Autonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation

Abstract Background: Nuclear factor of activated T cells (NFAT) factors regulate activation and Ca2+ signaling in B-cells. Store-operated Ca2+ entry (SOCE) is regulated by Orai1 and Stim1 and upstream of NFAT. We previously reported on the observation of autonomous oscillatory Ca2+ signal activity in BCR-ABL1-driven B-ALL. Autonomous Ca2+ oscillations may provide oncogenic survival signals to B-ALL cells, however their significance and mechanism remained unclear. Results: Here we found that autonomous Ca2+ oscillations are common across multiple subtypes of B-cell lineage ALL and mature B-cell lymphoma and reflect downstream survival and proliferation signals from oncogenic BCR-signaling or oncogenes that mimic active BCR-signaling (e.g. ABL1-kinase fusions, CD79B mutation, EBV-encoded oncoprotein LMP2A, RAS-pathway lesions). By contrast, multiple myeloma and Hodgkin's lymphoma that lack BCR-expression and function also lack Ca2+ oscillations (Figure, top panel). As Orai1 and Stim1/2 are essential SOCE-effector genes, we performed genetic experiments to test the impact of Cre-mediated deletion of Orai1 and Stim1/2 in BCR-ABL1 and NRASG12D-dependent models of B-ALL. Inducible deletion of Orai1 or Stim1/2 not only abrogated SOCE but also autonomous Ca2+ oscillations. Signal amplitudes of residual autonomous Ca2+ oscillations were significantly reduced (P < 0.0001; Figure, bottom panel). Further, deletion of either Orai1 or Stim1/2 induced cell death and abrogated colony-forming capacity in both models of B-ALL. In agreement with these findings, NFATc1 no longer translocated to the nucleus upon Cre-mediated ablation of Orai1 or Stim1/2 induced, which reflected functional inactivation of NFATc1. These results demonstrated that Orai1- and Stim1/2-mediated SOCE signaling and autonomous Ca2+ oscillations are critical in BCR-ABL1 and NRASG12D-dependent B-ALL. A NFAT-calcineurin association inhibitor, INCA-6, was tested for its ability to suppress NFATc1 and autonomous Ca2+ signaling in patient-derived xenograft (PDX) models of B-ALL, mantle cell lymphoma and DLBCL. Treatment with INCA-6 suppressed survival and proliferation signals in all six PDX of B-ALL, mantle cell lymphoma and DLBCL but not multiple myeloma cells. Unlike myeloma cells, B-ALL, mantle cell and DLBCL cells expressed a functional (pre-)BCR. These findings suggest that the SOCE-NFAT pathway is linked to Ca2+ signaling downstream of a functional BCR- or oncogenic BCR-mimics. Furthermore, to determine whether high expression levels of ORAI1, STIM1, STIM2 and NFATC1 represents a biomarker of clinical outcome for patients with B-ALL, we segregated patients from two clinical trials (Children's Oncology Group P9906 (n=207) and Eastern Cooperative Oncology Group (E2993; n=215)) into two groups on the basis of higher or lower than median expression levels of ORAI1, STIM1, STIM2 and NFATC1 at the time of diagnosis. Higher than median expression levels of each of these four genes at the time of diagnosis predicted shorter overall and relapse-free survival (P < 0.02 or lower for each of these genes). These findings identify SOCE-NFAT signal as a novel biomarker with potential use in risk stratification of children and adults with B-ALL. Conclusions: We identified Orai1 and Stim1 as central mediators of SOCE. Most BCR-dependent B-cell malignancies are driven by oncogenic BCR-signals, which result in autonomous Ca2+ oscillations. While the significance of autonomous Ca2+-oscillations remains unclear, deletion of Orai1 and Stim1/2 resulted in a complete loss of Ca2+ oscillations, loss of NFATc1-activation and cell death. We conclude that previously unrecognized Ca2+-oscillations downstream of oncogenic BCR-signaling are required for survival and proliferation of B-ALL and B-cell lymphoma cells. Pharmacological inhibition of SOCE (Orai1 and Stim1/2) or NFATC1 (e.g. INCA-6) represents a selective strategy to disrupt autonomous Ca2+ oscillations and oncogenic BCR-signaling in a broad range of B-cell malignancies. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Co-Expression of SYK and ZAP70 Subverts Negative B-Cell Selection and Enables Oncogenic Signaling in Multiple B-Cell Malignancies

Blood ◽

10.1182/blood-2019-128999 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 295-295

Author(s):

Teresa Sadras ◽

Mickaël Martin ◽

Lauren Kim-Sing ◽

Jevon Cutler ◽

Gal Lenz ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Cell Selection ◽

B Cell Malignancies ◽

Close Proximity ◽

Mantle Cell ◽

Bcr Signaling

B-cells are under intense selective pressure to eliminate autoreactive or premalignant clones. B-cell receptor (BCR) signals are required for survival, however, BCR-signaling exceeding maximum thresholds often reflects signaling from an autoreactive BCR or a transforming oncogene and triggers negative selection and cell death. The tyrosine kinase SYK initiates BCR-downstream signaling in B-cells while its close relative ZAP70 is almost exclusively expressed in T-cells. Interestingly, the segregation of SYK to B-cells and ZAP70 to T-cells is less confined in malignant lymphopoiesis suggesting that the balance of these related kinases may alter signaling output in disease and contribute to development of leukemia. As previously shown in B-cell chronic lymphocytic leukemia (B-CLL), we identified aberrant ZAP70 expression as a frequent feature in multiple other B-cell malignancies that depend on survival signals from a functional (pre-) BCR (E2A-PBX1+ pre-B ALL, and mantle cell lymphoma) or harbor oncogenic mimics of the BCR (BCR-ABL1+ B-ALL). Studying SYK and ZAP70 expression by single-cell Western blot, co-expression of the two tyrosine kinases was extremely rare in normal B- and T-cell populations. In contrast, >50% of tumor B-cells in mantle cell lymphoma, pre-B ALL and CLL co-expressed SYK and ZAP70. Despite their structural similarities, genetic deletion and engineered reconstitution of SYK and ZAP70 in human B-cell lymphoma cells revealed striking functional differences. Proximity-dependent biotin identification (BioID) analyses identified that SYK, but not ZAP70, engaged the PI3K pathway via interaction with CD19. Consistent with this, reconstitution with SYK and SYK-ZAP70 but not ZAP70 alone promoted survival and proliferation. Detailed analysis of BCR-mediated cascades in lymphoma cells expressing SYK, ZAP70 or SYK-ZAP70 established that ZAP70 is only weakly efficient at propagating BCR-mediated calcium and downstream pathway activation in B-cells. Strikingly, co-expression of ZAP70 with SYK resulted in re-wired BCR-signaling of intermediate strength: compared to cells expressing only SYK, SYK-ZAP70 co-expressing cells had markedly reduced activation of the BLNK-BTK-PLCγ pathway, further reflected in BCR-induced Ca2+ signaling with delayed onset, lower amplitude but longer duration. In this way, we speculated that SYK and ZAP70 may be present within close proximity at the apex of BCR-initiated interactions, and hence compete for downstream substrates resulting in a re-wiring of classic signaling programs propagated normally by SYK. To explore this, we utilized proximity ligation assays (PLA) to monitor the proximity of SYK and ZAP70 in resting or BCR-stimulated B-cells, and found that SYK and ZAP70 co-exist within close proximity consistent with the view that varying levels of these kinases may alter B-cell signaling output. Functional experiments further showed that phosphomimetic activation of SYK, but not ZAP70, induced hyperactivation of PI3K-signaling and acute BTK-mediated cell death in pre-B ALL cells. In line with altered BCR-signaling strength and quality in SYK and ZAP70 co-expressing cells, over-expression of Zap70 in pre-B ALL cells rescued auto-immune checkpoint activation induced by hyper-activation of BCR-associated signaling. To study functional consequences of SYK-ZAP70 co-expression during normal B-cell development, we generated a novel knock in Zap-70+/Mb1-Cre+mouse model, to induce conditional expression of Zap70 in the B cell compartment from the proB stage. Consistent with compromised central tolerance checkpoints, Syk-Zap70 co-expressing pro/pre-B and immature B-cells had reduced spontaneous apoptosis rates and gave rise to autoantibody production against multiple self-antigens. Importantly, our findings highlight a previously unrecognized role for ZAP70 in oncogenic BCR-signaling and we conclude that the co-expression of ZAP70 mitigates the ability of SYK, downstream of an autoreactive BCR or a transforming oncogene, to trigger negative B-cell selection and cell death (Figure 1). Disclosures Weinstock: Celgene: Research Funding. Meffre:AbbVie: Consultancy, Other: Grant.

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Phase 1 Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.2722.2722 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2722-2722 ◽

Cited By ~ 1

Author(s):

Stephen Ansell ◽

Thomas E. Witzig ◽

Anne Novak ◽

David James ◽

Luis Porrata ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Disease Progression ◽

Stable Disease ◽

Cell Lymphoma ◽

Phase 1 ◽

B Cell Lymphoma ◽

B Cell Malignancies ◽

Mantle Cell ◽

Heavily Pretreated

Abstract Background: Atacicept (TACI-Ig) is a recombinant fusion protein that inhibits BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand), cytokines that are involved in B-cell homeostasis and immunoglobulin (Ig) expression and are overexpressed in B-cell malignancies. In vitro, atacicept decreases the survival of lymphoma cells and in vivo, atacicept decreases serum immunoglobulin levels. Based on its effects on B cells, atacicept may offer a novel treatment for B-cell malignancies. Methods: A Phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was performed. Atacicept was administered subcutaneously for 5 weeks in single weekly doses of 2, 4, 7, or 10 mg/kg to sequential patient cohorts. After 8 weeks, patients with responding or stable disease were eligible for treatment on an extension study at the dose previously received for up to 24 weeks or until disease progression. The primary study objective was evaluation of overall safety and the maximum tolerated dose. Pharmacokinetics and biomarkers were also investigated. Results: As of July 2006, 15 patients with relapsed and refractory diffuse large B-cell lymphoma (7), follicular lymphoma (4), small lymphocytic lymphoma/chronic lymphocytic leukemia (2), and mantle-cell lymphoma (2) received 2, 4, or 7 mg/kg atacicept (4 patients per dose cohort) or 10 mg/kg atacicept (3 patients). All patients were heavily pretreated (median number of previous treatments was 5, range 1–10) and 4 patients had previously received a stem cell transplant. All patients completed study treatment (5 doses), except 2 who withdrew due to disease progression after receiving 2 and 4 doses. Atacicept was well tolerated at all doses. The most common adverse events (AEs) that occurred in ≥20% of patients were fatigue (47%) and injection site bruising (20%). Three AEs with ≥ grade 3 severity were reported for 1 patient including pain in jaw, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Four SAEs considered unrelated to atacicept were reported for 2 patients who withdrew due to disease progression. Pharmacokinetic results were nonlinear and consistent with observations in other indications. Five weekly doses produced low to moderate accumulation of free total atacicept and atacicept/BLyS complex in serum. IgA, IgG, and IgM concentrations decreased in a dose-related pattern with a mean decrease of 15–40% from baseline after 4 weeks of atacicept. Peripheral B-cell numbers were variable and were difficult to evaluate due to low B-cell values at baseline in the majority of patients. At the 8-week evaluation, no objective responses were observed. Two patients had stable disease (1 with mantle cell lymphoma and 1 with follicular lymphoma) at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns. Both patients however later discontinued treatment due to disease progression. Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and demonstrated biological activity by decreasing Ig concentrations in this heavily pretreated cohort of patients with refractory B-cell lymphoma, although tumor responses were not observed.

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Forodesine (Immucillin H, BCX-1777) Shows Activity on Mantle Cell Lymphoma Primary Cells

Blood ◽

10.1182/blood.v112.11.4997.4997 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4997-4997

Author(s):

Andrea Rinaldi ◽

Emilia Ceresa ◽

Davide Rossi ◽

Gianluca Gaidano ◽

Shanta Bantia ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Annexin V ◽

B Cell Lymphoma ◽

B Cell Malignancies ◽

New Therapeutic Approaches ◽

Mantle Cell

Abstract Mantle cell lymphoma (MCL) represents a subtype of B-cell lymphoma associated with a very unfavourable clinical outcome. Currently no therapy can be considered as standard, and new therapeutic approaches are needed. Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP), whose major role is to catalyze the cleavage of inosine, deoxyinosine guanosine, and deoxyguanosine (dGuo) to their corresponding base and sugar 1-phosphate by phosphorolysis. In the presence of deoxycytidine kinase, PNP inhibition leads to an increase in the concentration of dGuo triphosphate (dGTP), followed by inhibition of DNA synthesis and cell death by apoptosis. When combined with dGuo, forodesine has been shown to have in vitro cytotoxic activity on T-cell (T-ALL, T-PLL) and on B-cell malignancies (CLL, B-ALL), and Phase I/II trials are on going in CLL and CTCL patients. Here, we report the first data on in vitro activity of forodesine in MCL. Primary MCL cells, derived from six patients, were exposed to forodesine (0, 2, 20 μM) in combination with dGuo (0, 10, 20 μM), for 48 hrs. Cells were cultured in X-VIVO 10 medium (Cambrex) with 10% FBS. Cell viability was assessed by flow cytometry with the Annexin V - propidium iodide assay. Four patient samples (67%) showed an increase in the number of Annexin V positive cells ranging from 1.9 to 5.3 times compared to untreated cells. The effect was larger for 20 μM forodesine compared with 2 μM. There was no effect of dGuo alone and only a minimal effect of increasing dGuo concentration from 10 μM to 20 μM. Cell lines did not appear to be ideal models to evaluate the efficacy of forodesine in vitro. Three established MCL cell lines (Granta-519, Rec, JeKo1) were treated with escalating doses of forodesine, but the results were not reproducible, while the same cells showed expected IC50 values between 25–30 μM when exposed to bendamustine for 72 hrs. In conclusion, the in vitro data reported here with 4/6 MCL patients primary samples sensitive to forodesine and the results from various groups on other T- and B-cell malignancies suggest that clinical trials of forodesine in MCL may be warranted.

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CD25 Enables Oncogenic BCR Signaling and Represents a Therapeutic Target in Refractory B Cell Malignancies

Blood ◽

10.1182/blood.v128.22.4088.4088 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4088-4088 ◽

Cited By ~ 2

Author(s):

Jae-Woong Lee ◽

Huimin Geng ◽

Zhengshan Chen ◽

Lars Klemm ◽

Kadriye Nehir Cosgun ◽

...

Keyword(s):

B Cell ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Surface Expression ◽

Cell Leukemia ◽

B Cell Malignancies ◽

Expression Levels ◽

Cd25 Expression ◽

Conventional Drug ◽

Bcr Signaling

Abstract Background and hypothesis: B cells critically depend on continuous survival and proliferation signals from a functional B cell receptor (BCR). In >50% of B cell malignancies, the tumor clone is driven by an oncogenic BCR-mimic. Oncogenic mimics of BCR-signaling include BCR-ABL1 (Ph+ ALL) and other ABL1-fusion genes (Ph-like ALL), viral oncoproteins (e.g. EBV; KSHV), BRAF- (hairy cell leukemia) and NF-kB-pathway lesions (Hodgkin's lymphoma, primary mediastinal B cell lymphoma). B cell tumors driven by oncogenic BCR-signaling represent a highly heterogeneous group of various cellular origins, genetic lesions and divergent clinical outcomes. Despite this heterogeneity, our correlative analyses showed that these B cell malignancies are uniformly characterized by high expression levels of CD25. Features of CD25 function in B cell malignancies: While CD25 mediates IL2 signaling on T cells and is highly expressed on regulatory T cells (Tregs), we recently discovered that CD25 is a critical feedback regulator of B cell receptor (BCR) and oncogenic BCR-mimics in human B cell malignancies. Indeed, we found that CD25 is a biomarker of tumor clones driven by oncogenic BCR-mimics and predicts sensitivity to small molecule inhibitors of the BCR signaling pathway (e.g. Ibrutinib, entospletinib). Studying Cd25-/- models for B cell tumors, our genetic experiments demonstrated that CD25 is critical for the initiation of B cell leukemia in transplant recipient mice. Pulldown and mass-spectometry proteomic analyses identified strong binding and phosphorylation of the CD25 cytoplasmic tail by PKCd. Surface expression is rapidly induced by activity of PKCd and NF-kB downstream of the BCR. CD25 then recruits an inhibitory complex to the surface to reduce kinase signaling downstream of the BCR or its oncogenic mimics. Analysis of three clinical cohorts revealed that high expression levels of CD25 are strongly predictive of poor clinical outcome in various B cell malignancies. While CD25 expression is associated with drug-resistance, inhibition of CD25 sensitized multiple B cell malignancies to conventional drug-treatment. CD25 is required for B cell tumor-initiation: Our genetic studies showed that BCR signaling rapidly induces CD25 cell surface translocation by PKCd-dependent phosphorylation of the CD25 cytoplasmic tail (S268). In addition, BCR signaling induces CD25 expression at the transcriptional level through activation of NF-kB. In response to oncogenic BCR signaling, CD25 shuttles inhibitory phosphatases (e.g. SHIP1) from the cytoplasm to the cell membrane. CD25-mediated membrane recruitment of inhibitory phosphatases calibrates signal output and enables robustness of oncogenic signaling. Consistent with a role as dynamic feedback regulator, CD25 surface expression levels on individual cells oscillate in parallel with BTK- and PKCd-dependent Ca2+ oscillations. Genetic experiments demonstrated that CD25 is critical for the initiation of B cell leukemia and lymphoma in transplant recipients. Genetic ablation of CD25 subverted the ability of B cell lymphoma cells to balance oncogenic signal strength, resulting in p53 checkpoint activation, cell cycle arrest and cell death. Analysis of three clinical cohorts revealed that CD25+ B cell tumors are associated to relapse and poor clinical outcome. While CD25 expression induced drug-resistance, CD25-inhibition sensitized to conventional drug-treatment. Conclusions: Based on these and other findings, we propose CD25 as a biomarker of BCR-dependent B cell tumors that are highly sensitive to established BCR signaling antagonists (e.g. Ibrutinib, entospletinib) and therapeutic target in refractory B cell tumors. Disclosures Melnick: Janssen: Research Funding.

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Activity of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Mantle Cell Lymphoma (MCL) Identifies Btk As a Novel Therapeutic Target,

Blood ◽

10.1182/blood.v118.21.3688.3688 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3688-3688 ◽

Cited By ~ 3

Author(s):

Sabine Ponader ◽

Sriram Balasubramanian ◽

Lan V Pham ◽

Jun Chen ◽

Archito T. Tamayo ◽

...

Keyword(s):

Tyrosine Kinase ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Actin Polymerization ◽

Cell Lymphoma ◽

B Cell Malignancies ◽

Mantle Cell ◽

Bcr Signaling ◽

Btk Inhibitor

Abstract Abstract 3688 B cell receptor (BCR) signaling is critically involved in the progression of several B cell malignancies, but its role in mantle cell lymphoma (MCL) remains incompletely defined. Bruton's tyrosine kinase (Btk) is a central regulator of BCR signaling and can be selectively and irreversibly inhibited by PCI-32765, which is emerging as a new, molecularly targeted therapy for patients with B cell malignancies. In this study, we explored the role of Btk and the activity of PCI-32765 on BCR signaling in several MCL lines, including Granta-519, Jeko-1, JVM-2, JVM-13, Maver-1, Mino, NCEB-1, Rec-1 and Z-138. Btk and surface IgM protein expression was detected in all MCL lines at variable levels. In a 3-day proliferation assay, JVM-2 & MINO emerged as the most sensitive lines to PCI-32765 (GI50: 1.75–4.4uM). Rec-1 was resistant to PCI-32765 alone (11.3uM) but became much more sensitive (1.45uM) upon BCR stimulation using anti-IgM (10ug/mL). Other lines such as Maver-1, Granta-519 & Jeko-1 all required >10uM of PCI-32765 for inhibition and BCR stimulation did not make much difference. When signaling pathways downstream of BCR activation were studied, intracellular calcium flux following stimulation with IgM was observed in all lines (except JVM-2) and was inhibited at <100nM PCI-32765 in most of them, but no correlation between this and growth inhibition was observed. Constitutive BTK autophosphorylation was observed in all lines and was completely abolished by PCI-32765. BCR stimulation increased p-BTK which was also blocked by PCI-32765 in all lines. Mino and JVM-2 showed constitutive p-ERK activity, which was slightly increased upon BCR stimulation and could be blocked with PCI-32765, whereas the more resistant lines such as Maver-1 and Rec-1 had low endogeneous levels of p-ERK, but which was increased by BCR stimulation and only partially or not reversed by PCI-32765 at 5uM. Little change was observed in levels of p-PLCg1 or p-NF-kB p65. Additionally, in all cell lines stimulation with anti-IgM led to an increased secretion of the chemokines CCL3 and CCL4, which are surrogate biomarkers for BCR-derived activation of neoplastic B cells (Burger JA et al., Blood 113:3050–8, 2009) with greatest increase in JVM-13 and Rec-1 cells. Pre-treatment of these two MCL lines with PCI-32765 significantly inhibited CCL3 and CCL4 secretion in a dose dependent fashion with total abrogation of chemokine secretion at concentrations of 10 mM PCI-32765 (see Figure). Early clinical data indicate that PCI-32765 induces a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis (in CLL, but also in MCL patients), presumably due to mobilization of the malignant B cells from the tissue compartments into the peripheral blood. Therefore, we analyzed the effect of PCI-32765 (conc. 0.5 and 1 mM) on MCL responses to a lymph node homing chemokine, CXCL13. We found that CXCL13-induced actin polymerization in Rec-1 cells was significantly reduced by PCI-32765, even at lower concentration. We conclude that MCL cells express functional Btk, which is involved in BCR signaling in MCL cells. Blockade of Btk function using PCI-32765 inhibits MCL cell proliferation, BCR signaling, chemokine secretion, and interferes with MCL cell actin polymerization. These findings highlight the importance of BCR signaling and Btk in MCL, help explain the activity of the Btk inhibitor PCI-32765 in MCL patients, and provide biomarkers that may be of value in the clinic. Disclosures: Balasubramanian: Pharmacyclics: Employment. Chen:Pharmacyclics: Employment. Wang:Pharmacyclics: Research Funding. O'Brien:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Burger:Cellgene: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genzyme: Consultancy; Calistoga: Research Funding; Noxxon: Consultancy, Research Funding.

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Ongoing phase 1/2 study of INCB050465 for relapsed/refractory (R/R) B-cell malignancies (CITADEL-101).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.7530 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 7530-7530 ◽

Cited By ~ 1

Author(s):

Rod Ramchandren ◽

Tycel Jovelle Phillips ◽

Michael Wertheim ◽

Martin Gutierrez ◽

William Jeffery Edenfield ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Phase 1 ◽

B Cell Lymphoma ◽

Pneumocystis Jirovecii Pneumonia ◽

B Cell Malignancies ◽

Mantle Cell ◽

Dosing Regimens ◽

Ongoing Phase

7530 Background: INCB050465 is a selective PI3Kδ inhibitor with no preclinical hepatotoxicity at clinically relevant doses. We report emerging safety and efficacy data from a phase 1/2 study of INCB050465 in patients (pts) with r/r B-cell malignancies (NCT02018861). Methods: The protocol was initiated with a single patient cohort, treated with INCB050465 5 mg QD PO. Subsequent cohorts used a 3+3 design and evaluated doses of 10–45 mg QD. Based on PK/PD, the 20 and 30 mg QD cohorts were expanded. Responses were assessed Q9W by the Lugano Classification or International Working Group on Chronic Lymphocytic Lymphoma (CLL) criteria. Results: As of the data cutoff (Nov 1, 2016), 52 pts were treated (median age, 65 y [range, 30–88]; baseline tumors: diffuse large B-cell lymphoma [DLBCL], n=14; follicular lymphoma [FL], n=10; Hodgkin lymphoma [HL], n=9; marginal zone lymphoma [MZL], n=8; CLL, n=6; mantle cell lymphoma [MCL], n=5; 62% had >3 prior systemic regimens). Median duration of therapy was 3.3 mo (range, 0.6–13.4); no DLTs were identified. 67% of pts discontinued therapy (disease progression, 31%; AEs, 25%); 33% had dose interruption; 4% had reduction. Most common nonhematologic AEs (all grade [Gr]; Gr ≥3): nausea (38%; 0%), diarrhea (31%; 6%), vomiting (25%; 0%); Gr ≥3 hematologic AEs: neutropenia (21%), lymphopenia (17%), thrombocytopenia (10%), anemia (4%). 40% of pts had serious AEs, most frequently colitis, diarrhea, hypotension (all n=3). 1 pt had Gr 3 pneumonitis; none had Pneumocystis jirovecii pneumonia (PJP) or Gr ≥2 elevated transaminase. Objective responses (ORs) occurred at all doses (Table), except 5 mg QD; 90% were observed at first assessment. Conclusions: INCB050465 demonstrated manageable toxicities with no clinically meaningful transaminitis/PJP. OR rates were generally high, with 90% observed at first assessment. Different dosing regimens/schedules, long-term safety, and disease-specific cohorts are being evaluated. Clinical trial information: NCT02018861. [Table: see text]

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Correlations between baseline 18F-FDG PET tumour parameters and circulating DNA in diffuse large B cell lymphoma and Hodgkin lymphoma

EJNMMI Research ◽

10.1186/s13550-020-00717-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Pierre Decazes ◽

Vincent Camus ◽

Elodie Bohers ◽

Pierre-Julien Viailly ◽

Hervé Tilly ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Fdg Pet ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Circulating Dna ◽

Tumour Burden ◽

B Cell Malignancies ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background 18F-FDG PET/CT is a standard for many B cell malignancies, while blood DNA measurements are emerging tools. Our objective was to evaluate the correlations between baseline PET parameters and circulating DNA in diffuse large B cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). Methods Twenty-seven DLBCL and forty-eight cHL were prospectively included. Twelve PET parameters were analysed. Spearman’s correlations were used to compare PET parameters each other and to circulating cell-free DNA ([cfDNA]) and circulating tumour DNA ([ctDNA]). p values were controlled by Benjamini–Hochberg correction. Results Among the PET parameters, three different clusters for tumour burden, fragmentation/massiveness and dispersion parameters were observed. Some PET parameters were significantly correlated with blood DNA parameters, including the total metabolic tumour surface (TMTS) describing the tumour–host interface (e.g. ρ = 0.81 p < 0.001 for [ctDNA] of DLBLC), the tumour median distance between the periphery and the centroid (medPCD) describing the tumour’s massiveness (e.g. ρ = 0.81 p < 0.001 for [ctDNA] of DLBLC) and the volume of the bounding box including tumours (TumBB) describing the disease’s dispersion (e.g. ρ = 0.83 p < 0.001 for [ctDNA] of DLBLC). Conclusions Some PET parameters describing tumour burden, fragmentation/massiveness and dispersion are significantly correlated with circulating DNA parameters of DLBCL and cHL patients. These results could help to understand the pathophysiology of B cell malignancies.

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Ibrutinib in B-cell lymphoma: single fighter might be enough?

Cancer Cell International ◽

10.1186/s12935-020-01518-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Chao Xue ◽

Xin Wang ◽

Lingyan Zhang ◽

Qingyuan Qu ◽

Qian Zhang ◽

...

Keyword(s):

B Cell ◽

Signaling Pathway ◽

Cell Lymphoma ◽

Critical Role ◽

B Cell Lymphoma ◽

Cell Receptor ◽

High Response Rate ◽

Main Body ◽

Combination Strategies ◽

Bcr Signaling

Abstract Background In recent years, the B cell receptor (BCR) signaling pathway has become a “hot point” because it plays a critical role in B-cell proliferation and function. Bruton’s tyrosine kinase (BTK) is overexpressed in many subtypes of B-cell lymphoma as a downstream kinase in the BCR signaling pathway. Ibrutinib, the first generation of BTK inhibitor, has shown excellent antitumor activity in both indolent and aggressive B-cell lymphoma. Main body Ibrutinib monotherapy has been confirmed to be effective with a high response rate (RR) and well-tolerated in many B-cell lymphoma subgroups. To achieve much deeper and faster remission, combination strategies contained ibrutinib were conducted to evaluate their synergistic anti-tumor effect. Conclusions For patients with indolent B-cell lymphoma, most of them respond well with ibrutinib monotherapy. Combination strategies contained ibrutinib might be a better choice to achieve deeper and faster remission in the treatment of aggressive subtypes of B-cell lymphoma. Further investigations on the long-term efficacy and safety of the ibrutinib will provide novel strategies for individualized treatment of B-cell lymphoma.

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Phase II Study of Rituximab Plus Three Cycles of CHOP and Involved-Field Radiotherapy for Patients With Limited-Stage Aggressive B-Cell Lymphoma: Southwest Oncology Group Study 0014

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.6929 ◽

2008 ◽

Vol 26 (14) ◽

pp. 2258-2263 ◽

Cited By ~ 175

Author(s):

Daniel O. Persky ◽

Joseph M. Unger ◽

Catherine M. Spier ◽

Baldassarre Stea ◽

Michael LeBlanc ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Serum Lactate Dehydrogenase ◽

Oncology Group ◽

Southwest Oncology Group ◽

Limited Stage ◽

Involved Field

Purpose To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) followed by involved-field radiation therapy (IFRT). Patients and Methods Southwest Oncology Group (SWOG) study S0014 enrolled patients with newly diagnosed, aggressive, CD20-expressing non-Hodgkin's lymphoma (NHL). Patients had limited-stage disease and at least one adverse risk factor as defined by the stage-modified International Prognostic Index (nonbulky stage II disease, age > 60 years, WHO performance status of 2, or elevated serum lactate dehydrogenase). Four doses of rituximab were infused on days −7, 1, 22, and 43, and CHOP was administered on days 3, 24, and 45, followed 3 weeks later by 40 to 46 Gy of IFRT. Results Sixty patients with aggressive NHL were eligible. With the median follow-up of 5.3 years, treatment resulted in a progression-free survival (PFS) of 93% at 2 years and 88% at 4 years. Overall survival (OS) was 95% at 2 years and 92% at 4 years. These results were compared with those from a historic group of patients treated without rituximab on S8736, demonstrating PFS of 78% and OS of 88% at 4 years. Conclusion In limited-stage DLBCL, the addition of rituximab to three cycles of CHOP plus IFRT met prespecified study criteria of efficacy, with 2-year PFS of at least 84%, meriting further investigation. There is a pattern of continuing relapse with modest survival gains. We hypothesize that such a pattern may be the result of biologic differences between limited- and advanced-stage lymphoma.

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