Successful rapid desensitization to the antibody–drug conjugate brentuximab vedotin in a patient with refractory Hodgkin lymphoma

Overview: CD30 expression is characteristic of the malignant Reed-Sternberg cell in Hodgkin lymphoma (HL) and several other lymphoid malignancies, such as anaplastic large-cell lymphoma (ALCL). Although unconjugated anti-CD30 antibodies have had minimal therapeutic activity in patients with HL as single agents, the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin has demonstrated activity that has resulted in its recent regulatory approval for the treatment of patients with relapsed HL and ALCL. Approximately 75% of patients with recurrent HL achieve objective responses, with the principal toxicity being peripheral neuropathy. Ongoing studies are evaluating treatment with this agent as part of first-line therapy, for patients with relapsed disease, and for patients with resistant disease and limited other options. Brentuximab vedotin demonstrates the therapeutic value of antibody-drug conjugation and serves as a model of how a novel, targeted approach can be employed to potentially further improve outcomes in settings where curative chemotherapeutic regimens are already available.

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A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody–Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-19-0711 ◽

2019 ◽

Vol 25 (23) ◽

pp. 6986-6994 ◽

Cited By ~ 19

Author(s):

Brad S. Kahl ◽

Mehdi Hamadani ◽

John Radford ◽

Carmelo Carlo-Stella ◽

Paolo Caimi ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Hodgkin Lymphoma ◽

Phase I Study ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Non Hodgkin Lymphoma ◽

Antibody Drug

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DCDT2980S, an Anti-CD22-Monomethyl Auristatin E Antibody–Drug Conjugate, Is a Potential Treatment for Non-Hodgkin Lymphoma

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-12-1173 ◽

2013 ◽

Vol 12 (7) ◽

pp. 1255-1265 ◽

Cited By ~ 50

Author(s):

Dongwei Li ◽

Kirsten Achilles Poon ◽

Shang-Fan Yu ◽

Randall Dere ◽

MaryAnn Go ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Potential Treatment ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Non Hodgkin Lymphoma ◽

Antibody Drug

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Development and Integration of Antibody–Drug Conjugate in Non-Hodgkin Lymphoma

Current Oncology Reports ◽

10.1007/s11912-015-0466-9 ◽

2015 ◽

Vol 17 (9) ◽

Cited By ~ 13

Author(s):

Amitkumar Mehta ◽

Andres Forero-Torres

Keyword(s):

Hodgkin Lymphoma ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Non Hodgkin Lymphoma ◽

Antibody Drug

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The Antibody-Drug Conjugate Brentuximab Vedotin (SGN-35) Induced Multiple Objective Responses in Patients with Relapsed or Refractory CD30-Positive Lymphomas in a Phase 1 Weekly Dosing Study.

Blood ◽

10.1182/blood.v114.22.2731.2731 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2731-2731 ◽

Cited By ~ 17

Author(s):

Michelle Fanale ◽

Nancy L Bartlett ◽

Andres Forero-Torres ◽

Joseph Rosenblatt ◽

Sandra J Horning ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Objective Response ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Antibody Drug Conjugate ◽

Phase 1 Study ◽

Drug Conjugate ◽

Antibody Drug

Abstract Abstract 2731 Poster Board II-707 Background: The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the antitubulin agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. In a previous phase 1 study with every 3 week dosing, 54% of patients achieved an objective response (CR/PR) at brentuximab vedotin doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To investigate the tolerability and antitumor activity of a more frequent dosing regimen, a multicenter phase 1 study was conducted in patients with refractory or recurrent CD30-positive lymphomas using a 3 + 3 dose-escalation design. Brentuximab vedotin was administered weekly for 3 weeks in 28-day treatment cycles at doses of 0.4 to 1.4 mg/kg (30-min or 2-hr IV infusions). Patients with stable disease or better (Cheson 2007) after two cycles were eligible to receive additional brentuximab vedotin treatment cycles. Results: A total of 37 patients, 31 with Hodgkin lymphoma (HL), 5 with systemic anaplastic large cell lymphoma (ALCL), and 1 with peripheral T-cell lymphoma, were enrolled and treated. Median age was 35 (range 13–82) and most patients (89%) had an ECOG performance status of 0/1. Patients received a median of 3 prior chemotherapy regimens (range 1–8); 62% previously received an autologous stem cell transplant. More than 50% of patients (21 of 37) had disease that did not respond to their most recent prior therapy. Dose-limiting toxicities included G3 diarrhea, G3 vomiting, and G4 hyperglycemia. The maximum tolerated dose was exceeded at 1.4 mg/kg. The most common treatment-related adverse events were peripheral neuropathy, nausea, fatigue, diarrhea, dizziness, and neutropenia; most were grade 1 or 2 in severity. Exposure to brentuximab vedotin (AUC) increased relative to dose level. Among efficacy evaluable patients across all dose levels, the objective response rate (ORR) was 46% (16 of 35), with 29% of patients (10 of 35) attaining a complete remission. Median duration of response to date is at least 16 weeks (range, 0.1+ to 34+); 15 patients continue on treatment. Conclusions: Weekly dosing with brentuximab vedotin was generally well tolerated and induced a high rate of objective responses in heavily pretreated patients with HL and systemic ALCL. A pivotal trial of this ADC in patients with relapsed or refractory HL has completed enrollment. Disclosures: Fanale: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is an investigational agent. Bartlett:Seattle Genetics, Inc.: Research Funding. Forero-Torres:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Horning:Seattle Genetics, Inc.: Research Funding. Franklin:Seattle Genetics, Inc.: Research Funding. Lynch:Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment.

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Anti CD-30 Antibody-Drug Conjugate Brentuximab Vedotin (ADCETRIS®) May Be a Promising Treatment Option for Systemic Mastocytosis (SM).

Blood ◽

10.1182/blood.v120.21.2857.2857 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2857-2857 ◽

Cited By ~ 4

Author(s):

Amitkumar Mehta ◽

Vishnu V B Reddy ◽

Uma Borate

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Systemic Mastocytosis ◽

White Male ◽

Brentuximab Vedotin ◽

Antibody Drug Conjugate ◽

Antimitotic Agent ◽

Drug Conjugate ◽

Tryptase Level ◽

Antibody Drug

Abstract Abstract 2857 Mastocytosis is a clonal proliferation of abnormal mast cells in single or multiple organs leading to clinical syndromes ranging from a benign self-resolving cutaneous disease to the highly aggressive malignancy, mast cell leukemia (MCL). Mastocytosis is categorized under myeloproliferative neoplasms in the 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid diseases. In almost all cases of SM, the bone marrow (BM) is involved by atypical mast cells. The characteristic Asp816Val (D816V) mutation in the KIT gene present in most cases gives the atypical mast cells a survival advantage that leads to treatment resistance with tyrosine kinase inhibitor (TKIs) like imatinib. According to the 2008 WHO classification, 1 major and 1 minor or 3 minor criterion are required for the diagnosis of systemic mastocytosis (Fig. 1a). Systemic Mastocytosis (SM) is subcategorized into four distinct categories in order of indolent to highly aggressive disease: Indolent Systemic Mastocytosis (ISM), SM with an associated hematologic non-MC-lineage disease (SM-AHNMD), aggressive SM (ASM) and MCL. SM with C findings categorized as ASM (Fig. 1b) is treated with cytoreductive chemotherapy such as interferon 2α or 2-chlorodeoxyadenosine (2-CdA). The overall response rate (ORR) with these agents is 40–50% with significant chemotherapy-related toxicity and short durable responses. The majority of patients with ASM and MCL relapse within a year with a very poor prognosis. The CD30 (Ki-1) antigen is expressed in the majority of ASM cases. Thus, CD30 can serve as a potential therapeutic target as well as a reliable tumor marker to follow disease status. Brentuximab vedotin is an antibody-drug conjugate compound consisting of a chimeric monoclonal antibody against CD30 linked to the antimitotic agent monomethyl auristatin E (MMAE). Here we report evidence of anti-tumor activity in two patients with CD30-positive ASM treated with brentuximab vedotin. Case #1: A 62 year old white male with significant medical history of rheumatoid arthritis, diabetes mellitus and coronary artery disease was evaluated for pancytopenia and hepatomegaly. His initial BM aspiration and biopsy revealed multifocal dense mast cell infiltrate (30–40% involvement with tryptase and CD117 positivity). His initial serum tryptase level was 276 ng/ml. He was treated with 2-CdA continuous infusion for three cycles with no significant response and substantial toxicities. He was subsequently enrolled in a clinical trial with brentuximab vedotin given every 3 weeks at 1.8 mg/kg after confirmation of CD30 positivity on BM aspirate and biopsy (Fig. 2). His peripheral blood counts started to improve after the 5thcycle and he had a durable partial response as assessed by his peripheral blood counts and BM biopsies (Fig 2). Importantly, his sequential bone marrow biopsies showed a decrease in mast cell involvement and CD30 intensity with improved normal marrow cellularity (Fig 2). His only treatment-related toxicities were grade II neuropathy and neutropenia for which his dose was reduced to 1.2 mg/kg. He is currently asymptomatic with ECOG performance status of 0 and does not require any growth factor support at Cycle 12 of this regimen. Case #2: A 79 yr old white male with significant medical history of hypertension, obstructive sleep apnea, coronary artery disease s/p CABG was referred for new diagnosis of ASM on BM biopsy (60–70% marrow involvement with 3+ mast cell density). His initial tryptase level was 224ng/ml. He was enrolled on the same clinical protocol as described above. His sequential BM biopsies revealed significant reduction in mast cell density with mild improvement in overall normal cellularity after 3 cycles of treatment. (Fig 3). Conclusion: Brentuximab vedotin is a promising targeted therapy for SM and needs to be confirmed further by a prospective multicenter clinical trial. In two patients reported here treatment is well tolerated, targets the malignant mast cells and seems to prevent disease progression in a rare disorder with few treatment options and limited response rates. Disclosures: Off Label Use: Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate compound consisting of a chimeric monoclonal antibody against CD30 linked to the antimitotic agent monomethyl auristatin E (MMAE). It is not FDA approved for use in Mastocytosis.

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Single Agent Brentuximab As Bridging Therapy for Hodgkin Lymphoma Patients with Hepatic Impairment

Blood ◽

10.1182/blood.v126.23.5105.5105 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5105-5105

Author(s):

Arjun Gupta ◽

Jan Petrasek ◽

Shiraj Sen ◽

Harris V. Naina

Keyword(s):

Liver Injury ◽

Hodgkin Lymphoma ◽

Hepatic Impairment ◽

Serum Bilirubin ◽

Brentuximab Vedotin ◽

Antibody Drug Conjugate ◽

Bridging Therapy ◽

Prior Chemotherapy ◽

To Receive ◽

Antibody Drug

Abstract Background: Patients with Hodgkin lymphoma (HL) can rarely present with hepatic impairment which may preclude administration of definitive therapy (ABVD, or other cytotoxic regimens). Brentuximab Vedotin (BV) is an antibody drug conjugate directed at CD30 and is approved for the treatment of refractory HL after failure of at least two prior chemotherapy regimens or after failure of autologous stem cell transplant. We report our experience of patients presenting with advanced stage HL and moderate to severe hepatic impairment who were unfit to receive ABVD therapy. Methods: Patients with HL, unfit to receive definitive ABVD therapy, treated with BV between 5/2014 and 5/2015, were included in the study. Patient charts were reviewed for administration of BV; and those with baseline hepatic impairment were included in the study. Structured forms were used to abstract relevant clinical data. Results: Five patients were included in this study; median age 38 (range 27-71 years); all were male. Three were Hispanic and two were African-American. Two had known history of human immunodeficiency virus-1 (HIV) infection. All had stage 4 disease at presentation, 3 had bone marrow involvement, while four reported 'B' symptoms. All had hepatocellular and cholestatic pattern of liver injury on admission laboratory exam, and were not considered candidates for standard ABVD therapy. Two patients had HIV infection controlled by antiviral therapy. Liver biopsy showed hepatic HL infiltrate in two patients, VBDS in two patients, and suspected drug induced liver injury (DILI) in one patient. Patients with intrahepatic HL and VBDS had not received any therapy for HL; the patient with DILI had recently received therapy with gemcitabine. Due to concern for potential ABVD-related toxicity, all patients were treated with BV. Therapy was continued every 3 weeks till normalization of serum bilirubin to <1 mg/dL; this was achieved in all patients. Three patients received 3 doses of BV, while 2 patients received 5 doses. BV therapy was initially given at reduced dose (1.2 mg/kg) and dose was increased to the standard 1.8 mg/kg once serum bilirubin levels started to trend down and reached <5 mg/dl. Median time to halving of serum bilirubin from pre-treatment value was 15 (range, 8- 58 days. Median time to normalization of serum bilirubin (<1 mg/dL) was 64 (range, 41and 154 days. Three patients demonstrated partial response to BV and were switched to ABVD therapy after liver function normalized. Two patients had mixed response to BV and multi-agent therapy (ABVD, and AVD with BV respectively) was initiated once liver function normalized. There were no serious adverse effects of therapy with BV. Conclusions: Treatment with BV provided successful bridging to definitive chemotherapy in patients with HL with hepatic involvement. In HL patients, liver biopsy may help distinguishing liver injury related to HL, requiring aggressive chemotherapy, from liver injury related to HL treatment, which necessitates alternative regimens. BV can successfully be used as a bridging therapy in advanced HL patients presenting with liver injury who may be unfit to receive more cytotoxic chemotherapy. This was seen in both HIV negative and positive patients. Further studies to establish the safety and efficacy of BV in this scenario is warranted. Disclosures Off Label Use: Brentuximab Vedotin is an antibody drug conjugate directed at CD30 and is approved in the treatment of refractory Hodgkin lymphoma after failure of at least 2 prior chemotherapy regimens. We describe the use of Brentuximab Vedotin in Hodgkin lymphoma after no (4 patients) or 1 therapy (1 patient)..

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Management of relapsed/refractory classical Hodgkin lymphoma in transplant-ineligible patients

Blood ◽

10.1182/blood-2017-09-772681 ◽

2018 ◽

Vol 131 (15) ◽

pp. 1698-1703 ◽

Cited By ~ 4

Author(s):

Neha Mehta-Shah ◽

Nancy L. Bartlett

Keyword(s):

Hodgkin Lymphoma ◽

Brentuximab Vedotin ◽

Classical Hodgkin Lymphoma ◽

Antibody Drug Conjugate ◽

Barr Virus ◽

Drug Conjugates ◽

Improved Outcomes ◽

Individualized Approach ◽

Epstein Barr ◽

Antibody Drug

AbstractAddition of brentuximab vedotin, a CD30-targeted antibody–drug conjugate, and the programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab to the armamentarium for transplant-ineligible relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine may result in prolonged survival with a minimal or modest effect on quality of life. Participation in clinical trials evaluating new approaches such as combination immune checkpoint inhibition, novel antibody–drug conjugates, or cellular therapies such as Epstein-Barr virus–directed cytotoxic T lymphocytes and chimeric antigen receptor T cells offer additional options for eligible patients.

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