Adding brentuximab vedotin to lenalidomide and rituximab improves OS in R/R DLBCL
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Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax
Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently.
Subgrouping germinal center-derived B-cell lymphomas based on machine learning-deduced DNA methylation modules
To the Editor: Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common lymphomas, both exhibiting features of germinal center-derived B-cells (gcBCs).…
Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes
In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (<70, ≥70 to <75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45–0.67; P < 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P < 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.
CNS prophylaxis is (mostly) futile in DLBCL
Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis, with a median overall survival of approximately five months [1]. The risk for CNS disease has been estimated to be about 5% overall [2], but it is significantly higher in certain high-risk groups [3]. CNS prophylaxis is often administered to patients felt to be at high risk for CNS recurrence. Options for CNS prophylaxis include high-dose methotrexate (HD-MTX) and intrathecal (IT) chemotherapy with methotrexate and/or cytarabine. However, a number of recent retrospective analyses have called into question the efficacy of prophylaxis. Here, we aim to review the literature regarding CNS prophylaxis with HD-MTX or IT chemotherapy in DLBCL. Our review and discussion exclude Burkitt lymphoma and lymphoblastic leukemia/lymphoma, for which standard treatment protocols include CNS prophylaxis. We also exclude double and triple hit lymphoma (DHL, THL) as it is generally accepted that these patients are at a high risk of CNS relapse. Based on the results of several recent studies, we recommend consideration of IT chemotherapy instead of HD-MTX if prophylaxis is desired due to better tolerability. If HD-MTX is desired, it should be done after systemic therapy is completed to avoid treatment delays. We provide an algorithm to guide decision making. However, our review of the literature suggests that CNS prophylaxis by either means has no clear benefit.
Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm
Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the CSNK1A1 gene located in the commonly deleted region (CDR) of chromosome 5q. However, lenalidomide-resistance is common, often secondary to loss-of-function mutations in TP53 or RUNX1. The CDR in del(5q) harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. miR-143 and miR-145 are located within the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is lacking. Here we provide evidence that deficiency of miR-143 and miR-145 plays a role in clonal expansion of del(5q) MDS. We show that insulin-like growth factor 1 receptor (IGF-1R) is a direct target of both miR-143 and miR-145. Our data demonstrate that IGF-1R inhibition reduces proliferation and viability of del(5q) cells in vitro and in vivo, and that lenalidomide-resistant del(5q) MDS cells depleted of either TP53 or RUNX1 are sensitive to IGF-1R inhibition. Resistant del(5q) MDS-L cells, as well as primary MDS marrow cells, are also sensitive to targeting of IGF-1R-related dependencies in del(5q) MDS, which include the Abl and MAPK signaling pathways. This work thus provides potential new therapeutic avenues for lenalidomide-resistant del(5q) MDS.
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