A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refactory B-Lineage Non-Hodgkin Lymphoma

Moskowitz, Craig H.; Fanale, Michelle A.; Shah, Bijal; Advani, Ranjana H.; Chen, Robert; Kim, Stella; Kostić, Ana; Liu, Tina; Peng, Joanna; Forero‐Torres, Andres

doi:10.1182/blood.v126.23.182.182

Cited by 38 publications

(27 citation statements)

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“…But distinct clinical scenarios, such as primary refractory, early or late relapse, nodal or extranodal relapse, autoHCT eligible or not, and relapse post-autoHCT, may variably apply to a given patient over time, each probably with unique outcomes. Clinical trials with new agents targeting relapsed or refractory DLBCL often include only subsets of this population and the ability to judge the efficacy of these agents is limited by unknown historical outcomes of the enrolled subset (Witzig et al, 2011a,b;Salles et al, 2013;Morschhauser et al, 2014;Christian et al, 2015;Gerecitano et al, 2015;Jacobsen et al, 2015;Kochenderfer et al, 2015;Locke et al, 2015;Maddocks et al, 2015;Moskowitz et al, 2015;Ribrag et al, 2015;Wang et al, 2015;Coiffier et al, 2016;Viardot et al, 2016;Walter et al, 2016). Populationbased studies attempting to define these outcomes to date are limited by lack of inclusivity, treatment and outcome detail, or adequate follow-up (Danese et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, OS is substantially better for the subjects selected for autoHCT. Accordingly, response rates may be an inadequate measure of clinical benefit and clinical trials exploring novel drugs or combinations in this setting might choose endpoints other than simply response rates in trial design (Witzig et al, 2011a,b;Salles et al, 2013;Morschhauser et al, 2014;Christian et al, 2015;Gerecitano et al, 2015;Jacobsen et al, 2015;Kochenderfer et al, 2015;Locke et al, 2015;Maddocks et al, 2015;Moskowitz et al, 2015;Ribrag et al, 2015;Wang et al, 2015;Coiffier et al, 2016;Viardot et al, 2016;Walter et al, 2016). For patients not deemed appropriate for aggressive therapy, median PFS or even median OS would be a meaningful endpoint without requiring a significant duration of follow up for analysable events.…”

Section: Discussionmentioning

confidence: 99%

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Clinical heterogeneity of diffuse large B cell lymphoma following failure of front‐line immunochemotherapy

et al. 2017

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Summary This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma (DLBCL) after failure of front line anthracycline-based immunochemotherapy (IC). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence. All DLBCL and primary mediastinal B-cell lymphoma (PMBL) patients treated with front-line anthracycline-based IC were followed for relapse. Patients with relapse on follow-up and subsequently retreated were included in this analysis. 1039 patients received anthracycline-based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years (OS4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (autoHCT) with OS4 from autoHCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS4 of 47% but those with a transient or no response to initial therapy had OS4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo autoHCT. The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical heterogeneity of diffuse large B cell lymphoma following failure of front‐line immunochemotherapy

et al. 2017

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“…An interim analysis of the paediatric patients on this trial reported no objective responses, however only nine patients were evaluable (Fathi et al , ). A more recent update of adult patients with B‐NHL reported a 33% ORR and a 22% complete response rate among patients with DLBCL ( n = 53), mantle cell lymphoma ( n = 5) and follicular lymphoma ( n = 3) (Moskowitz et al , ). Other antibody‐drug conjugates are currently in clinical development for adult patients with B‐cell lymphoma including polatuzumab vedotin, directed at CD79B, and pinatuzumab vedotin and inotuzumab ozogamacin, both directed at CD22 (Mehta & Forero‐Torres, ).…”

Section: Novel Targeted Therapiesmentioning

confidence: 99%

Recent molecular and therapeutic advances in B‐cell non‐Hodgkin lymphoma in children

Giulino‐Roth

Goldman

2016

Br J Haematol

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Paediatric B-cell non-Hodgkin lymphoma (B-NHL) compromises a heterogeneous group of histological entities of which Burkitt lymphoma is the most common. In resource-rich countries, the expected cure rate is in excess of 85% with application of risk-adapted short intensive chemotherapy. In recent years, large paediatric cooperative group trials have sought to improve upon outcomes by decreasing the intensity of cytotoxic treatment as well as introducing targeted therapies, such as rituximab. These efforts have resulted in excellent outcomes, however there remains a group of high-risk patients for whom novel treatment approaches are needed. In this review, we will summarize the recent paediatric clinical trials in B-NHL as well as compare treatment approaches across the major cooperative groups. We will also highlight our current understanding of the molecular biology of paediatric B-NHL with a focus on how this may help guide future rational targeted therapy.

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“…week following the final dose, which is in accordance with a half-life of approximately 2 weeks observed in patients. 37 It is also noteworthy however that relapse occurred rapidly upon apparent clearance of denintuzumab mafodotin. Imaging data also showed considerable activity of the ADC in regions encompassing the brain and spine of treated mice, although the apparent activity of the ADC in these regions may also be explained by the infiltration of leukemia cells into the marrow of bones surrounding the CNS, such as vertebrae or calvarial bones.…”

Section: Discussionmentioning

confidence: 99%

“…45 By contrast, approximately 20% of more than 100 patients with relapsed/refractory ALL achieved complete response (with or without platelet recovery) to denintuzumab mafodotin. 15,37 This lack of clinical success against ALL for ADCs with tubulin-targeted payloads raises questions about CD19 targeting using an ADC therapeutic strategy for this patient population. Does the lack of clinical activity comparable to that of other ALL immunotherapy approaches indicate that CD19 is a poorer target for ADCs compared to other lymphoid surface antigens possibly due to less efficient CD19 internalization compared with, for example, CD22?…”

Section: Discussionmentioning

confidence: 99%

Preclinical activity of the antibody‐drug conjugate denintuzumab mafodotin (SGN‐CD19A) against pediatric acute lymphoblastic leukemia xenografts

Jones

McCalmont

Evans

et al. 2019

Pediatric Blood & Cancer

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Background Denintuzumab mafodotin (SGN‐CD19A) is a CD19‐targeting antibody‐drug conjugate, comprising a monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin F. Since denintuzumab mafodotin has previously shown activity against B‐cell malignancies in early‐stage clinical trials, it was of interest to test it against the Pediatric Preclinical Testing Program preclinical models of CD19+ pediatric acute lymphoblastic leukemia (ALL). Procedures Denintuzumab mafodotin was evaluated against eight B‐cell lineage ALL patient‐derived xenografts (PDXs), representing B‐cell precursor ALL, Ph‐like ALL, and mixed‐lineage leukemia rearranged infant ALL. Denintuzumab mafodotin was administered weekly for 3 weeks at 3 mg/kg. It was also tested in combination with an induction‐type chemotherapy regimen of vincristine, dexamethasone, and l‐asparaginase (VXL) against three PDXs. The relationship between cell surface and gene expression of CD19 and drug activity was also assessed. Results Denintuzumab mafodotin significantly delayed the progression of seven of eight PDXs tested and achieved objective responses in five of eight. There was no apparent subtype specificity of denintuzumab mafodotin activity. No correlations were observed between CD19 mRNA or cell surface expression and denintuzumab mafodotin activity, perhaps due to small sample size, and denintuzumab mafodotin treatment did not select for reduced CD19 expression. Combining denintuzumab mafodotin with VXL achieved therapeutic enhancement compared to either treatment alone. Conclusions Denintuzumab mafodotin showed single‐agent activity against selected B‐lineage ALL PDXs, although leukemia growth was evident in most models at 28 days from treatment initiation. This level of activity for denintuzumab mafodotin is consistent with that observed in adults with ALL.

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A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refactory B-Lineage Non-Hodgkin Lymphoma

Cited by 38 publications

References 0 publications

Clinical heterogeneity of diffuse large B cell lymphoma following failure of front‐line immunochemotherapy

Clinical heterogeneity of diffuse large B cell lymphoma following failure of front‐line immunochemotherapy

Recent molecular and therapeutic advances in B‐cell non‐Hodgkin lymphoma in children

Preclinical activity of the antibody‐drug conjugate denintuzumab mafodotin (SGN‐CD19A) against pediatric acute lymphoblastic leukemia xenografts

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