrate asciminib's excellent benefit-risk profile as a frontline therapy for a broad range of patients with newly diagnosed CML-CP.
A CD79B-targeted antibody-drug conjugate, polatuzumab-vedotin has significantly improved outcomes in DLBCL, particularly in the activated B-cell-like (ABC) subtype. This indicates that CD79B expression varies among COO subtypes, although the expression level was not necessarily higher in ABC-DLBCL. Here, we evaluated CD79B protein expression by immunohistochemistry (IHC) in 590 de novo DLBCL cases, observing a CD79B gradient according to COO subtypes, with ABC-DLBCL showing the lowest expression, followed by GCB and dark-zone signature-positive (DZsigpos) cases in ascending order (P < 0.0001). This observation was fully validated in an independent population-based cohort of 272 cases derived from BC Cancer registry. Given that COO classification reflects the stages of normal germinal center (GC) B-cell differentiation, we further explored CD79B expression dynamics during B-cell maturation by performing single-cell proteomic and transcriptomic analyses. Analyses of 2,447 normal GC B-cells demonstrated a progressive decrease in CD79B expression as GC B-cells transitioned toward terminal differentiation. Collectively, our findings reveal a novel COO-dependent gradient of CD79B expression, particularly with lower expression in ABC-DLBCL.
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The bone marrow is a highly dynamic organ that undergoes continuous remodeling to maintain all different hematopoietic cell populations throughout life, adapting during development, aging, and disease. It serves as the primary site of both normal hematopoiesis and leukemic initiation and progression. While mesenchymal stromal cells have received substantial attention for their contribution to support acute leukemia, the bone marrow adipocyte lineage has remained largely overlooked. This has two main reasons: first, adipogenic progenitors are typically grouped under the broad mesenchymal stromal cell umbrella, obscuring the distinct contributions of specific stromal subsets; second, mature bone marrow adipocytes have traditionally been regarded as inert energy reservoirs rather than active components of the marrow microenvironment. Recent evidence challenges this view, demonstrating that different types of adipocyte lineage cells actively promote acute leukemia progression and chemotherapy resistance through distinct mechanisms. In this review, we summarize recent advances in defining subpopulations within the bone marrow adipocyte lineage and outline how leukemic cells exploit their functions. We further discuss how standard chemotherapy may inadvertently reshape leukemic-adipocyte lineage interactions, mediating resistance and facilitating the re-emergence of disease.
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To improve mechanism-based pharmacotherapy for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed mode of action and potential synergies of inotuzumab ozogamicin (INO) with the p38 kinase inhibitor BIRB 796 and the BCL2-specific BH3 mimetic venetoclax (VEN) in BCP-ALL cell lines and patient-derived xenograft (PDX) models including t(17;19) PDX cells. INO is an antibody-drug conjugate (ADC) consisting of an anti-CD22 antibody linked to calicheamicin (CAL). CAL and INO induced DNA strand cleavage and activated DNA damage response signaling, including phosphorylation of ATM, H2AX (γH2AX) and p38, as well as induction of p53 protein expression. Pharmacologic inhibition of p38 with BIRB 796 selectively potentiated INO-induced DNA strand cleavage, increased γH2AX expression and enhanced cytotoxicity, whereas CAL activity remained unaffected in line with drug-interaction upstream of DNA damage. Furthermore, INO induced mitochondrial priming and augmented VEN-mediated mitochondrial outer membrane permeabilization, which was further enhanced by BIRB 796. Accordingly, INO and VEN exerted synergistic cytotoxicity in the presence and absence of BIRB 796. Finally, this triple therapy induced complete remissions assessed by bioluminescence imaging and long-term leukemia-free and overall survival in 5 out of 7 (71%) NSG mice engrafted with L707 (t(17;19)) PDX cells. These findings identify time-limited p38 inhibition as a mechanism-based strategy to enhance INO-induced DNA cleavage and mitochondrial priming, resulting in markedly improved therapeutic efficacy in a very high-risk leukemia model. This work may provide a rationale for optimizing ADCbased combination therapies through transient inhibition of p38.
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Chronic myeloid leukemia stem cells (LSCs) drive disease initiation, persistence, and relapse. To improve LSC-based prognostication and patient stratification, we evaluated six LSC markers (CD26, CD25, IL1-RAP, CD56, CD93, and CD69) using a single-tube analysis of CD34+CD38- cells in a cohort of 48 chronic phase chronic myeloid leukemia patients at diagnosis, month 3, or month 6. We demonstrate that these markers (including the novel marker CD69) are co-expressed, and their combination enhances LSC detection, especially during follow-up when marker expression is reduced. Furthermore, LSC data from month 3 and month 6 predict patient outcomes. We also show that quantifying residual normal hematopoietic stem cells at diagnosis enables early hematological toxicity prediction. Our findings provide technological LSC detection advancements and highlight the potential of these data for prognostic applications.
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