A phase <scp>II</scp> trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre <scp>GOAL</scp> trial

Heß, Georg; Hüttmann, Andreas; Witzens‐Harig, Mathias; Dreyling, Martin; Keller, Ulrich; Marks, Reinhard; Ernst, Thomas; Pott, Christiane; Viardot, Andreas; Frontzek, Fabian; Trautmann, Marcel; Ruckes, Christian; Deuster, Oliver; Rosenwald, Andreas; Theobald, Matthias; Lenz, Georg

doi:10.1111/bjh.18161

Cited by 8 publications

(11 citation statements)

References 31 publications

(55 reference statements)

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“…This is presumably caused by abnormal Fas signaling and can be overcome by combination therapies [ 9 , 10 ]. There are a large number of completed and ongoing studies of phase 1 to 3 with obinutuzumab to enable the application in further clinical indications and to increase efficacy by combining it with other anti-cancer drugs including acalabrutinib, bendamustine, chlorambucil, duvelisib, entospletinib, ibrutinib, idasanutlin, pixantrone, tirabrutinib, and venetocla [ 4 , 11 , 12 , 13 ]. For instance, 229 patients were included in a phase 3 study comparing obinutuzumab in combination with either chlorambucil or ibrutinib.…”

Section: Introductionmentioning

confidence: 99%

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Panjideh

Niesler

Weng

et al. 2022

Toxins

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Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of antibody-toxin conjugates in non-hematopoietic cells, thus increasing their cytotoxicity manifold. Here we tested this technology for the first time in a lymphoma in vivo model. First, the therapeutic CD20 antibody obinutuzumab was chemically conjugated to the ribosome-inactivating protein dianthin. The cytotoxicity of obinutuzumab-dianthin (ObiDi) was evaluated on human B-lymphocyte Burkitt’s lymphoma Raji cells and compared to human T-cell leukemia off-target Jurkat cells. When tested in combination with SO1861, the cytotoxicity for target cells was 131-fold greater than for off-target cells. In vivo imaging in a xenograft model of B-cell lymphoma in mice revealed that ObiDi/SO1861 efficiently prevents tumor growth (51.4% response rate) compared to the monotherapy with ObiDi (25.9%) and non-conjugated obinutuzumab (20.7%). The reduction of tumor volume and overall survival was also improved. Taken together, our results substantially contribute to the development of a combination therapy with SO1861 as a platform technology to enhance the efficacy of therapeutic antibody-toxin conjugates in lymphoma and leukemia.

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Section: Introductionmentioning

confidence: 99%

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Panjideh

Niesler

Weng

et al. 2022

Toxins

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“…Although both drugs were initially reported as DNA topoisomerase inhibitors 39 and had been evaluated extensively in clinics to treat various tumors 40,41 , PIXN has an overall improved clinical safety pro le 31 . This fact, combined with the observed in vivo anti-SARS-CoV-2 activity, suggests further testing the antiviral activity of PIXN or other HS inhibitors in clinical trials for patients with severe COVID-19 symptoms.…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfate promotes ACE2 super-cluster assembly to enhance SARS-CoV-2-associated syncytium formation

Zhang

Tang

Stancanelli³

et al. 2023

Preprint

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The mechanism of syncytium formation, caused by spike-induced cell-cell fusion in severe COVID-19, is largely unclear. Here we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical host factor exploited by SARS-CoV-2 to enhance spike’s fusogenic activity. HS binds spike to facilitate ACE2 clustering, generating synapse-like cell-cell contacts to promote fusion pore formation. ACE2 clustering, and thus, syncytium formation is significantly mitigated by chemical or genetic elimination of cell surface HS, while in a cell-free system consisting of purified HS, spike, and lipid-anchored ACE2, HS directly induces ACE2 clustering. Importantly, the interaction of HS with spike allosterically enables a conserved ACE2 linker in receptor clustering, which concentrates spike at the fusion site to overcome fusion-associated activity loss. This fusion-boosting mechanism can be effectively targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice.

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“…In several cases, pixantrone was successfully used as a bridge to ASCT, allogeneic SCT and CAR T‐cells or even after failure of allogeneic SCT 22,28,29 . In some of these cases, a continuous CR of at least 2‐years was demonstrated and it is predictive of long‐term survival for DLBCL, in which late relapses are seldom observed 28–30 . In the phase II GOAL trial, in which the combination of pixantrone with obinutuzumab was investigated, even if CR rate and median PFS were unsatisfactory (16.6% and 2.8 months, respectively), 11 responding patients achieved a durable remission up to 4 years and PFS was improved for patients with good risk characteristics 30 .…”

Section: Discussionmentioning

confidence: 99%

Long‐term efficacy in patients with relapsed/refractory diffuse large B‐cell lymphoma achieving a complete response with pixantrone

Cencini

Rocco²,

Ghio

et al. 2023

European J of Haematology

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Introduction:The prognosis of diffuse large B-cell lymphoma (DLBCL) patients with refractory or multiply relapsed (R/R) disease is disappointing. Pixantrone is currently approved as third or fourth line regimen, with encouraging results, even if long-term follow-up data are limited. Methods:In this post-hoc analysis of our observational study, we retrospectively investigated disease outcome and clinical characteristics of 16 R/R DLBCL patients who achieved a complete response with pixantrone.Results: Pixantrone was administered as third or fourth line in 12/16 (75%) and 4/16 (25%) cases. After a median follow-up of 24 months, 14/16 patients (87.5%) were alive (causes of death were progressive disease and secondary acute myeloid leukemia, one case each). Median progression-free survival was 23.8 months, median duration of response was 17.8 months and median overall survival (OS) was not reached (2-years OS was 84%). A significant proportion of patients achieved a long-lasting response >12 months (7/16 cases). Response to prior therapy did not influence longterm remission after pixantrone. Conclusion:In this real-life experience, pixantrone demonstrated long-term efficacy in a cohort of R/R DLBCL cases who had previously received at least two prior regimens; many of whom had characteristics associated with poor prognosis.complete response, diffuse large B-cell lymphoma, long-term efficacy, pixantrone Novelty statementsTo our knowledge it is the first, Italian, long-term post-hoc analysis about the possibility to achieve a durable complete response (CR) with pixantrone in its approved indication. Our real-life study confirms data obtained by clinical trials in a hard-to-treat population of relapsed/refractory (R/R) DLBCL. The clinical relevance is represented by the achievement of a durable CR in a significant proportion of R/R DLBCL patients with manageable adverse events. Furthermore, we suggest the possibility to use pixantrone as a bridging therapy to transplant or CAR-T cells.

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A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre GOAL trial

Cited by 8 publications

References 31 publications

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Heparan sulfate promotes ACE2 super-cluster assembly to enhance SARS-CoV-2-associated syncytium formation

Long‐term efficacy in patients with relapsed/refractory diffuse large B‐cell lymphoma achieving a complete response with pixantrone

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